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  • 1.
    Basu, Samar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Oxidative Stress and Inflammation.
    Miclescu, Adriana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Propofol mitigates systemic oxidative injury during experimental cardiopulmonary cerebral resuscitation2011In: Prostaglandins, Leukotrienes and Essential Fatty Acids, ISSN 0952-3278, E-ISSN 1532-2823, Vol. 84, no 5-6, p. 123-130Article in journal (Refereed)
    Abstract [en]

    Effects of propofol, an intravenous anesthetic agent that exerts potent antioxidant properties, were investigated in an experimental model of cardiac arrest and cardiopulmonary resuscitation. An extended cardiac arrest with 15 randomized piglets was studied to assess the effect of propofol or its solvent intralipid as the control group. Oxidative stress (as measured by a major F(2)-isoprostane) and inflammation (a major metabolite of PGF(2α)) were evaluated in addition to the hemodynamic evaluation, protein S-100β and in situ tissue brain damage by immunochemistry at sacrifice after 3h of reperfusion following cardiac arrest and restoration of spontaneous circulation (ROSC). ROSC increased jugular bulb plasma levels of F(2)-isoprostane and PGF(2α) metabolite significantly more in controls than in the propofol-treated group. In situ tissue damage after ischemia-reperfusion was variable among the pigs at sacrifice, but tended to be greater in the control than the propofol-treated group. Propofol significantly reduced an ROSC-mediated oxidative stress in the brain.

  • 2. Castellani, Rudy J.
    et al.
    Nugent, Summer L.
    Morrison, Alan L.
    Zhu, Xiongwei
    Lee, Hyoung-Gon
    Harris, Peggy L. R.
    Bajić, Vladan
    Sharma, Hari S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Chen, Shu G.
    Oettgen, Peter
    Perry, George
    Smith, Mark A.
    CD3 in Lewy pathology: does the abnormal recall of neurodevelopmental processes underlie Parkinson's disease2011In: Journal of neural transmission, ISSN 0300-9564, E-ISSN 1435-1463, Vol. 118, no 1, p. 23-26Article in journal (Refereed)
    Abstract [en]

    CD3ζ is a subunit of the CD3 molecule that, until recently, appeared restricted to T cells and natural killer cells. However, experimental studies have demonstrated a role of CD3ζ in dendritic outgrowth in the visual system as well as in synaptic plasticity. Given the increasing evidence for uncharacteristic recapitulation of neurodevelopmental processes in neurodegenerative diseases, in this study, we evaluated brains from subjects with Parkinson's disease and Lewy body dementia for evidence of aberrant CD3 expression. Our data shows marked CD3ζ in association with the α-synuclein containing pathological lesions, i.e., Lewy bodies and Lewy neurites, in the brains of subjects with Parkinson's disease and Lewy body dementia. This finding raises the novel concept of CD3 dysregulation in these disorders as a pathogenic factor and also furthers the increasing evidence that the recall of aberrant neurodevelopmental processes underlies the pathogenesis of neurodegenerative diseases.

  • 3.
    Chen, Lin
    et al.
    Tsinghua Univ, Yuquan Hosp, Beijing 100040, Peoples R China..
    Ao, Qiang
    China Med Univ, Dept Tissue Engn, Shenyang 110122, Peoples R China..
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Wang, Aijun
    Univ Calif Davis, Med Ctr, Surg Bioengn Lab, Dept Surg, Sacramento, CA 95817 USA..
    Feng, Shiqing
    Tianjin Med Univ, Tianjin, Peoples R China..
    Neurorestoratologic Strategies and Mechanisms in the Nervous System2015In: BioMed Research International, ISSN 2314-6133, E-ISSN 2314-6141, article id 163170Article in journal (Other academic)
  • 4. Chen, Lin
    et al.
    Guo, Jiangfeng
    Sharma, Alok
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Skaper, Stephen D.
    Huang, Hongyun
    Summary Report of the International Association of Neurorestoratology VII Conference: Regulations, Ethics, Science, and the Need of Patients Care in Neurorestoratology2014In: CNS & Neurological Disorders: Drug Targets, ISSN 1871-5273, E-ISSN 1996-3181, Vol. 13, no 6, p. 921-925Article in journal (Refereed)
  • 5. Chen, Lin
    et al.
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Guo, Jiangfeng
    Muresanu, Dafin
    Huang, Hongyun
    Skaper, Stephen
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Conference Report Annual advances in neurorestoratology: a summary of IANR VI and 10th GCNN conference, Bucharest, Romania, April 4-7, 20132013In: CNS & Neurological Disorders: Drug Targets, ISSN 1871-5273, E-ISSN 1996-3181, Vol. 12, no 5, p. 547-549Article in journal (Refereed)
  • 6. Feng, L.
    et al.
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Muresanu, D. F.
    Patnaik, R.
    Tian, Z. R.
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Nanowired Delivery of Mesenchymal Stem Cells (MSCs) Attenuates Pathophysiology of Spinal Cord Injury and Enhances Brain-Derived Neurotrophic Factor and Insulin-Like Growth Factor-1 Concentrations in the Plasma and the Spinal Cord2014In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 23, no 6, p. 769-770Article in journal (Other academic)
  • 7. Feng, L.
    et al.
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Muresanu, D. F.
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Engineered Nanoparticles From Metals (Ag, Cu, Al, 50-60 nm) Aggravate Neuropathic Pain Syndrome and Exacerbate Blood-Spinal Cord Barrier Breakdown, Astrocytic Activation, and Neural Injury: Neuroprotection by Cerebrolysin Treatment2012In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 21, no 4, p. 777-777Article in journal (Other academic)
  • 8. Feng, Lianyuan
    et al.
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Muresanu, Dafin Fior
    Moessler, Herbert
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Engineered nanoparticles from metals aggravate spinal cord injury induced neuropathic pain syndrome and exacerbate blood-spinal cord barrier breakdown, astrocytic activation and neural injury: Neuroprotective effects of cerebrolysin2014In: Brain Injury, ISSN 0269-9052, E-ISSN 1362-301X, Vol. 28, no 5-6, p. 525-525Article in journal (Other academic)
  • 9.
    Feng, Lianyuan
    et al.
    Bethune Int Peace Hosp, Dept Neurol, Zhongshan Rd West, Shijiazhuang, Hebei, Peoples R China..
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Niu, Feng
    CSPC NBP Pharmaceut Med, Zhongshan Rd West, Shijiazhuang, Hebei, Peoples R China..
    Huang, Yin
    CSPC NBP Pharmaceut Med, Zhongshan Rd West, Shijiazhuang, Hebei, Peoples R China..
    Vicente Lafuente, Jose
    Univ Basque Country UPV EHU, Dept Neurosci, LaNCE, Leioa, Bizkaia, Spain.;BioCruces Hlth Res Inst, Nanoneurosurg Grp, Baracaldo 48903, Bizkaia, Spain.;Univ Autonoma Chile, Fac Hlth Sci, Santiago, Chile..
    Muresanu, Dafin Fior
    RoNeuro Inst Neurol Res & Diagnost, 37 Mircea Eliade St, Cluj Napoca 400364, Romania.;Univ Med & Pharm, Dept Clin Neurosci, Cluj Napoca, Romania..
    Ozkizilcik, Asya
    Univ Arkansas, Dept Biomed Engn, Fayetteville, AR 72701 USA..
    Tian, Z. Ryan
    Univ Arkansas, Dept Chem & Biochem, J William Fulbright Coll Arts & Sci, Fayetteville, AR 72701 USA..
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala Univ, Univ Hosp, Int Expt CNS Injury & Repair IECNSIR, Frodingsgatan 12,Bldg 28, SE-75421 Uppsala, Sweden..
    TiO2-Nanowired Delivery of DL-3-n-butylphthalide (DL-NBP) Attenuates Blood-Brain Barrier Disruption, Brain Edema Formation, and Neuronal Damages Following Concussive Head Injury2018In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 55, no 1, p. 350-358Article in journal (Refereed)
    Abstract [en]

    DL-3-n-butylphthalide (DL-NBP) is one of the constituents of Chinese celery extract that is used to treat stroke, dementia, and ischemic diseases. However, its role in traumatic brain injury is less well known. In this investigation, neuroprotective effects of DL-NBP in concussive head injury (CHI) on brain pathology were explored in a rat model. CHI was inflicted in anesthetized rats by dropping a weight of 114.6 g from a height of 20 cm through a guide tube on the exposed right parietal bone inducing an impact of 0.224 N and allowed them to survive 4 to 24 h after the primary insult. DL-NBP was administered (40 or 60 mg/kg, i.p.) 2 and 4 h after injury in 8-h survival group and 8 and 12 h after trauma in 24-h survival group. In addition, TiO2-nanowired delivery of DL-NBP (20 or 40 mg/kg, i.p.) in 8 and 24 h CHI rats was also examined. Untreated CHI showed a progressive increase in blood-brain barrier (BBB) breakdown to Evans blue albumin (EBA) and radioiodine (I[131]-), edema formation, and neuronal injuries. The magnitude and intensity of these pathological changes were most marked in the left hemisphere. Treatment with DL-NBP significantly reduced brain pathology in CHI following 8 to 12 h at 40-mg dose. However, 60-mg dose is needed to thwart brain pathology at 24 h following CHI. On the other hand, TiO2-DL-NBP was effective in reducing brain damage up to 8 or 12 h using a 20-mg dose and only 40-mg dose was needed for neuroprotection in CHI at 24 h. These observations are the first to suggest that (i) DL-NBP is quite effective in reducing brain pathology and (ii) nanodelivery of DL-NBP has far more superior effects in CHI, not reported earlier.

