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  • 1.
    Bryukhovetskiy, Igor
    et al.
    Far Eastern Fed Univ, Vladivostok 690091, Russia;Russian Acad Sci, Far Eastern Branch, Natl Sci Ctr Marine Biol, Vladivostok 690059, Russia.
    Ponomarenko, Arina
    Far Eastern Fed Univ, Vladivostok 690091, Russia;Russian Acad Sci, Far Eastern Branch, Natl Sci Ctr Marine Biol, Vladivostok 690059, Russia.
    Lyakhova, Irina
    Far Eastern Fed Univ, Vladivostok 690091, Russia.
    Zaitsev, Sergey
    Far Eastern Fed Univ, Vladivostok 690091, Russia.
    Zayats, Yulia
    Far Eastern Fed Univ, Vladivostok 690091, Russia.
    Korneyko, Maria
    Far Eastern Fed Univ, Vladivostok 690091, Russia.
    Eliseikina, Marina
    Russian Acad Sci, Far Eastern Branch, Natl Sci Ctr Marine Biol, Vladivostok 690059, Russia.
    Mischenko, Polina
    Far Eastern Fed Univ, Vladivostok 690091, Russia;Russian Acad Sci, Far Eastern Branch, Natl Sci Ctr Marine Biol, Vladivostok 690059, Russia.
    Shevchenko, Valerie
    Far Eastern Fed Univ, Vladivostok 690091, Russia;NN Blokhin Russian Canc Res Ctr, Moscow 115478, Russia.
    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.
    Khotimchenko, Yuri
    Far Eastern Fed Univ, Vladivostok 690091, Russia;Russian Acad Sci, Far Eastern Branch, Natl Sci Ctr Marine Biol, Vladivostok 690059, Russia.
    Personalized regulation of glioblastoma cancer stem cells based on biomedical technologies: From theory to experiment (Review)2018In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 42, no 2, p. 691-702Article, review/survey (Refereed)
    Abstract [en]

    Glioblastoma multiforme (GBM) is one of the most aggressive brain tumors. GBM represents >50% of primary tumors of the nervous system and similar to 20% of intracranial neoplasms. Standard treatment involves surgery, radiation and chemotherapy. However, the prognosis of GBM is usually poor, with a median survival of 15 months. Resistance of GBM to treatment can be explained by the presence of cancer stem cells (CSCs) among the GBM cell population. At present, there are no effective therapeutic strategies for the elimination of CSCs. The present review examined the nature of human GBM therapeutic resistance and attempted to systematize and put forward novel approaches for a personalized therapy of GBM that not only destroys tumor tissue, but also regulates cellular signaling and the morphogenetic properties of CSCs. The CSCs are considered to be an informationally accessible living system, and the CSC proteome should be used as a target for therapy directed at suppressing clonal selection mechanisms and CSC generation, destroying CSC hierarchy, and disrupting the interaction of CSCs with their microenvironment and extracellular matrix. These objectives can be achieved through the use of biomedical cellular products.

  • 2. 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)
  • 3. 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)
  • 4. 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)
  • 5. 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)
  • 6. 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)
  • 7.
    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.

  • 8. 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.

  • 9. Lin, Jiuluan
    et al.
    Zhou, Wenjing
    Zhang, GuangMing
    Zhang, Yuqi
    Sharma, Hari S.
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Zuo, Huancong
    Novel Method to Identify the Precentral Gyrus and Its Detailed Functional Distribution in Real Brain Surfaces Using Reconstructed 3D Brain Surface Imaging2015In: JOURNAL OF MEDICAL IMAGING AND HEALTH INFORMATICS, ISSN 2156-7018, Vol. 5, no 2, p. 216-222Article in journal (Refereed)
    Abstract [en]