  • 10.
    Gordh, T
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Sharma, H S
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Chronic spinal nerve ligation induces microvascular permeability disturbances, astrocytic reaction, and structural changes in the rat spinal cord.2006In: Acta Neurochir Suppl, ISSN 0065-1419, Vol. 96, p. 335-40Article in journal (Refereed)
  • 11.
    Gordh, Torsten
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Chu, Haichen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Spinal nerve lesion alters blood-spinal cord barrier function and activates astrocytes in the rat2006In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 124, no 1-2, p. 211-221Article in journal (Refereed)
    Abstract [en]

    Alterations in the spinal cord microenvironment in a neuropathic pain model in rats comprising right L-4 spinal nerve lesion were examined following 1, 2, 4 and 10 weeks using albumin and glial fibrillary acidic protein (GFAP) immunoreactivity. Rats subjected to nerve lesion showed pronounced activation of GFAP indicating astrocyte activation, and exhibited marked leakage of albumin, suggesting defects of the blood-spinal cord barrier (BSCB) function in the corresponding spinal cord segment. The intensities of these changes were most prominent in the gray matter of the lesioned side compared to them contralateral cord in both the dorsal and ventral horns. The most marked changes in albumin and GFAP inummoreaction were seen after 2 weeks and persisted with mild intensities even after 10 weeks. Distortion of nerve cells, loss of neurons and general sponginess were evident in the gray matter of the spinal cord corresponding to the lesion side. These nerve cell and glial cell changes are mainly evident in the areas showing leakage of endogenous albumin in the spinal cord. These novel observations indicate that chronic nerve lesion has the capacity to induce a selective increase in local BSCB permeability that could be instrumental in nerve cell and glial cell activation. These findings may be relevant to our current understanding on the pathophysiology of neuropathic pain.

  • 12.
    Halvorsen, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Basu, Samar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Oxidative Stress and Inflammation.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Neural injury after use of vasopressin and adrenaline during porcine cardiopulmonary resuscitation2015In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 120, no 1, p. 11-19Article in journal (Refereed)
    Abstract [en]

    Background. Our aim was to investigate cerebral and cardiac tissue injury subsequent to use of vasopressin and adrenaline in combination compared with vasopressin alone during cardiopulmonary resuscitation (CPR). Methods. In a randomized, prospective, laboratory animal study 28 anesthetized piglets were subject to a 12-min untreated cardiac arrest and subsequent CPR. After 1 min of CPR, 10 of the piglets received 0.4 U/kg of arg(8)-vasopressin (V group), and 10 piglets received 0.4 U/kg of arg(8)-vasopressin, 1 min later followed by 20 mu g/kg body weight of adrenaline, and another 1 min later continuous administration (10 mu g/kg/min) of adrenaline (VA group). After 8 min of CPR, the piglets were defibrillated and monitored for another 3 h. Then they were killed and the brain immediately removed pending histological analysis. Results. During CPR, the VA group had higher mean blood pressure and cerebral cortical blood flow (CCBF) but similar coronary perfusion pressure. After restoration of spontaneous circulation there was no difference in the pressure variables, but CCBF tended to be (36% +/- 16%) higher in the V group. Neuronal injury and signs of a disrupted blood-brain barrier (BBB) were greater, 20% +/- 4% and 21% +/- 4%, respectively, in the VA group. In a background study of repeated single doses of adrenaline every third minute after 5 min arrest but otherwise the same protocol, histological measurements showed even worse neural injury and disruption of the BBB. Conclusion. Combined use of vasopressin and adrenaline caused greater signs of cerebral and cardiac injury than use of vasopressin alone during experimental cardiopulmonary resuscitation.

  • 13. Huang, Hongyun
    et al.
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Neurorestoratology: one of the most promising new disciplines at the forefront of neuroscience and medicine2013In: Journal of Neurorestoratology, Vol. 1, p. 37-41Article in journal (Refereed)
    Abstract [en]

    Neurorestoratology is a new and emerging distinct discipline put forward on the basis of nervous restorable (neurorestorable) theory, which states that nerve damage to the central nervous system (CNS) can be restored. Neurorestorable theory in CNS was proposed by Huang et al based on clinical achievements obtained from cell-based neurorestorative therapy1.  Neurorestoratology, same as neurology, neurosurgery, neurorehabilitation, etc is a distinct discipline in neuroscience and medicine. The Beijing Declaration of International Association of Neurorestoratology (IANR) determined its definition in 2009.2 The aim of neurorestoratology is to restore or promote recovery of damaged or lost neuronal functions. As depicted in Figure 1,3 it can clearly be seen that there was a blank space – indicated by the question mark in the figure – that needed to be filled with a new discipline, neurorestoratology, so it can be likened to an inexorable biological law and its development to a natural process quite similar to that of the periodic law of chemistry discovered and proposed by Dmitri Mendeleev. In recent years, neurorestoratology has become one of the most interesting core areas of neuroscience and medicine worldwide, representing a novel aspect of translational medicine.

  • 14. Huang, Hongyun
    et al.
    Sun, Tiansheng
    Chen, Lin
    Moviglia, Gustavo
    Chernykh, Elena
    von Wild, Klaus
    Deda, Haluk
    Kang, Kyung-Sun
    Kumar, Anand
    Jeon, Sang Ryong
    Zhang, Shaocheng
    Brunelli, Giorgio
    Bohbot, Albert
    Soler, Maria Dolors
    Li, Jianjun
    Cristante, Alexandre Fogaca
    Xi, Haitao
    Onose, Gelu
    Kern, Helmut
    Carraro, Ugo
    Saberi, Hooshang
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sharma, Alok
    He, Xijing
    Muresanu, Dafin
    Feng, Shiqing
    Otom, Ali
    Wang, Dajue
    Iwatsu, Koichi
    Lu, Jike
    Al-Zoubi, Adeeb
    Consensus of Clinical Neurorestorative Progress in Patients With Complete Chronic Spinal Cord Injury2014In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 23, no S1, p. S5-S17Article, review/survey (Refereed)
    Abstract [en]

    Currently, there is a lack of effective therapeutic methods to restore neurological function for chronic complete spinal cord injury (SCI) by conventional treatment. Neurorestorative strategies with positive preclinical results have been translated to the clinic, and some patients have gotten benefits and their quality of life has improved. These strategies include cell therapy, neurostimulation or neuromodulation, neuroprosthesis, neurotization or nerve bridging, and neurorehabilitation. The aim of this consensus by 31 experts from 20 countries is to show the objective evidence of clinical neurorestoration for chronic complete SCI by the mentioned neurorestorative strategies. Complete chronic SCI patients are no longer told, "nothing can be done." The clinical translation of more effective preclinical neurorestorative strategies should be encouraged as fast as possible in order to benefit patients with incurable CNS diseases. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation.

  • 15. Johanson, C E
    et al.
    Donahue, J E
    Spangenberger, A
    Stopa, E G
    Duncan, J A
    Sharma, H S
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Atrial natriuretic peptide: its putative role in modulating the choroid plexus-CSF system for intracranial pressure regulation.2006In: Acta Neurochir Suppl, ISSN 0065-1419, Vol. 96, p. 451-6Article in journal (Refereed)
  • 16. Johanson, Conrad
    et al.
    Stopa, Edward
    Baird, Andrew
    Sharma, Hari
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Traumatic brain injury and recovery mechanisms: peptide modulation of periventricular neurogenic regions by the choroid plexus-CSF nexus2011In: Journal of neural transmission, ISSN 0300-9564, E-ISSN 1435-1463, Vol. 118, no 1, p. 115-133Article, review/survey (Refereed)
    Abstract [en]

    In traumatic brain injury (TBI), severe disruptions occur in the choroid plexus (CP)-cerebrospinal fluid (CSF) nexus that destabilize the nearby hippocampal and subventricular neurogenic regions. Following invasive and non-invasive injuries to cortex, several adverse sequelae harm the brain interior: (i) structural damage to CP epithelium that opens the blood-CSF barrier (BCSFB) to protein, (ii) altered CSF dynamics and intracranial pressure (ICP), (iii) augmentation of leukocyte traffic across CP into the CSF-brain, (iv) reduction in CSF sink action and clearance of debris from ventricles, and (v) less efficient provision of micronutritional and hormonal support for the CNS. However, gradual post-TBI restitution of the injured CP epithelium and ependyma, and CSF homeostatic mechanisms, help to restore subventricular/subgranular neurogenesis and the cognitive abilities diminished by CNS damage. Recovery from TBI is faciltated by upregulated choroidal/ependymal growth factors and neurotrophins, and their secretion into ventricular CSF. There, by an endocrine-like mechanism, CSF bulk flow convects the neuropeptides to target cells in injured cortex for aiding repair processes; and to neurogenic niches for enhancing conversion of stem cells to new neurons. In the recovery from TBI and associated ischemia, the modulating neuropeptides include FGF2, EGF, VEGF, NGF, IGF, GDNF, BDNF, and PACAP. Homeostatic correction of TBI-induced neuropathology can be accelerated or amplified by exogenously boosting the CSF concentration of these growth factors and neurotrophins. Such intraventricular supplementation via the CSF route promotes neural restoration through enhanced neurogenesis, angiogenesis, and neuroprotective effects. CSF translational research presents opportunities that involve CP and ependymal manipulations to expedite recovery from TBI.

  • 17. Kiyatkin, E. A.
    et al.
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Permeability of the blood-brain barrier depends on brain temperature2009In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 161, no 3, p. 926-939Article in journal (Refereed)
    Abstract [en]

    Increased permeability of the blood-brain barrier (BBB) has been reported in different conditions accompanied by hyperthermia, but the role of brain temperature per se in modulating brain barrier functions has not been directly examined. To delineate the contribution of this factor, we examined albumin immunoreactivity in several brain structures (cortex, hippocampus, thalamus and hypothalamus) of pentobarbital-anesthetized rats (50 mg/kg i.p.), which were passively warmed to different levels of brain temperature (32-42 degrees C). Similar brain structures were also examined for the expression of glial fibrillary acidic protein (GFAP), an index of astrocytic activation, water and ion content, and morphological cell abnormalities. Data were compared with those obtained from drug-free awake rats with normal brain temperatures (36-37 degrees C). The numbers of albumin- and GFAP-positive cells strongly correlate with brain temperature, gradually increasing from approximately 38.5 degrees C and plateauing at 41-42 degrees C. Brains maintained at hyperthermia also showed larger content of brain water and Na(+), K(+) and Cl(-) as well as structural abnormalities of brain cells, all suggesting acute brain edema. The latter alterations were seen at approximately 39 degrees C, gradually progressed with temperature increase, and peaked at maximum hyperthermia. Temperature-dependent changes in albumin immunoreactivity tightly correlated with GFAP immunoreactivity, brain water, and numbers of abnormal cells; they were found in each tested area, but showed some structural specificity. Notably, a mild BBB leakage, selective glial activation, and specific cellular abnormalities were also found in the hypothalamus and piriform cortex during extreme hypothermia (32-33 degrees C); in contrast to hyperthermia these changes were associated with decreased levels of brain water, Na(+) and K(+), suggesting acute brain dehydration. Therefore, brain temperature per se is an important factor in regulating BBB permeability, alterations in brain water homeostasis, and subsequent structural abnormalities of brain cells.

  • 18. Kiyatkin, Eugene A.
    et al.
    Brown, P. Leon
    Sharma, Hari S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Brain edema and breakdown of the blood-brain barrier during methamphetamine intoxication: critical role of brain hyperthermia2007In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 26, no 5, p. 1242-1253Article in journal (Refereed)
    Abstract [en]

    To clarify the role of brain temperature in permeability of the blood-brain barrier (BBB), rats were injected with methamphetamine (METH 9 mg/kg) at normal (23 °C) and warm (29 °C) environmental conditions and internal temperatures were monitored both centrally (nucleus accumbens, NAcc) and peripherally (skin and nonlocomotor muscle). Once NAcc temperatures peaked or reached 41.5 °C (a level suggesting possible lethality), animals were administered Evans blue dye (protein tracer that does not normally cross the BBB), rapidly anaesthetized, perfused and had their brains removed. All METH-treated animals showed brain and body hyperthermia associated with relative skin hypothermia, suggesting metabolic activation coupled with peripheral vasoconstriction. While METH-induced NAcc temperature elevation varied from 37.60 to 42.46 °C (or 1.2-5.1 °C above baseline), it was stronger at 29 °C (+4.13 °C) than 23 °C (+2.31 °C). Relative to control, METH-treated animals had significantly higher brain levels of water, Na+, K+ and Cl-, suggesting brain edema, and intense immunostaining for albumin, indicating breakdown of the BBB. METH-treated animals also showed strong immunoreactivity for glial fibrillary acidic protein (GFAP), possibly suggesting acute abnormality or damage of astrocytes. METH-induced changes in brain water, albumin and GFAP correlated linearly with NAcc temperature (r = 0.93, 0.98 and 0.98, respectively), suggesting a key role of brain hyperthermia in BBB permeability, development of brain edema and subsequent functional and structural neural abnormalities. Therefore, along with a direct destructive action on neural cells and functions, brain hyperthermia, via breakdown of the BBB, may be crucial for both decompensation of brain functions and cell injury following acute METH intoxication, possibly contributing to neurodegeneration resulting from chronic drug use.

  • 19.
    Kiyatkin, Eugene A.
    et al.
    NIDA, Behav Neurosci Branch, Intramural Res Program, NIH, 333 Cassell Dr, Baltimore, MD 21224 USA..
    Sharma, Hari S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Breakdown of Blood-Brain and Blood-Spinal Cord Barriers During Acute Methamphetamine Intoxication: Role of Brain Temperature2016In: CNS & Neurological Disorders: Drug Targets, ISSN 1871-5273, E-ISSN 1996-3181, Vol. 15, no 9, p. 1129-1138Article, review/survey (Refereed)
    Abstract [en]

    Methamphetamine (METH) is a powerful and often-abused stimulant with potent addictive and neurotoxic properties. While it is generally believed that structural brain damage induced by METH results from oxidative stress, in this work we present data suggesting robust disruption of blood-brain and blood-spinal cord barriers during acute METH intoxication in rats. We demonstrate the relationships between METH-induced brain hyperthermia and widespread but structure-specific barrier leakage, acute glial cell activation, changes in brain water and ionic homeostasis, and structural damage of different types of cells in the brain and spinal cord. Therefore, METH-induced leakage of the blood-brain and blood-spinal cord barriers is a significant contributor to different types of functional and structural brain abnormalities that determine acute toxicity of this drug and possibly neurotoxicity during its chronic use.

  • 20. Kiyatkin, Eugene A.
    et al.
    Sharma, Hari S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Expression of heat shock protein (HSP 72 kDa) during acute methamphetamine intoxication depends on brain hyperthermia: neurotoxicity or neuroprotection?2011In: Journal of neural transmission, ISSN 0300-9564, E-ISSN 1435-1463, Vol. 118, no 1, p. 47-60Article in journal (Refereed)
    Abstract [en]

    In the present study, light and electron microscopy were used to examine heat shock protein (HSP 72kD) expression during acute methamphetamine (METH) intoxication in rats and evaluate its relationships with brain temperature and alterations in a number of other histochemical and morphological parameters. Freely moving rats received METH at the same dose (9 mg/kg, sc) but at different ambient temperatures (23 and 29°C), showing a wide range of brain temperature elevations (37.6-42.5°C); brains were taken for histochemical and morphological evaluations at peak of brain temperature increase. We found that acute METH intoxication induces massive and wide-spread HSP expression in neural and glial cells examined in detail in the cortex, hippocampus, thalamus, and hypothalamus. In each of these structures, the number of HSP-positive cells tightly correlated with brain temperature elevation. The changes in HSP immunoreactivity were also tightly related to alterations in permeability of the blood-brain barrier, acute glial activation, and brain edema assessed by albumin and GFAP immunoreactivity and measuring tissue water content, respectively. While robust and generalized HSP production normally appears to be the part of an adaptive brain response associated with METH-induced metabolic activation, activation of this protective mechanism has its natural limits and could not counteract the damaging effects of oxidative stress, high temperature, and edema-the leading factors of METH-induced neurotoxicity.

  • 21. Kiyatkin, Eugene A.
    et al.
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Acute Methamphetamine Intoxication: Brain Hyperthermia, Blood–Brain Barrier, Brain Edema, and morphological cell abnormalities2009In: International review of neurobiology, ISSN 0074-7742, E-ISSN 2162-5514, Vol. 88, p. 65-100Article, review/survey (Refereed)
    Abstract [en]

    Methamphetamine (METH) is a powerful and often abused stimulant with potent addictive and neurotoxic properties. While it is generally assumed that multiple chemical substances released in the brain following METH-induced metabolic activation (or oxidative stress) are primary factors underlying damage of neural cells, in this work we present data suggesting a role of brain hyperthermia and associated leakage of the blood-brain barrier (BBB) in acute METH-induced toxicity. First, we show that METH induces a dose-dependent brain and body hyperthermia, which is strongly potentiated by associated physiological activation and in warm environments that prevent proper heat dissipation to the external environment. Second, we demonstrate that acute METH intoxication induces robust, widespread but structure-specific leakage of the BBB, acute glial activation, and increased water content (edema), which are related to drug-induced brain hyperthermia. Third, we document widespread morphological abnormalities of brain cells, including neurons, glia, epithelial, and endothelial cells developing rapidly during acute METH intoxication. These structural abnormalities are tightly related to the extent of brain hyperthermia, leakage of the BBB, and brain edema. While it is unclear whether these rapidly developed morphological abnormalities are reversible, this study demonstrates that METH induces multiple functional and structural perturbations in the brain, determining its acute toxicity and possibly contributing to neurotoxicity.

  • 22. Kiyatkin, Eugene A
    et al.
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Chapter 6: Environmental conditions modulate neurotoxic effects of psychomotor stimulant drugs of abuse2012In: New Perspectives of Central Nervous System Injury and Neuroprotection / [ed] Sharma, HS, Elsevier, 2012, p. 147-171Chapter in book (Refereed)
    Abstract [en]

    Psychomotor stimulants such as methamphetamine (METH), amphetamine, and 3,4-metylenedioxymethamphetamine (MDMA or ecstasy) are potent addictive drugs. While it is known that their abuse could result in adverse health complications, including neurotoxicity, both the environmental conditions and activity states associated with their intake could strongly enhance drug toxicity, often resulting in life-threatening health complications. In this review, we analyze results of animal experiments that suggest that even moderate increases in environmental temperatures and physiological activation, the conditions typical of human raves parties, dramatically potentiate brain hyperthermic effects of METH and MDMA. We demonstrate that METH also induces breakdown of the blood-brain barrier, acute glial activation, brain edema, and structural abnormalities of various subtypes of brain cells; these effects are also strongly enhanced when the drug is used at moderately warm environmental conditions. We consider the mechanisms underlying environmental modulation of acute drug neurotoxicity and focus on the role of brain temperature, a critical homeostatic parameter that could be affected by metabolism-enhancing drugs and environmental conditions and affect neural activity and functions.