    Objective: To study the use of reconstructed 3D brain surface imaging (RBSI) to identify the precentral gyrus and its detailed functional distribution in epileptic patients. Method: A total of 12 refractory epilepsy cases that need intracranial electrode implantation were studied. In these patients, pre-operative magnetic resonance imaging (MRI) and functional MRI (fMRI) were conducted, and a cranial computed tomography (CT) scan was performed after electrode implantation. The RBSI was accomplished using Brain Voyager software based on MRI data, and then the 3D brain surface was integrated with the subdural electrode CT scan. The precentral gyrus was found in the reconstructed brain surface imaging according to their anatomical shape, and then were identified in the surgical field by comparing the exposed gyrus in the RBSI with the help of intraoperative photographs. Results: Total 12 cases of precentral gyrus was found and marked in the RBSI. There were 101 electrodes covering the precentral gyrus and 73 (72%) of them had motor response to electrical stimulation. In the contrast, (the area which is 1 cm ahead of the precentral gyrus), the motor response rate was 13% (17/130) (p < 0.05). During fMRI, 100% of the precentral gyrus and 58% (7/12) of post central gyrus was activated during hand movement. Whereas, no activation of the areas ahead of precentral gyrus was seen showing a significant difference between precentral gyrus and gyrus ahead. Conclusion: Our results demonstrated that using RBSI technique, it is possible to identify the precentral gyrus with precision.

  • 10.
    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)
  • 11.
    Menon, Preeti K.
    et al.
    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, Uppsala, Sweden.
    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, Uppsala, Sweden.
    Lafuente, Jose V.
    Univ Basque Country UPV EHU, Lab Clin & Expt Neurosci LaNCE, Leioa, Vizcaya, Spain;Univ Autonoma Chile, Fac Hlth Sci, Santiago, Chile.
    Muresanu, Dafin F.
    Univ Med & Pharm, Dept Clin Neurosci, Cluj Napoca, Romania;RoNeuro Inst Neurol Res & Diagnost, Cluj Napoca, Romania.
    Aguilar, Zoraida P.
    Ocean NanoTech, Springdale, AR USA.
    Wang, Y. Anderw
    Ocean NanoTech, Springdale, AR USA.
    Patnaik, Ranjana
    Banaras Hindu Univ, Indian Inst Technol, Sch Biomed Engn, Varanasi, Uttar Pradesh, India.
    Moessler, Herbert
    Ever NeuroPharma Oberburgau, 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, Uppsala, Sweden.
    Intravenous Administration of Functionalized Magnetic Iron Oxide Nanoparticles Does Not Induce CNS Injury in the Rat: Influence of Spinal Cord Trauma and Cerebrolysin Treatment2017In: Nanomedicine In Central Nervous System Injury And Repair / [ed] Sharma, HS & Sharma, A, Elsevier, 2017, p. 47-63Chapter in book (Refereed)
    Abstract [en]

    Influence of iron oxide magnetic nanoparticles (IOMNPs, 10nm in diameter, 0.25 or 0.50mg/mL in 100 mu L, i.v.) on the blood-brain barrier (BBB) permeability, edema formation, and neuronal or glial changes within 4-24h after administration was examined in normal rats and after a focal spinal cord injury (SCI). Furthermore, effect of cerebrolysin, a balanced composition of several neurotrophic factors, and active peptide fragments was also evaluated on IOMNP-induced changes in central nervous system (CNS) pathology. The SCI was inflicted in rats by making a longitudinal incision into the right dorsal horn of the T10-11 segments and allowed to survive 4 or 24h after trauma. Cerebrolysin (2.5 mL/kg, i.v.) was given either 30min before IOMNP injection in the 4-h SCI group or 4h after injury in the 24-h survival groups. Control group received cerebrolysin in identical situation following IOMNP administration. In all groups, leakage of serum albumin in the CNS as a marker of BBB breakdown and activation of astrocytes using glial fibrillary acidic protein was evaluated by immunohistochemistry. The neuronal injury was examined by Nissl staining. The IOMNPs alone in either low or high doses did not induce CNS pathology either following 4 or 24h after administration. However, administration of IOMNPs in SCI group slightly enhanced the pathological changes in the CNS after 24h but not 4h after trauma. Cerebrolysin treatment markedly attenuated IOMNP-induced aggravation of SCI-induced cord pathology and induced significant neuroprotection. These observations are the first to show that IOMNPs are safe for the CNS and cerebrolysin treatment prevented CNS pathology following a combination of trauma and IOMNP injection. This indicated that cerebrolysin might be used as adjunct therapy during IOMNP administration in disease conditions, not reported earlier.

  • 12. 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.