  • 23. Kiyatkin, Eugene A.
    et al.
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Not Just the Brain: Methamphetamine Disrupts Blood-Spinal Cord Barrier and Induces Acute Glial Activation and Structural Damage of Spinal Cord Cells2015In: CNS & Neurological Disorders: Drug Targets, ISSN 1871-5273, E-ISSN 1996-3181, Vol. 14, no 2, p. 282-294Article in journal (Refereed)
    Abstract [en]

    Acute methamphetamine (METH) intoxication induces metabolic brain activation as well as multiple physiological and behavioral responses that could result in life-threatening health complications. Previously, we showed that METH (9 mg/kg) used in freely moving rats induces robust leakage of blood-brain barrier, acute glial activation, vasogenic edema, and structural abnormalities of brain cells. These changes were tightly correlated with drug-induced brain hyperthermia and were greatly potentiated when METH was used at warm ambient temperatures (29 degrees C), inducing more robust and prolonged hyperthermia. Extending this line of research, here we show that METH also strongly increases the permeability of the blood-spinal cord barrier as evidenced by entry of Evans blue and albumin immunoreactivity in T9-12 segments of the spinal cord. Similar to the blood-brain barrier, leakage of bloodspinal cord barrier was associated with acute glial activation, alterations of ionic homeostasis, water tissue accumulation (edema), and structural abnormalities of spinal cord cells. Similar to that in the brain, all neurochemical alterations correlated tightly with drug-induced elevations in brain temperature and they were enhanced when the drug was used at 29 degrees C and brain hyperthermia reached pathological levels (>40 degrees C). We discuss common features and differences in neural responses between the brain and spinal cord, two inseparable parts of the central nervous system affected by METH exposure.

  • 24. Lafuente, Jose Vicente
    et al.
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Patnaik, Ranjana
    Muresanu, Dafin Fior
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Diabetes Exacerbates Nanoparticles Induced Brain Pathology2012In: CNS & Neurological Disorders: Drug Targets, ISSN 1871-5273, E-ISSN 1996-3181, Vol. 11, no 1, p. 26-39Article, review/survey (Refereed)
    Abstract [en]

    Long term exposure of nanoparticles e.g., silica dust (SiO2) from desert environments, or engineered nanoparticles from metals viz., Cu, Al or Ag from industry, ammunition, military equipment and related products may lead to adverse effects on mental health. However, it is unclear whether these nanoparticles may further adversely affect human health in cardiovascular or metabolic diseases e.g., hypertension or diabetes. It is quite likely that in diabetes or hypertension where the body immune system is already compromised there will be greater adverse effects following nanoparticles exposure on human health as compared to their exposure to healthy individuals. Previous experiments from our laboratory showed that diabetic or hypertensive animals are more susceptible to heat stress-induced neurotoxicity. Furthermore, traumatic injury to the spinal cord in SiO2 exposed rats resulted in exacerbation of cord pathology. However, whether nanoparticles such as Cu, Ag or SiO2 exposure will lead to enhanced neurotoxicity in diabetic animals are still not well investigated. Previous data from our laboratory showed that Cu or Ag intoxication (50 mg/kg, i.p. per day for 7 days) in streptozotocine induced diabetic rats exhibited enhanced neurotoxicity and exacerbation of sensory, motor and cognitive function as compared to normal animals under identical conditions. Thus the diabetic animals showed exacerbation of regional blood-brain barrier (BBB) disruption, edema formation and cell injuries along with greater reduction in the local cerebral blood flow (CBF) as compared to normal rats. These observations suggest that diabetic animals are more vulnerable to nanoparticles induced brain damage than healthy rats. The possible mechanisms and functional significance of these findings are discussed in this review largely based on our own investigations.

  • 25. Leng, Z
    et al.
    Guo, L
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Huang, H
    He, X
    Conference Report: IANR V and 9th GCNN Conference with 4th ISCITT Symposium2012In: CNS & Neurological Disorders: Drug Targets, ISSN 1871-5273, E-ISSN 1996-3181, Vol. 11, no 6, p. 643-646Article in journal (Refereed)
  • 26. Leng, Zikuan
    et al.
    Guo, Lei
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Huang, Hongyun
    He, Xijing
    IANR V and 9th GCNN Conference with 4th ISCITT Symposium2012In: CNS & Neurological Disorders: Drug Targets, ISSN 1871-5273, E-ISSN 1996-3181, Vol. 11, no 6, p. 643-646Article in journal (Refereed)
    Abstract [en]

    The International Association of Neurorestoratology (IANR) V and the 9th Global College of Neuroprotection and Neuroregeneration (GCNN) Conference with the 4th International Spinal Cord Injury Treatments & Trials (ISCITT) Symposium were successfully hosted in Xi'an, China on May 4th to 7th, 2012 by IANR, GCNN and the Second Affiliated Hospital, Medical School of Xi'an Jiaotong University. More than 600 experts in the Neurorestoratology field from over 40 countries and regions attended this combined novel international summit. The purpose of the 4-day conference was to provide a platform for basic scientists and clinicians to share their latest discoveries and foster possible cooperation in the global Neurorestoratology field. The chairman of the Chinese Medical Doctor Association (CMDA) and former National Deputy Minister of Health, Dakui Yin inaugurated the joint conference in a gala opening ceremony and warmly welcomed the delegates.

  • 27.
    Menon, P. K.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Muresanu, D. F.
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Aguilar, Z. P.
    Wang, Y. A.
    Lafuente, J. V.
    Moessler, H.
    Patnaik, R.
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Functionalized Magnetic Iron Oxide Nanoparticles Influence Spinal Cord Trauma-Induced Pathology: Neuroprotective Effects of Cerebrolysin Treatment2013In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 22, no 5, p. 909-909Article in journal (Other academic)
  • 28. Menon, Preeti Kumaran
    et al.
    Muresanu, Dafin Fior
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Moessler, Herbert
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Cerebrolysin, a Mixture of Neurotrophic Factors Induces Marked Neuroprotection in Spinal Cord Injury Following Intoxication of Engineered Nanoparticles from Metals2012In: CNS & Neurological Disorders - Drug Targets, ISSN 1871-5273, Vol. 11, no 1, p. 40-49Article, review/survey (Refereed)
    Abstract [en]

    Spinal cord injury (SCI) is the world's most disastrous disease for which there is no effective treatment till today. Several studies suggest that nanoparticles could adversely influence the pathology of SCI and thereby alter the efficacy of many neuroprotective agents. Thus, there is an urgent need to find suitable therapeutic agents that could minimize cord pathology following trauma upon nanoparticle intoxication. Our laboratory has been engaged for the last 7 years in finding suitable therapeutic strategies that could equally reduce cord pathology in normal and in nanoparticle-treated animal models of SCI. We observed that engineered nanoparticles from metals e.g., aluminum (Al), silver (Ag) and copper (Cu) (50-60 nm) when administered in rats daily for 7 days (50 mg/kg, i.p.) resulted in exacerbation of cord pathology after trauma that correlated well with breakdown of the blood-spinal cord barrier (BSCB) to serum proteins. The entry of plasma proteins into the cord leads to edema formation and neuronal damage. Thus, future drugs should be designed in such a way to be effective even when the SCI is influenced by nanoparticles. Previous research suggests that a suitable combination of neurotrophic factors could induce marked neuroprotection in SCI in normal animals. Thus, we examined the effects of a new drug; cerebrolysin that is a mixture of different neurotrophic factors e.g., brain-derived neurotrophic factor (BDNF), glial cell line derived neurotrophic factor (GDNF), nerve growth factor (NGF), ciliary neurotrophic factor (CNTF) and other peptide fragments to treat normal or nanoparticle-treated rats after SCI. Our observations showed that cerebrolysin (2.5 ml/kg, i.v.) before SCI resulted in good neuroprotection in normal animals, whereas nanoparticle-treated rats required a higher dose of the drug (5.0 ml/kg, i.v.) to induce comparable neuroprotection in the cord after SCI. Cerebrolysin also reduced spinal cord water content, leakage of plasma proteins and the number of injured neurons. This indicates that cerebrolysin in higher doses could be a good candidate for treating SCI cases following nanoparticle intoxication. The possible mechanisms and functional significance of these findings are discussed in this review.

  • 29.
    Miclescu, Adriana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Martijn, Cécile
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Methylene blue administration during cardio-pulmonary resuscitation and early reperfusion protects against cortical blood-brain barrier disruptionManuscript (preprint) (Other (popular science, discussion, etc.))
    Abstract [en]

    Objective: The present study was designed to study the effects of cardiac arrest and cardiopulmonary resuscitation (CPR) on blood-brain barrier (BBB) permeability and subsequent neurological injury. It also tests the cerebral effects of MB on the maintenance of BBB integrity, the production of nitric oxide (NO) and regulation of nitric oxide synthases (NOS) in cerebral cortex.

    Intervention: The control group (CA, n=16) underwent 12 min cardiac arrest without subsequent CPR, after which the brain of the animals was removed immediately or after 15 and 30 min. The other two groups with 12 min cardiac arrest and subsequent 8 min CPR received either an infusion of saline (CA-MB group, n=10) or an infusion of saline with MB (CA+MB, n= 12) started one minute after the start of CPR and continued 50 min after return of spontaneous circulation (ROSC).  In both the latter (CA-MB and CA+MB) groups the brains were removed for histological analysis at the following time points: 30, 60, 180 min after ROSC.

    Main Results: In all the groups an increase of necrotic neurons and albumin immunoreactivity was demonstrated with increasing duration of ischemia and reperfusion time. The immunohistochemistry analysis indicated less blood brain barrier disruption in the animals receiving MB (CA+MB group) evidenced by decreased albumin leakage (P<0.01), water content (P=0.02), potassium (P=0.04), but also decreased neuronal injury (P<0.001) in this group in comparison with the group that was not treated with MB (CA-MB). Similarly, MB treatment reduced nitrite/nitrate ratio (P=0.02), iNOS expression (P<0.01), nNOS expression (P<0.01).

    Conclusion: Cerebral edema, increase BBB permeability and neurologic injury are observed early in ischemia induced by cardiac arrest. MB markedly reduced BBB disruption and subsequent neurologic injury. These cerebral cortical effects after the exposure to MB appear to be associated with a decrease of NO measured by nitrate/nitrite and different effects on NOS.

  • 30.
    Miclescu, Adriana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Martijn, Cécile
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Methylene blue protects the cortical blood-brain barrier against ischemia/reperfusion-induced disruptions2010In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 38, no 11, p. 2199-2206Article in journal (Refereed)
    Abstract [en]

    Objectives: To investigate the effects of cardiac arrest and the reperfusion syndrome on blood-brain barrier permeability and evaluate whether methylene blue counteracts blood-brain barrier disruption in a pig model of controlled cardiopulmonary resuscitation. Design: Randomized, prospective, laboratory animal study. Setting: University-affiliated research laboratory. Subjects: Forty-five piglets. Interventions: Forty-five anesthetized piglets were subjected to cardiac arrest alone or 12-min cardiac arrest followed by 8 mins cardiopulmonary resuscitation. The first group (n = 16) was used to evaluate blood-brain barrier disruptions after untreated cerebral ischemia after 0, 15, or 30 mins after untreated cardiac arrest. The other two groups received either an infusion of saline (n = 10) or infusion of saline with methylene blue (n = 12) 1 min after the start of cardiopulmonary resuscitation and continued 50 mins after return of spontaneous circulation. In these groups, brains were removed for immunohistological analyses at 30, 60, and 180 mins after return of spontaneous circulation. Measurements and Main Results: An increase of injured neurons and albumin immunoreactivity was demonstrated with in-creasing duration of ischemia/reperfusion. Less blood-brain barrier disruption was observed in subjects receiving methylene blue as demonstrated by decreased albumin leakage (p<.01), water content (p<.05), and neuronal injury (p<.01). Methylene blue treatment reduced cerebral tissue nitrite/nitrate content (p<.05) and the number of inducible and neuronal nitric oxide synthase-activated cortical cells during administration (p<.01). Meanwhile, the number of cortical endothelial nitric oxide synthase-activated cells increased over time (p<.001). Conclusion: Cerebral tissue water content, blood-brain barrier permeability and neurologic injury were increased early in reperfusion after cardiac arrest. Methylene blue exerted neuroprotective effects against the brain damage associated with the ischemia/reperfusion injury and ameliorated the blood-brain barrier disruption by decreasing nitric oxide metabolites. (Crit Care Med 2010; 38: 2199-2206)

  • 31.
    Miclescu, Adriana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Crystalloid vs. hypertonic crystalloid-colloid solutions for induction of mild therapeutic hypothermia after experimental cardiac arrest2013In: Resuscitation, ISSN 0300-9572, E-ISSN 1873-1570, Vol. 84, no 2, p. 256-262Article in journal (Refereed)
    Abstract [en]

    PURPOSE:

    To compare cerebral and hemodynamic consequences of different volumes of cold acetated Ringer's solution or cold hypertonic saline dextran administered in order to achieve mild hypothermia after cardiac arrest (CA) in a pig model of experimental cardiopulmonary resuscitation (CPR).

    METHODS:

    Using an experimental pig model of 12min CA (followed by 8min CPR or no resuscitation) we compared four groups of piglets: a control group, a normothermic group and two groups with different solutions administered for induction of hypothermia. The control group of 5 piglets underwent 12min CA without subsequent CPR, after which the brain of the animals was removed immediately. After restoration of spontaneous circulation (ROSC) the resuscitated piglets were randomized into a normothermic group (NT group=10), and two hypothermic groups that received cold infusions of either 30mL/kg acetated Ringer's solution (Much fluid group, M, n=10) or 3mL/kg hypertonic saline dextran solution (Less fluid group, L, n=10), respectively, administered during 30min. Additional external cooling with ice packs was used in hypothermic groups. Sixty or 180min after ROSC the experiment was terminated. Immediately after arrest the brain was removed for histological analyses.

    RESULTS:

    The median time to reach the target core temperature of 34°C after ROSC was 51.5±7.8min in L group and 48.8±8.6min in M group. Less cerebral tissue content of water (p<0.001), sodium (p<0.0001), potassium (p<0.0001) and less central venous pressure (CVP) at 5 and 15min after ROSC were demonstrated in L group. Increased brain damage was demonstrated over time in NT group (p<0.001). Less neurologic damage and BBB disruptions (albumin leakage) was observed at 180min in M group in comparison with both NT and L groups (p<0.001).

    CONCLUSION:

    No statistical differences were observed between the hypothermic groups in the time to achieve mild hypothermia. Although inclusion of cold hypertonic crystalloid-colloidal solutions in the early resuscitation after ROSC may be more effective than cold crystalloids in reducing brain edema, this study demonstrates that mild hypothermia induced with small volumes of cold hypertonic crystalloid-colloids is less as effective as crystalloid's induced hypothermia in mitigating brain injury after cardiac arrest.

  • 32. Muresanu, D. F.
    et al.
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Patnaik, R.
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Enhanced Neuroprotection by Nanowired Delivery of Cerebrolysin in Hyperthermia-Induced Brain Damage2012In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 21, no 4, p. 786-786Article in journal (Other academic)
  • 33.
    Muresanu, D. F.
    et al.
    Univ Med & Pharm, Clin Neurosci.;RoNeuro Inst Neurol Res & Diagnost, Neurol..
    Sharma, Aruna
    Uppsala Univ Hosp, Surg Sci Anesthesiol & Intens Care Med..
    Sharma, Hari Shanker
    Uppsala Univ Hosp, Surg Sci Anesthesiol & Intens Care Med..
    Pathophysiology of high altitude traumatic brain edema: New roles of cererbrolysin and nanomedicine2017In: Journal of Cerebral Blood Flow and Metabolism, ISSN 0271-678X, E-ISSN 1559-7016, Vol. 37, p. 208-209Article in journal (Other academic)
  • 34. Muresanu, D. F.
    et al.
    Winkler, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Nozari, A.
    Menon, P. K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Cerebrolysin enhances spinal cord conduction and reduces blood-spinal cord barrier breakdown, oedema formation, immediate early gene expression and cord pathology after injury2012In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 19, no S1, p. 798-798Article in journal (Other academic)
  • 35.
    Muresanu, D.
    et al.
    Univ Med & Pharm, Clin Neurosci, Cluj Napoca, Romania..
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Lafuente, J.
    Univ Basque Country, Neurosci, Bilbao, Spain..
    Patnaik, R.
    Banaras Hindu Univ, IIT, Biomed Engn, Varanasi, Uttar Pradesh, India..
    Tian, Z.
    Univ Arkansas Faytteville, Chem & Biochem, Faytteville, AR USA..
    Ozkizilcik, A. S. Y. A.
    Univ Arkansas Faytteville, Chem & Biochem, Faytteville, AR USA..
    Moessler, H.
    Ever Neuro Pharma, Drug Dev & Discovery, Oberburgau, Austria..
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Nanowired cerebrolysin potentiates mesenchymal stem cells induced neuroprotection and neurorepair following heat stroke2016In: Journal of Cerebral Blood Flow and Metabolism, ISSN 0271-678X, E-ISSN 1559-7016, Vol. 36, no Suppl. 1, p. 317-317, article id 457Article in journal (Other academic)
  • 36.
    Muresanu, Dafin F.
    et al.
    RoNeuro Inst Neurol Res & Diagnost, Cluj Napoca, Romania.;Univ Med & Pharm Iuliu Haticganu, Dept Clin Neurosci, Cluj Napoca, Romania..
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Lafuente, Jose V.
    Univ Basque Country, Dept Neurosci, LaNCE, Bilbao, Spain.;Univ Autonoma Chile, Fac Hlth Sci, Santiago, Chile..
    Patnaik, Ranjana
    Banaras Hindu Univ, Sch Biomed Engn, Indian Inst Technol, Dept Biomat, Varanasi 221005, Uttar Pradesh, India..
    Tian, Z. Ryan
    Univ Arkansas, Dept Chem & Biochem, Fayetteville, AR 72701 USA..
    Nyberg, Fred
    Uppsala Univ, Biomed Ctr, Dept Pharmaceut Biosci Biol Res Drug Dependence, Uppsala, Sweden..
    Sharma, Hari S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Univ Basque Country, Dept Neurosci, LaNCE, Bilbao, Spain..
    Nanowired Delivery of Growth Hormone Attenuates Pathophysiology of Spinal Cord Injury and Enhances Insulin-Like Growth Factor-1 Concentration in the Plasma and the Spinal Cord2015In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 52, no 2, p. 837-845Article in journal (Refereed)
    Abstract [en]

    Previous studies from our laboratory showed that topical application of growth hormone (GH) induced neuroprotection 5 h after spinal cord injury (SCI) in a rat model. Since nanodelivery of drugs exerts superior neuroprotective effects, a possibility exists that nanodelivery of GH will induce long-term neuroprotection after a focal SCI. SCI induces GH deficiency that is coupled with insulin-like growth factor-1 (IGF-1) reduction in the plasma. Thus, an exogenous supplement of GH in SCI may enhance the IGF-1 levels in the cord and induce neuroprotection. In the present investigation, we delivered TiO2-nanowired growth hormone (NWGH) after a longitudinal incision of the right dorsal horn at the T10-11 segments in anesthetized rats and compared the results with normal GH therapy on IGF-1 and GH contents in the plasma and in the cord in relation to blood-spinal cord barrier (BSCB) disruption, edema formation, and neuronal injuries. Our results showed a progressive decline in IGF-1 and GH contents in the plasma and the T9 and T12 segments of the cord 12 and 24 h after SCI. Marked increase in the BSCB breakdown, as revealed by extravasation of Evans blue and radioiodine, was seen at these time points after SCI in association with edema and neuronal injuries. Administration of NWGH markedly enhanced the IGF-1 levels and GH contents in plasma and cord after SCI, whereas normal GH was unable to enhance IGF-1 or GH levels 12 or 24 h after SCI. Interestingly, NWGH was also able to reduce BSCB disruption, edema formation, and neuronal injuries after trauma. On the other hand, normal GH was ineffective on these parameters at all time points examined. Taken together, our results are the first to demonstrate that NWGH is quite effective in enhancing IGF-1 and GH levels in the cord and plasma that may be crucial in reducing pathophysiology of SCI.