  • 13. 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.
    Moessler, H.
    Sharma, H. S.
    Blood-Brain Barrier Breakdown, Edema Formation, Nitric Oxide Synthase Upregulation and Brain Pathology in Diabetic and Hypertensive Rats Following Heat Stroke: Neuroprotective Effects of Titanium Nanowired Cerebrolysin2013In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 22, no 5, p. 910-911Article in journal (Other academic)
  • 14. 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)
  • 15.
    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)
  • 16. 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)
  • 17.
    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)
  • 18.
    Muresanu, D.
    et al.
    Univ Med & Pharm, 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 UPV EHU, Dept Neurosci, LaNCE, Leioa, Spain.
    Tian, Z.
    Univ Arkansas, Dept Chem & Biochem, Fayetteville, AR USA.
    Ozikzilcik, A.
    Univ Arkansas, Dept Biomed Engn, Fayetteville, AR USA.
    Sharma, Hari
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Repeated TiO2-Nanowired Delivery of Cerebrolysin Reduces Pathophysiology of Blast Brain Injury2018In: The journal of head trauma rehabilitation, ISSN 0885-9701, E-ISSN 1550-509X, Vol. 33, no 3, p. E75-E76Article in journal (Other academic)
  • 19.
    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.

  • 20. 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)
  • 21.
    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)
  • 22. 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.

  • 23.
    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.

  • 24.
    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.

  • 25. 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.

  • 26.
    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.

  • 27. 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.

  • 28.
    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.

  • 29.
    Sharma, Aruna
    et al.
    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, Uppsala, Sweden;Uppsala Univ, Univ Hosp, Lab Cerebrovasc Res, Uppsala, Sweden.
    Menon, Preeti K.
    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, Uppsala, Sweden;Uppsala Univ, Univ Hosp, Lab Cerebrovasc Res, Uppsala, Sweden.
    Patnaik, Ranjana
    Banaras Hindu Univ, Indian Inst Technol, Sch Biomed Engn, Varanasi, Uttar Pradesh, India.
    Muresanu, Dafin F.
    Univ Med & Pharm, Dept Clin Neurosci, Cluj Napoca, Romania;RoNeuro Inst Neurol Res & Diagnost, Cluj Napoca, Romania.
    Lafuente, Jose V.
    Univ Basque Country UPV EHU, Lab Clin & Expt Neurosci LaNCE, Leioa, Vizcaya, Spain.
    Tian, Z. Ryan
    Univ Arkansas, Dept Chem & Biochem, Fayetteville, AR 72701 USA.
    Ozkizilcik, Asya
    Univ Arkansas, Dept Biomed Engn, Fayetteville, AR 72701 USA.
    Castellani, Rudy J.
    Univ Maryland, Dept Pathol, Baltimore, MD 21201 USA.
    Moessler, Herbert
    RoNeuro Inst Neurol Res & Diagnost, Cluj Napoca, Romania;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. Uppsala Univ, Univ Hosp, Int Expt CNS Injury & Repair IECNSIR, Uppsala, Sweden;Uppsala Univ, Univ Hosp, Lab Cerebrovasc Res, Uppsala, Sweden.
    Novel Treatment Strategies Using TiO2-Nanowired Delivery of Histaminergic Drugs and Antibodies to Tau With Cerebrolysin for Superior Neuroprotection in the Pathophysiology of Alzheimer's Disease2017In: Nanomedicine In Central Nervous System Injury And Repair / [ed] Sharma, HS & Sharma, A, Elsevier, 2017, p. 123-165Chapter in book (Refereed)
    Abstract [en]

    More than 5.5 million Americans of all ages are suffering from Alzheimer's disease (AD) till today for which no suitable therapy has been developed so far. Thus, there is an urgent need to explore novel therapeutic measures to contain brain pathology in AD. The hallmark of AD includes amyloid-beta peptide (A beta P) deposition and phosphorylation of tau in AD brain. Recent evidences also suggest a marked decrease in neurotrophic factors in AD. Thus, exogenous supplement of neurotrophic factors could be one of the possible ways for AD therapy. Human postmortem brain in AD shows alterations in histamine receptors as well, indicating an involvement of the amine in AD-induced brain pathology. In this review, we focused on role of histamine 3 and 4 receptor-modulating drugs in the pathophysiology of AD. Moreover, antibodies to histamine and tau appear to be also beneficial in reducing brain pathology, blood-brain barrier breakdown, and edema formation in AD. Interestingly, TiO2-nanowired delivery of cerebrolysin-a balanced composition of several neurotrophic factors attenuated A beta P deposition and reduced tau phosphorylation in AD brain leading to neuroprotection. Coadministration of cerebrolysin with histamine antibodies or tau antibodies has further enhanced neuroprotection in AD. These novel observations strongly suggest a role of nanomedicine in AD that requires further investigation.

  • 30.
    Sharma, Aruna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Menon, Preeti
    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, Dept Clin Neurosci, Cluj Napoca, Romania.;RoNeuro Inst Neurol Res & Diagnost, 37 Mircea Eliade St, Cluj Napoca 400364, Romania..
    Ozkizilcik, Asya
    Univ Arkansas, Dept Biomed Engn, Fayetteville, AR 72701 USA..
    Tian, Z. Ryan
    Univ Arkansas, Chem & Biochem, Fayetteville, AR 72701 USA..
    Lafuente, Jose V.
    Univ Basque Country, UPV EHU, Dept Neurosci, Lab Clin & Expt Neurosci LaNCE, Leioa, Bizkaia, Spain.;Univ Autonoma Chile, Fac Hlth Sci, Santiago, Chile..
    Sharma, Hari S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Nanowired Drug Delivery Across the Blood-Brain Barrier in Central Nervous System Injury and Repair2016In: CNS & Neurological Disorders: Drug Targets, ISSN 1871-5273, E-ISSN 1996-3181, Vol. 15, no 9, p. 1092-1117Article, review/survey (Refereed)
    Abstract [en]

    The blood-brain barrier (BBB) is a physiological regulator of transport of essential items from blood to brain for the maintenance of homeostasis of the central nervous system (CNS) within narrow limits. The BBB is also responsible for export of harmful or metabolic products from brain to blood to keep the CNS fluid microenvironment healthy. However, noxious insults to the brain caused by trauma, ischemia or environmental/chemical toxins alter the BBB function to small as well as large molecules e.g., proteins. When proteins enter the CNS fluid microenvironment, development of brain edema occurs due to altered osmotic balance between blood and brain. On the other hand, almost all neurodegenerative diseases and traumatic insults to the CNS and subsequent BBB dysfunction lead to edema formation and cell injury. To treat these brain disorders suitable drug therapy reaching their brain targets is needed. However, due to edema formation or only a focal disruption of the BBB e.g., around brain tumors, many drugs are unable to reach their CNS targets in sufficient quantity. This results in poor therapeutic outcome. Thus, new technology such as nanodelivery is needed for drugs to reach their CNS targets and be effective. In this review, use of nanowires as a possible novel tool to enhance drug delivery into the CNS in various disease models is discussed based on our investigations. These data show that nanowired delivery of drugs may have superior neuroprotective ability to treat several CNS diseases effectively indicating their role in future therapeutic strategies.