  • 37. Muresanu, Dafin F.
    et al.
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Patnaik, Ranjana
    Moessler, Herbert
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Cerebrolysin restores amino acid neurotransmitters balance in the brain following traumatic head injury: an experimental study in the rat2013In: Amino Acids, ISSN 0939-4451, E-ISSN 1438-2199, Vol. 45, no 3, p. 565-565Article in journal (Other academic)
  • 38.
    Muresanu, Dafin F.
    et al.
    Univ Med & Pharm, Dept Neurosci, Cluj Napoca, Romania..
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Patnaik, Ranjana
    Banaras Hindu Univ, Indian Inst Technol, Varanasi 221005, Uttar Pradesh, India..
    Nozari, Ala
    Harvard Univ, Massachusetts Gen Hosp, Anesthesiol, Boston, MA 02115 USA..
    Tian, Z. Ryan
    Univ Arkansas, Chem & Biochem, Fayetteville, AR 72701 USA..
    Ozkizilcik, Asya
    Univ Arkansas, Chem & Biochem, Fayetteville, AR 72701 USA..
    Moessler, Herbert
    Ever NeuroPharma, Oberburgau, Austria..
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Univ Uppsala Hosp, Dept Surg Sci Anesthesiol & Intens Care Med, Uppsala, Sweden..
    Nanodelivery of cerebrolysin induces profound neuroprotection in heat stroke following chronic hypertension in combination with carbon nanoparticles induced exacerbation of brain damage2016In: Brain Injury, ISSN 0269-9052, E-ISSN 1362-301X, Vol. 30, no 5-6, p. 506-507Article in journal (Other academic)
  • 39. Muresanu, Dafin F.
    et al.
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Tian, Z. Ryan
    Smith, Mark A.
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Nanowired Drug Delivery of Antioxidant Compound H-290/51 Enhances Neuroprotection in Hyperthermia-Induced Neurotoxicity2012In: CNS & Neurological Disorders: Drug Targets, ISSN 1871-5273, E-ISSN 1996-3181, Vol. 11, no 1, p. 50-64Article, review/survey (Refereed)
    Abstract [en]

    Nanoparticles from the environment or through industrial sources can induce profound alterations in human health, often leading to brain dysfunction. However, it is still unclear whether nanoparticle intoxication could also alter the physiological or pathological responses of additional brain injury, stress response or disease processes. Military personals engaged in combat or peacekeeping operations are often exposed to nanoparticles from various environmental sources, e.g., Ag, Cu, Si, C, Al. In addition, these military personals are often exposed to high environmental heat, or gun and missle explosion injury leading to head or spinal trauma. Thus it is likely that additional CNS injury or stress-induced pathophysiological processes are influenced by nanoparticle intoxication. In this situation, when a combination of nanoparticles and central nervous system (CNS) injury or stress exist together, drug therapy needed to correct these anomalies may not work as effectively as in normal situation. Previous studies from our laboratory show that nanoparticle-intoxicated animals when subjected to hyperthermia resulted in exacerbation of brain pathology. In these animals, antioxidant compounds, e.g., H-290/51 that inhibits free radical formation and induces marked neuroprotection in normal rats after heat stress, failed to protect brain damage when a combination of nanoparticles and heat exposure was used. However, nanowired H-290/51 resulted in better neuroprotection in nanoparticles intoxicated animals after heat stress. Interestingly, high doses of the normal compound induced some neuroprotection in these nanoparticle-treated, heat-stressed rats. These observations suggest that a combination of nanoparticles and heat stress is dangerous and in such situations modification of drug dosage is needed to achieve comparable neuroprotection. In this review possible mechanisms of nanoparticle-induced exacerbation of heat induced neurotoxicity and brain protection achieved by nanowired drug delivery is discussed that is largely based on our own investigations.

  • 40. Muresanu, Dafin F
    et al.
    Sharma, Hari S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Chronic hypertension aggravates heat stress induced cognitive dysfunction and brain pathology: an experimental study in the rat, using growth hormone therapy for possible neuroprotection2007In: Neuroprotective agents: Eighth international neuroprotection society meeting / [ed] Slikker W; Andrew RJ; Trembly B, 2007, Vol. 1122, no 1, p. 1-22Conference paper (Refereed)
    Abstract [en]

    Hyperthermia following heat stress results in profound brain edema formation and damage to the central nervous system (CNS). However, whether acute or chronic diseases such as cardiovascular, endocrine, or metabolic ailments further influence the vulnerability of human populations to heat-related deaths is still unclear. In this investigation, we examined the effect of hyperthermia on chronic hypertensive rats. The influence of growth hormone (GH) as a therapy to attenuate brain dysfunction was also evaluated. Subjecting rats to 4 h of heat stress at 38°C in a biological oxygen demand (BOD) incubator resulted in profound impairment of motor and cognitive functions, breakdown of the blood-brain barrier (BBB), reduction in regional cerebral blood flow (CBF), edema formation, and brain damage. These effects were further aggravated when chronic hypertensive rats (two-kidney, one-clip model for 4 weeks) were subjected to similar hyperthermic conditions (38°C for 4 h). Interestingly, the behavioral alterations and impairment of motor and cognitive functions in hypertensive rats were much worse than those in the normotensive animals subjected to heat stress. Pretreatment with GH (50 μg/kg/min i.v. for 60 min, before heat stress) significantly attenuated behavioral and cognitive deficits in normotensive rats and reduced the BBB dysfunction and brain pathology. On the other hand, similar treatment with GH in hypertensive animals only mildly reduced brain damage or cognitive dysfunction after heat stress. These novel observations indicate that patients suffering from various chronic diseases respond differently to various health hazards such as hyperthermia and to other neuroprotective agents.

  • 41.
    Muresanu, Dafin Fior
    et al.
    Univ Med & Pharm, Cluj-Napoca, Romania.
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Vicente Lafuente, Jose
    Univ Basque Country, Bilbao, Spain.
    Nozari, Ala
    Harvard Univ, Boston, USA.
    Patnaik, Ranjana
    Banaras Hindu Univ, Varanasi, Uttar Pradesh, India.
    Tian, Z. Ryan
    Univ Arkansas, Fayetteville, USA.
    Ozkizilcik, Asya
    Univ Arkansas, Fayetteville, USA.
    Moessler, Herbert
    Ever Neuro Pharma, Oberburgau, Austria.
    Sharma, Aruna
    Univ Med & Pharm, Cluj-Napoca, Romania.
    Hypertension Associated With Silica Dust Intoxication Aggravates Brain Pathology Following Traumatic Brain Injury: New Roles of Neurotrophic Factors2017In: The journal of head trauma rehabilitation, ISSN 0885-9701, E-ISSN 1550-509X, Vol. 32, no 6, p. E68-E69Article in journal (Other academic)
    Abstract [en]

    Introduction/Rational: Military personnel engaged in combat operation are often exposed to desert storm resulting in silica dust (SiO2 nanoparticles) intoxication. In addition, combat stress, sleep deprivation and continuous attention for enemy group results in mild to moderate hypertension. Under such situations, any traumatic brain or spinal cord injury could result in massive brain pathology due to stress induced hypertension and possibly SiO2 nanoparticles intoxication. However, effects of trauma in hypertension and SiO2 intoxication are still not well known. In present study we investigated the effects of hypertension and SiO2 intoxication of the pathophysiology of traumatic brain injury (TBI).

    Method/Approach: Male Wistar rats (250-300 g) were made renal hypertensive by 2kidney 1clip (2K1C) procedure allowing mean arterial blood pressure (MABP) reaching 180 ± 8 torr over 6 weeks. These hypertensive rats were exposed to SiO2NPs (40-50 nm) once daily (50 mg/kg, i.p.) for 8 days. On the 9th day these hypertensive and SiO2NPs intoxicated animals were subjected to TBI under anesthesia by making an incision (3 mm long and 2.5 mm deep) on the right parietal cerebral cortex after opening the skull (4mmOD) on both sides. The animas were allowed to survive 48 h after TBI.

    Results/Effects: TBI in hypertensive and SiO2 nanoparticles intoxicated rats showed 4-to-6 fold higher breakdown of the blood-brain barrier (BBB) to Evans blue albumin (EBA) and [131]-Iodine, edema formation and neuronal injuries as compared to TBI in normal animals at 48 h. Treatment with a multimodal drug Cerebrolysin-containing balanced composition of neurotrophic factors and active peptide fragments (10 ml/kg, i.v.) started 4 h after TBI followed by 4 injections at every 8 h markedly reduced brain pathologies. Whereas only 5 ml/kg of the drug is needed to achieve identical neuroprotection in normal rats after TBI.

    Conclusions/Limitations: These observations are the first to show that a combination of hypertension and SiO2 nanoparticles worsens brain pathology in TBI. Under these situations almost double dose of drugs is needed to induce neuroprotection, not reported earlier. Our laboratory is engaged to see whether nanodelivery of cerebrolysin could have an added therapeutic value in this complicated situation of brain injury, a subject that is currently being investigated in our laboratory.