  • 31.
    Sharma, Aruna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Muresanu, D. F.
    Patnaik, R.
    Huang, H.
    Tian, Z. R.
    Moeessler, H.
    Sharma, H. S.
    Superior Neuroprotective Efficacy of Nanodrug Delivery of Cerebrolysin Compared to Other Neurotrophic Factors in Concussive Head Injury2014In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 23, no 6, p. 782-782Article in journal (Other academic)
  • 32.
    Sharma, Aruna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Muresanu, D. F.
    Patnaik, R.
    Lafuente, J. V.
    Sharma, Hari Shanker
    Engineered nanoparticles Ag, Cu and Al (50-60nm) induce oxidative stress, neuronal nitric oxide synthase upregulation and brain pathology. Neuroprotection by Insulin-like growth factor12012In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 19, no S1, p. 441-441Article in journal (Other academic)
  • 33.
    Sharma, Aruna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Muresanu, D. F.
    Patnaik, R.
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Age- and size-dependent neurotoxicity of engineered nanoparticles from metals2012In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 19, no S1, p. 440-440Article in journal (Other academic)
  • 34.
    Sharma, Aruna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Muresanu, D. F.
    Patnaik, R.
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Blood-Brain Barrier Breakdown and Brain Dysfunction Following Sleep Deprivation Are Exacerbated by Size-Related Nanoparticles2013In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 22, no 5, p. 915-915Article in journal (Other academic)
  • 35.
    Sharma, Aruna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Muresanu, D. F.
    Univ Med & Pharm, Clin Neurosci.;RoNeuro Inst Neurol Res & Diagnost, Neurol..
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Co-administration of nanowired mesenchymal stem cells and cerebrolysin potentiates neuroprotection in Parkinsons disease following mild traumatic brain injury2017In: Journal of Cerebral Blood Flow and Metabolism, ISSN 0271-678X, E-ISSN 1559-7016, Vol. 37, p. 19-19Article in journal (Other academic)
  • 36.
    Sharma, Aruna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Muresanu, D.
    Univ Med & Pharm, Clin Neurosci, Cluj Napoca, Romania..
    Lafuente, J.
    Univ Basque Country, Neurosci, Bilbao, Spain..
    Patnaik, R.
    Banaras Hindu Univ IIT, Biomed Engn, Varanasi, Uttar Pradesh, India..
    Moessler, H.
    Ever Neuro Pharma, Drug Dev & Discovery, Oberburgau, Austria..
    Tian, Z.
    Univ Arkansas Faytteville, Chem & Biochem, Faytteville, AK USA..
    Ozkizilcik, A.
    Univ Arkansas Faytteville, Chem & Biochem, Faytteville, AK USA..
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Intoxication of engineered nanoparticles in cold environment exacerbates ischemia and brain pathology following trauma2016In: Journal of Cerebral Blood Flow and Metabolism, ISSN 0271-678X, E-ISSN 1559-7016, Vol. 36, no Suppl. 1, p. 266-266, article id 400Article in journal (Other academic)
  • 37.
    Sharma, Aruna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Muresanu, D.
    Univ Med & Pharm, Dept Clin Neurosci, Cluj Napoca, Romania.
    Lafuente, J.
    Univ Basque Country UPV EHU, Dept Neurosci, LaNCE, Leioa, Spain.
    Tian, Z.
    Univ Arkansas, Dept Chem & Biochem, Fayetteville, AR USA.
    Ozikzilcik, A.
    Univ Arkansas, Dept Biomed Engn, Fayetteville, AR USA.
    Sharma, Hari
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Nanodelivery of Cerebrolysin With 5-HT6 Receptor Antagonist Induces Superior Neuroprotective Effects Following Concussive Head Injury Induced Exacerbation of Brain Pathology in Sleep Deprivation2018In: The journal of head trauma rehabilitation, ISSN 0885-9701, E-ISSN 1550-509X, Vol. 33, no 3, p. E76-E76Article in journal (Other academic)
  • 38.
    Sharma, Aruna
    et al.
    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..
    Lafuente, Jose V.
    Univ Basque Country, Dept Neurosci, Bilbao, Spain..
    Patnaik, Ranjana
    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 221005, Uttar Pradesh, India..
    Tian, Z. Ryan
    Univ Arkansas, Dept Chem & Biochem, Fayetteville, AR 72701 USA..
    Buzoianu, Anca D.
    Univ Med & Pharm, Fac Med, Dept Pharmacol, 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.
    Sleep Deprivation-Induced Blood-Brain Barrier Breakdown and Brain Dysfunction are Exacerbated by Size-Related Exposure to Ag and Cu Nanoparticles. Neuroprotective Effects of a 5-HT3 Receptor Antagonist Ondansetron2015In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 52, no 2, p. 867-881Article in journal (Refereed)
    Abstract [en]

    Military personnel are often subjected to sleep deprivation (SD) during combat operations. Since SD is a severe stress and alters neurochemical metabolism in the brain, a possibility exists that acute or long-term SD will influence blood-brain barrier (BBB) function and brain pathology. This hypothesis was examined in young adult rats (age 12 to 14 weeks) using an inverted flowerpot model. Rats were placed over an inverted flowerpot platform (6.5 cm diameter) in a water pool where the water levels are just 3 cm below the surface. In this model, animals can go to sleep for brief periods but cannot achieve deep sleep as they would fall into water and thus experience sleep interruption. These animals showed leakage of Evans blue in the cerebellum, hippocampus, caudate nucleus, parietal, temporal, occipital, cingulate cerebral cortices, and brain stem. The ventricular walls of the lateral and fourth ventricles were also stained blue, indicating disruption of the BBB and the blood-cerebrospinal fluid barrier (BCSFB). Breakdown of the BBB or the BCSFB fluid barrier was progressive in nature from 12 to 48 h but no apparent differences in BBB leakage were seen between 48 and 72 h of SD. Interestingly, rats treated with metal nanoparticles, e.g., Cu or Ag, showed profound exacerbation of BBB disruption by 1.5- to 4-fold, depending on the duration of SD. Measurement of plasma and brain serotonin showed a close correlation between BBB disruption and the amine level. Repeated treatment with the serotonin 5-HT3 receptor antagonist ondansetron (1 mg/kg, s.c.) 4 and 8 h after SD markedly reduced BBB disruption and brain pathology after 12 to 24 h SD but not following 48 or 72 h after SD. However, TiO2-nanowired ondansetron (1 mg/kg, s.c) in an identical manner induced neuroprotection in rats following 48 or 72 h SD. However, plasma and serotonin levels were not affected by ondansetron treatment. Taken together, our observations are the first to show that (i) SD could induce BBB disruption and brain pathology, (ii) nanoparticles exacerbate SD-induced brain damage, and (iii) serotonin 5-HT3 receptor antagonist ondansetron is neuroprotective in SD that is further potentiated byTiO2-nanowired delivery, not reported earlier.

  • 39.
    Sharma, Aruna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Muresanu, Dafin F.
    Patnaik, Ranjana
    Sharma, Hari S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Size- and Age-Dependent Neurotoxicity of Engineered Metal Nanoparticles in Rats2013In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 48, no 2, p. 386-396Article in journal (Refereed)
    Abstract [en]

    Earlier we showed that chronic administration of engineered nanoparticles (NPs) from metals, e.g., Cu, Ag, or Al (50-60 nm, 50 mg/kg, i.p. daily for 1 week) alter blood-brain barrier (BBB) disruption and induce brain pathology in adult rats (age 18 to 22 weeks). However, effects of size-dependent neurotoxicity of NPs in vivo are still largely unknown. In present investigation, we examined the effects of different size ranges of the above-engineered NPs on brain pathology in rats. Furthermore, the fact that age is also an important factor in brain pathology was also investigated in our rat model. Our results showed that small-sized NPs induced the most pronounced BBB breakdown (EBA +480 to 680 %; radioiodine +850 to 1025 %), brain edema formation (+4 to 6 %) and neuronal injuries (+30 to 40 %), glial fibrillary acidic protein upregulation (+40 to 56 % increase), and myelin vesiculation (+30 to 35 % damage) in young animals as compared to controls. Interestingly, the oldest animals (30 to 35 weeks of age) also showed massive brain pathology as compared to young adults (18 to 20 weeks old). The Ag and Cu exhibited greater brain damage compared with Al NPs in all age groups regardless of their size. This suggests that apart from the size, the composition of NPs is also important in neurotoxicity. The very young and elderly age groups exhibited greater neurotoxicity to NPs suggests that children and elderly are more vulnerable to NPs-induced brain damage. The NPs-induced brain damage correlated well with the upregulation of neuronal nitric oxide synthase activity in the brain indicating that NPs-induced neurotoxicity may be mediated via increased production of nitric oxide, not reported earlier.

  • 40.
    Sharma, Aruna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala Univ, Int Expt CNS Injury & Repair, Univ Hosp, Frodingsgatan 12,Bldg 28, SE-75421 Uppsala, Sweden.;Univ Basque Country UPV EHU, Dept Neurosci, LaNCE, Leioa, Bizkaia, Spain..
    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..
    Sjöquist, Per-Ove
    Karolinska Univ Hosp, Karolinska Inst, Div Cardiol, Dept Med, Stockholm, Sweden..
    Patnaik, Ranjana
    Banaras Hindu Univ, Sch Biomed Engn, Dept Biomat, Indian Inst Technol, Varanasi, Uttar Pradesh, India..
    Tian, Z. Ryan
    Univ Arkansas, Dept Chem & Biochem, Fayetteville, AR 72701 USA..
    Ozkizilcik, Asya
    Univ Arkansas, Dept Biomed Engn, Fayetteville, AR 72701 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, Int Expt CNS Injury & Repair, Univ Hosp, Frodingsgatan 12,Bldg 28, SE-75421 Uppsala, Sweden.;Univ Basque Country UPV EHU, Dept Neurosci, LaNCE, Leioa, Bizkaia, Spain..
    Cold Environment Exacerbates Brain Pathology and Oxidative Stress Following Traumatic Brain Injuries: Potential Therapeutic Effects of Nanowired Antioxidant Compound H-290/512018In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 55, no 1, p. 276-285Article in journal (Refereed)
    Abstract [en]