  • 42.
    Muresanu, Dafin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Univ Med & Pharm, Cluj Napoca, Romania..
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Nozari, Ala
    Harvard Univ, Harvard Med Sch, Boston, MA USA..
    Lafuente, Jose V.
    Univ Basque Country, Bilbao, Spain..
    Tian, Ryan
    Univ Arkansas, Fayetteville, AR 72701 USA..
    Ozkizilcik, Asya
    Univ Arkansas, Fayetteville, AR 72701 USA..
    Sharma, Aruna
    Univ Med & Pharm, Cluj Napoca, Romania..
    Traumatic brain injury in diabetic and hypertensive rats exacerbates brain pathology and functional outcome-role of neurotrophic factors and nanomedicine2017In: Brain Injury, ISSN 0269-9052, E-ISSN 1362-301X, Vol. 31, no 6-7, p. 842-842Article in journal (Other academic)
  • 43.
    Nyberg, Fred
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Drug Dependence.
    Sharma, Hari Shanker
    Faculty of Medicine, Department of Medical Cell Biology. Department of Surgical Sciences. Neuroanatomy.
    Growth hormone permeability across the blood-spinal cord and brain barriers and its therapeutic potential in trauma to the spinal cord.: Growth hormone and neuroprotection in spinal cord injury2004In: Blood-Spinal cord and Brain barriers in Health and Disease, Academic Press, Elsevier, San Diego, USA , 2004, p. 519-532Chapter in book (Refereed)
    Abstract [en]

    Growth hormone (GH) secretion decreases in ageing and in neurodegenerative diseases. The plasma level of the hormone declines in aged individuals and in victims of CNS injury. Exogenous GH is neuroprotective in animal models of CNS trauma. The GH replacement therapy improves psychological capabilities in young and in adult growth hormone deficient (GHD) patients suggesting that the hormone has profound beneficial effects on the CNS function. The mechanism by which GH reaches its presumable brain targets is, however, not fully clarified. Clinical studies suggest that the hormone reaches its responsive areas in the brain after passing the blood-brain-barrier (BBB). On the other hand, animal studies show that GH under normal conditions does not cross the CNS barriers. However, the hormone enters into the fluid microenvironments of the CNS and influences the brain or spinal cord neurons through leaky barriers in several disease conditions. Intracerebroventricular infusion of GH reduces neuronal loss in CNS injury and topical application of the hormone on the traumatised cord induces neuroprotection. This review summarizes basic aspects of GH permeability across the BBB or the blood-spinal cord barrier (BSCB) and the mechanisms of GH action on its CNS targets as well as its neuroprotective potential is described.

  • 44.
    Ozkizilcik, Asya
    et al.
    Univ Arkansas, Dept Biomed Engn, Fayetteville, AR 72701 USA..
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala Univ, Univ Hosp, Int Expt CNS Injury & Repair IECNSIR, Frodingsgatan 12,Bldg 28, SE-75421 Uppsala, Sweden..
    Muresanu, Dafin F.
    Univ Med & Pharm, Dept Clin Neurosci, Cluj Napoca, Romania.;RoNeuro Inst Neurol Res & Diagnost, 37 Mircea Eliade St, Cluj Napoca 400364, Romania..
    Lafuente, Jose V.
    Univ Basque Country UPV EHU, Dept Neurosci, LaNCE, Leioa, Biscay, Spain.;BioCruces Hlth Res Inst, Nanoneurosurg Grp, Baracaldo 48903, Biscay, Spain.;Univ Autonoma Chile, Fac Hlth Sci, Santiago, Chile..
    Tian, Z. Ryan
    Univ Arkansas, Chem & Biochem, Fayetteville, AR 72701 USA..
    Patnaik, Ranjana
    Banaras Hindu Univ, Indian Inst Technol, Sch Biomed Engn, Dept Biomat, Varanasi, Uttar Pradesh, India..
    Mössler, Herbert
    RoNeuro Inst Neurol Res & Diagnost, 37 Mircea Eliade St, Cluj Napoca 400364, Romania.;EVER Neuro Pharma, Oberburgau, Austria..
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala Univ, Univ Hosp, Int Expt CNS Injury & Repair IECNSIR, Frodingsgatan 12,Bldg 28, SE-75421 Uppsala, Sweden.;Univ Basque Country UPV EHU, Dept Neurosci, LaNCE, Leioa, Biscay, Spain..
    Timed Release of Cerebrolysin Using Drug-Loaded Titanate Nanospheres Reduces Brain Pathology and Improves Behavioral Functions in Parkinson's Disease2018In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 55, no 1, p. 359-369Article in journal (Refereed)
    Abstract [en]

    Previous studies from our laboratory show that intraperitoneal injections of 1-metyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP, 20 mg/kg) daily within 2-h intervals for 5 days in mice induce Parkinson's disease (PD)-like symptoms on the 8th day. A significant decrease in dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) along with a marked decrease in the number of tyrosine hydroxylase (TH)-positive cells in the substantia nigra pars compacta (SNpc) and striatum (STr) confirms the validity of this model for studying PD. Since cerebrolysin (CBL) is a well-balanced composition of several neurotrophic factors and active peptide fragments, in the present investigation we examined the timed release of CBL using titanate nanospheres (TiNS) in treating PD in our mouse model. Our observations show that TiNS-CBL (in a dose of 3 ml/kg, i.v.) given after 2 days of MPTP administration for 5 days resulted in a marked increase in TH-positive cells in the SNpc and STr as compared to normal CBL. Also, TiNS-CBL resulted in significantly higher levels of DA, DOPAC, and HVA in SNpc and STr on the 8th day as compared to normal CBL therapy. TiNS-CBL also thwarted increased alpha-synuclein levels in the brain and in the cerebrospinal fluid (CSF) as well as neuronal nitric oxide synthase (nNOS) in the in PD brain as compared to untreated group. Behavioral function was also significantly improved in MPTP-treated animals that received TiNS-CBL. These observations are the first to demonstrate that timed release of TiNS-CBL has far more superior neuroprotective effects in PD than normal CBL.

  • 45. Pandey, Anand Kumar
    et al.
    Patnaik, Ranjana
    Muresanu, Dafin F
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Quercetin in hypoxia-induced oxidative stress: novel target for neuroprotection2012In: New Perspectives of Central Nervous System Injury and Neuroprotection / [ed] Sharma, HS, Elsevier, 2012, p. 107-146Chapter in book (Refereed)
    Abstract [en]

    Oxidative stress in the central nervous system is one of the key players for neurodegeneration. Thus, antioxidants could play important roles in treating several neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and aging-related brain disorders. This review is focused on the new developments in oxidative stress-induced neurodegeneration. Further, based on our own investigations, new roles of quercetin, an antioxidant compound in hypoxia and ischemia induced neuroprotection in relation to suppression of oxidative stress, improvement in behavioral function, reduction in infarct volume, brain swelling, and cellular injury in both in vivo and in vitro models are discussed. Our new findings clearly suggest that antioxidant compounds have potential role in therapeutic strategies to treat neurodegenerative diseases in clinical settings.

  • 46.
    Patnaik, Ranjana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Banaras Hindu Univ, Indian Inst Technol, Dept Biomat, Sch Biomed Engn, Varanasi, Uttar Pradesh, India..
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala Univ, Univ Hosp, IECNSIR, Frodingsgatan 12,Bldg 28, SE-75421 Uppsala, Sweden..
    Skaper, Stephen D.
    Univ Padua, Dept Pharmaceut & Pharmacol Sci, Largo E Meneghetti 2, I-35131 Padua, Italy..
    Muresanu, Dafin F.
    RoNeuro Inst Neurol Res & Diagnost, 37 Mircea Eliade St, Cluj Napoca 400364, Romania.;Univ Med & Pharm, Dept Clin Neurosci, Cluj Napoca, Romania..
    Vicente Lafuente, Jose
    Univ Basque Country UPV EHU, Dept Neurosci, LaNCE, Leioa, Bizkaia, Spain.;BioCruces Hlth Res Inst, Nanoneurosurg Grp, Baracaldo 48903, Bizkaia, Spain.;Univ Autonoma Chile, Fac Hlth Sci, Santiago, Chile..
    Castellani, Rudy J.
    Univ Maryland, Dept Pathol, Baltimore, MD 21201 USA..
    Nozari, Ala
    Harvard Univ, Massachusetts Gen Hosp, Anesthesiol, Boston, MA USA..
    Sharma, Hari S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala Univ, Univ Hosp, IECNSIR, Frodingsgatan 12,Bldg 28, SE-75421 Uppsala, Sweden.;Univ Basque Country UPV EHU, Dept Neurosci, LaNCE, Leioa, Bizkaia, Spain..
    Histamine H3 Inverse Agonist BF 2649 or Antagonist with Partial H4 Agonist Activity Clobenpropit Reduces Amyloid Beta Peptide-Induced Brain Pathology in Alzheimer's Disease2018In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 55, no 1, p. 312-321Article in journal (Refereed)
    Abstract [en]

    Alzheimer's disease (AD) is one of the leading causes for disability and death affecting millions of people worldwide. Thus, novel therapeutic strategies are needed to reduce brain pathology associated with AD. In view of increasing awareness regarding involvement of histaminergic pathways in AD, we explored the role of one H3 receptor inverse agonist BF 2649 and one selective H3 receptor antagonist with partial H4 agonist activity in amyloid beta peptide (A beta P) infusion-induced brain pathology in a rat model. AD-like pathology was produced by administering A beta P (1-40) intracerebroventricular (i.c.v.) in the left lateral ventricle (250 ng/10 mu l, once daily) for 4 weeks. Control rats received saline. In separate group of rats, either BF 2649 (1 mg/kg, i.p.) or clobenpropit (1 mg/kg, i.p.) was administered once daily for 1 week after 3weeks of A beta P administration. After 30 days, blood-brain barrier (BBB) breakdown, edema formation, neuronal, glial injuries, and A beta P deposits were examined in the brain. A significant reduction in A beta P deposits along with marked reduction in neuronal or glial reactions was seen in the drug-treated group. The BBB breakdown to Evans blue albumin and radioiodine in the cortex, hippocampus, hypothalamus, and cerebellum was also significantly reduced in these drug-treated groups. Clobenpropit showed superior effects than the BF2649 in reducing brain pathology in AD. Taken together, our observations are the first to show that blockade of H3 and stimulation of H4 receptors are beneficial for the treatment of AD pathology, not reported earlier.

  • 47.
    Requejo, C.
    et al.
    Univ Basque Country UPV EHU, Dept Neurosci, LaNCE, Leioa, Vizcaya, Spain..
    Ruiz-Ortega, J. A.
    Univ Basque Country UPV EHU, Dept Pharmacol, Leioa, Vizcaya, Spain..
    Cepeda, H.
    Univ Basque Country UPV EHU, Dept Neurosci, LaNCE, Leioa, Vizcaya, Spain..
    Sharma, A.
    Uppsala Univ, Int Expt CNS Injury & Repair, Uppsala, Sweden..
    Sharma, H.S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Univ Basque Country UPV EHU, Dept Neurosci, LaNCE, Leioa, Vizcaya, Spain.;Uppsala Univ, Int Expt CNS Injury & Repair, Uppsala, Sweden..
    Ozkizilcik, A.
    Univ Arkansas, Dept Biomed Engn, Fayetteville, AR 72701 USA..
    Tian, R.
    Univ Arkansas, Dept Biomed Engn, Fayetteville, AR 72701 USA.;Univ Arkansas, Dept Chem & Biochem, Fayetteville, AR 72701 USA..
    Moessler, H.
    Ever Neuro Pharma, Drug Discovery & Develop, Oberburgau, Austria..
    Ugedo, L.
    Univ Basque Country UPV EHU, Dept Pharmacol, Leioa, Vizcaya, Spain..
    Lafuente, J. V.
    Univ Basque Country UPV EHU, Dept Neurosci, LaNCE, Leioa, Vizcaya, Spain.;BioCruces Hlth Res Inst, Nanoneurosurg Grp, Baracaldo 48903, Vizcaya, Spain.;Univ Autonoma Chile, Fac Hlth Sci, Santiago, Chile..
    Nanodelivery of Cerebrolysin and Rearing in Enriched Environment Induce Neuroprotective Effects in a Preclinical Rat Model of Parkinson's Disease2018In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 55, no 1, p. 286-299Article in journal (Refereed)
    Abstract [en]

    Rearing in enriched environment (EE) improves the recuperation in animal models of Parkinson's disease (PD). Administration of TiO2-nanowired cerebrolysin (CBL) could represent an additional strategy to protect or repair the nigrostriatal system. This study aims to explore morphofunctional and biochemical changes in a preclinical stage of PD testing the synergistic efficiency of combining both strategies, housing in EE, and nanodelivery of CBL. Sprague-Dawley male rats receiving intrastriatally 6-hydroxydopamine after a short evolution time were segregated into CBL group (rats receiving nanowired CBL), EE group (rats housed in EE), CBL + EE group (rats housed in EE and receiving nanowired CBL), and control group (rats without additional treatment). Prodromic stage and treatment effects were characterized by the presence of motor symptoms (amphetamine-induced rotational behavior test). Tyrosine hydroxylase (TH) immunohistochemistry and Western blot (p-Akt/Akt and p-ERK/ERK 1/2 as survival markers and caspase-3 as apoptotic marker) were performed in striatum and SN. A decrease in motor symptoms was shown by rats receiving CBL. EE monitoring cages revealed that rats from CBL + EE group showed more significant number of laps in the wheel than EE group. In SN, CBL + EE group also presented the highest neuronal density. Moreover, p-Akt/Akt and p-ERK/ERK 1/2 ratio was significant higher and caspase-3 expression was lower in CBL + EE group. In conclusion, the combination of CBL and EE provided evidence of neuoprotective-neurorestorative mechanisms by which this combined strategy promoted morphofunctional improvement by activation of survival pathways after dopamine depletion in a preclinical model of PD.

  • 48. Ruozi, Barbara
    et al.
    Belletti, Daniela
    Forni, Flavio
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Muresanu, Dafin
    Moessler, Herbert
    Vandelli, Maria A.
    Tosi, Giovanni
    Sharma, Hari S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Poly (D, L-Lactide-co-Glycolide) Nanoparticles Loaded with Cerebrolysin Display Neuroprotective Activity in a Rat Model of Concussive Head Injury2014In: CNS & Neurological Disorders: Drug Targets, ISSN 1871-5273, E-ISSN 1996-3181, Vol. 13, no 8, p. 1475-1482Article in journal (Refereed)
    Abstract [en]

    Cerebrolysin (CBL) is a neuroprotective agent in central nervous system (CNS) injury and stimulates neurorepair processes. Several studies in our laboratory suggest that CBL administered through nanowired technology may have superior neuroprotective efficacy in CNS trauma. In this investigation, we compared the neuroprotective efficacy of poly-lactide-co-glycolide nanoparticles (NPs) loaded with CBL vs free CBL in a rat model of concussive head injury (CHI). Free CBL or CBL loaded NPs was administered 30 min to 1 h after CHI and animals were sacrificed 5 h later. Changes in blood-brain barrier and brain edema formation were measured as parameters of neuroprotection in CHI after giving CBL alone or as the nanodelivered compound. Our results clearly show that delivery of CBL by NPs has superior neuroprotective effects following CHI as compared to normal CBL. This suggests that CBL delivered by NPs could have robust neuroprotective action in CNS trauma. These findings have potential clinical relevance with regard to nanodelivery of CBL, a feature that requires further investigation.

  • 49.
    Ruozi, Barbara
    et al.
    Univ Modena & Reggio Emilia, Dept Life Sci, Lab Pharmaceut Technol, I-41125 Modena, Italy..
    Belletti, Daniela
    Univ Modena & Reggio Emilia, Dept Life Sci, Lab Pharmaceut Technol, I-41125 Modena, Italy..
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Muresanu, Dafin F.
    Univ Med & Pharm, Univ Hosp, Dept Clin Neurosci, Cluj Napoca, Romania..
    Moessler, Herbert
    Ever Neuro Pharma, Oberburgau, Austria..
    Forni, Flavio
    Univ Modena & Reggio Emilia, Dept Life Sci, Lab Pharmaceut Technol, I-41125 Modena, Italy..
    Vandelli, Maria Angela
    Univ Modena & Reggio Emilia, Dept Life Sci, Lab Pharmaceut Technol, I-41125 Modena, Italy..
    Tosi, Giovanni
    Univ Modena & Reggio Emilia, Dept Life Sci, Lab Pharmaceut Technol, I-41125 Modena, Italy..
    PLGA Nanoparticles Loaded Cerebrolysin: Studies on Their Preparation and Investigation of the Effect of Storage and Serum Stability with Reference to Traumatic Brain Injury2015In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 52, no 2, p. 899-912Article in journal (Refereed)
    Abstract [en]

    Cerebrolysin is a peptide mixture able to ameliorate symptomatology and delay progression of neurological disorders such as Alzheimer's disease and dementia. The administration of this drug in humans presents several criticisms due to its short half-life, poor stability, and high doses needed to achieve the effect. This paper investigates the potential of polylactic-co-glycolide (PLGA) nanoparticles (NPs) as sustained release systems for iv administration of cerebrolysin in normal and brain injured rats. NPs were prepared by water-in-oil-in-water (w/o/w) double emulsion technique and characterized by light scattering for mean size and zeta potential and by scanning electron microscopy (SEM) for surface morphology. The NPs produced by double sonication under cooling at 60 W for 45 s, 12 mL of 1 % w:v of PVA, and 1:0.6 w:w drug/PLGA ratio (C-NPs4) displayed an adequate loading of drug (24 +/- 1 mg/100 mg of NPs), zeta potential value (-13 mV), and average diameters (ranged from 250 to 330 nm) suitable to iv administration. SEM images suggested that cerebrolysin was molecularly dispersed into matricial systems and partially adhered to the NP surface. A biphasic release with an initial burst effect followed by sustained release over 24 h was observed. Long-term stability both at room and at low temperature of freeze-dried NPs was investigated. To gain deeper insight into NP stability after in vivo administration, the stability of the best NP formulation was also tested in serum. These PLGA NPs loaded with cerebrolysin were able to reduce brain pathology following traumatic brain injury. However, the size, the polydispersivity, and the surface properties of sample were significantly affected by the incubation time and the serum concentration.

  • 50.
    Semenas, Egidijus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Nozari, A.
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Basu, Samar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Rubertsson, Sten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sex differences in cerebral injury after severe haemorrhage and ventricular fibrillation in pigs2010In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 54, no 3, p. 343-353Article in journal (Refereed)
    Abstract [en]

    Background: Experimental studies of haemorrhagic shock have documented a superior haemodynamic response and a better outcome in female animals as compared with male controls. Such sexual dimorphism has, nevertheless, not been reported after circulatory arrest that follows exsanguination and shock. We aimed to study differences in cerebral injury markers after exsanguination cardiac arrest in pre-pubertal piglets. The hypothesis was that cerebral injury is less extensive in female animals, and that this difference is independent of sexual hormones or choice of resuscitative fluid. Methods: Thirty-two sexually immature piglets (14 males and 18 females) were subjected to 5 min of haemorrhagic shock followed by 2 min of ventricular fibrillation and 8 min of cardiopulmonary resuscitation, using three resuscitation fluid regimens (whole blood, hypertonic saline and dextran, or acetated Ringers' solution plus whole blood and methylene blue). Haemodynamic values, cellular markers of brain injury and brain histology were studied. Results: After successful resuscitation, female piglets had significantly greater cerebral cortical blood flow, tended to have lower S-100beta values and a lower cerebral oxygen extraction ratio. Besides, in female animals, systemic and cerebral venous acidosis were mitigated. Female piglets exhibited a significantly smaller increase in neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS) expression in their cerebral cortex, smaller blood-brain-barrier (BBB) disruption and significantly smaller neuronal injury. Conclusion: After resuscitation from haemorrhagic circulatory arrest, cerebral reperfusion is greater, and BBB permeability and neuronal injury is smaller in female piglets. An increased cerebral cortical iNOS and nNOS expression in males implies a mechanistic relationship with post-resuscitation neuronal injury and warrants further investigation.

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