    The possibility that traumatic brain injury (TBI) occurring in a cold environment exacerbates brain pathology and oxidative stress was examined in our rat model. TBI was inflicted by making a longitudinal incision into the right parietal cerebral cortex (2 mm deep and 4 mm long) in cold-acclimatized rats (5 degrees C for 3 h daily for 5 weeks) or animals at room temperature under Equithesin anesthesia. TBI in cold-exposed rats exhibited pronounced increase in brain lucigenin (LCG), luminol (LUM), and malondialdehyde (MDA) and marked pronounced decrease in glutathione (GTH) as compared to identical TBI at room temperature. The magnitude and intensity of BBB breakdown to radioiodine and Evans blue albumin, edema formation, and neuronal injuries were also exacerbated in cold-exposed rats after injury as compared to room temperature. Nanowired delivery of H-290/51 (50 mg/kg) 6 and 8 h after injury in cold-exposed group significantly thwarted brain pathology and oxidative stress whereas normal delivery of H-290/51 was neuroprotective after TBI at room temperature only. These observations are the first to demonstrate that (i) cold aggravates the pathophysiology of TBI possibly due to an enhanced production of oxidative stress, (ii) and in such conditions, nanodelivery of antioxidant compound has superior neuroprotective effects, not reported earlier.

  • 41.
    Sharma, Aruna
    et al.
    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.
    Superior Neuroprotective Effects of Cerebrolysin in Nanoparticle-Induced Exacerbation of Hyperthermia-Induced Brain Pathology2012In: CNS & Neurological Disorders - Drug Targets, ISSN 1871-5273, Vol. 11, no 1, p. 7-25Article, review/survey (Refereed)
    Abstract [en]

    In recent years, the incidence of heat stroke and associated brain pathology are increasing Worldwide. More than half of the world's population are living in areas associated with high environmental heat especially during the summer seasons. Thus, new research is needed using novel drug targets to achieve neuroprotection in heat-induced brain pathology. Previous research from our laboratory showed that the pathophysiology of brain injuries following heat stroke are exacerbated by chronic intoxication of engineered nanoparticles of small sizes (50-60 nm) following identical heat exposure in rats. Interestingly, in nanoparticle-intoxicated animals the known neuroprotective agents in standard doses failed to induce effective neuroprotection. This suggests that the dose-response of the drugs either requires modification or new therapeutic agents are needed to provide better neuroprotection in nanoparticle-intoxicated animals after heat stroke. This review is focused on the use of cerebrolysin, a mixture of several neurotrophic factors and active peptide fragments, in relation to other neuroprotective agents normally used to treat ischemic stroke in clinics in nanoparticle-induced exacerbation of brain damage in heat stroke. It appears that cerebrolysin exerts the most superior neuroprotective effects in heat stress as compared to other neuroprotective agents on brain pathology in normal rats. Interestingly, to induce effective neuroprotection in nanoparticle-induced exacerbation of brain pathology a double dose of cerebrolysin is needed. On the other hand, double doses of the other drugs were quite ineffective in reducing brain damage. These observations suggest that the drug type and doses are important factors in attenuating nanoparticle-induced exacerbation of brain pathology in heat stroke. The functional significance and possible mechanisms of drug-induced neuroprotection in nanoparticle-treated, heat-stressed rats are discussed.

  • 42.
    Sharma, Aruna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Muresanu, Dafin Fior
    Patnaik, Ranjana
    Prasad, Vannemreaddy
    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.
    Anaesthetics influence closed head injury induced blood-brain barrier disruption, cerebral blood flow, brain oedema and brain pathology2014In: Brain Injury, ISSN 0269-9052, E-ISSN 1362-301X, Vol. 28, no 5-6, p. 522-523Article in journal (Other academic)
  • 43.
    Sharma, Aruna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Muresanu, Dafin Fior
    Univ Med & Pharm, Cluj-Napoca, Romania.
    Vicente Lafuente, Jose
    Univ Basque Country, Bilbao, Spain.
    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, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Spinal Cord Injury at Hot Environment Exacerbates Blood-spinal Cord Barrier Disruption, Edema Formation and Cellular Damages. Effective Treatment With a Multimodal Drug Cerebrolsyi2017In: The journal of head trauma rehabilitation, ISSN 0885-9701, E-ISSN 1550-509X, Vol. 32, no 6, p. E68-E68Article in journal (Other academic)
    Abstract [en]

    Introduction/Rational: Traumatic injuries to the central nervous system (CNS) occurring at cold or hot environments may affect the pathological outcome. In addition, this is not known whether injuries at these ambient temperatures may also affect the therapeutic potential of the drug treatments. Military personnel engaged in combat operations are often exposed to high environmental heat and thus under such situations if they are inflicted with trauma to the CNS their pathological outcome and drug therapy requires further investigation. In this investigation pathology and pharmacology of a focal spinal cord injury (SCI) at high environment was examined in a model experiment.

    Method/Approach: SCI was produced in Equithesin anesthetized rats either at room temperature (21 ± 1°C) or animals exposed to 38°C 1 h daily for 1 week by making a longitudinal incision (4 mm long and 2 mm deep) of the right dorsal horn of the T10-11 segments. In separate groups, Cerebrolsyin (2.5 ml or 5 ml/kg; Ever NeuroPharma, Austria) either as such or with TiO2 nanowired formulations was delivered intravenously 4 and 8 after SCI. After 48 h SCI blood-spinal cord barrier (BSCB), edema and neuronal injuries were examined. Uninjured animals at room or hot temperatures served as controls.

    Results/Effects: A focal SCI inflicted at hot environment resulted in marked exacerbation of BSCB breakdown to Evans blue albumin, edema formation and neuronal injuries as compared to identical SCI at room temperature. Treatment with 2.5 ml/kg cerebrolysin resulted in good neuroprotection in SCI at room temperature. However, either TiO2 nanowired cerebrolysin (2.5 ml) or higher dose of the drug (5 ml/kg) is needed to induce significant neuroprotection in SCI at inflicted at hot environment. TiO2 nanowires alone or TiO2 nanowired cerebrolysin did not influence cord pathology in normal animals at room temperature or at hot environment.

    Conclusions/Limitations: These observations are the first to demonstrate that SCI occurring at hot environments exacerbate pathological outcome. Furthermore injuries inflicted at hot temperatures require either higher doses of the therapeutic agents or their delivery through nanotechnologies to induce good neuroprotection, not reported earlier. It would be interesting to find out whether TiO2 nanowired cerebrolysin if given 12 to 24 hours after SCI could also reduce the pathological outcome at 48 hours or longer durations.

  • 44.
    Sharma, Aruna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Muresanu, Dafin
    Univ Med & Pharm, Cluj Napoca, Romania..
    Lafuente, Jose V.
    Univ Basque Country, Bilbao, Spain..
    Patnaik, Ranjana
    BHU, Indian Inst Technol, Varanasi, Uttar Pradesh, India..
    Tian, Z. Ryan
    Univ Arkansas, Faytteville, AR USA..
    Moessler, Herbert
    Ever NeuroPharma, Oberburgau, Austria..
    Sharma, Hari S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Univ Uppsala Hosp, Uppsala, Sweden..
    Cold environment exacerbates brain pathology and oxidative stress following traumatic brain injuries. Potential therapeutic effects of nanowired cerebrolysin2016In: Brain Injury, ISSN 0269-9052, E-ISSN 1362-301X, Vol. 30, no 5-6, p. 506-506Article in journal (Other academic)
  • 45.
    Sharma, Aruna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Muresanu, Dafin
    Moessler, Herbert
    Lafuente, Jose Vicente
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sleep Deprivation Exacerbates Pathophysiology of Concussive Head Injury: Neuroprotective Effects of a Multimodal Drug Cerebrolysin2015In: The journal of head trauma rehabilitation, ISSN 0885-9701, E-ISSN 1550-509X, Vol. 30, no 3, p. E80-E80Article in journal (Other academic)
  • 46.
    Sharma, Aruna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Muresanu, Dafin
    Univ Med & Pharm, Cluj Napoca, Romania..
    Nozari, Ala
    Harvard Univ, Harvard Med Sch, Boston, MA 02115 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, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Concussive head injury exacerbates sleep deprivation-induced brain pathology. Co-administration of nanowired antioxidant H-290/51 and serotonin 5-HT6 receptor antagonist SB-3998852017In: Brain Injury, ISSN 0269-9052, E-ISSN 1362-301X, Vol. 31, no 6-7, p. 817-817Article in journal (Other academic)
  • 47.
    Sharma, Aruna
    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.
    Chapter 2: Monoclonal antibodies as novel neurotherapeutic agents in CNS injury and repair2012In: New Perspectives of Central Nervous System Injury and Neuroprotection / [ed] Sharma, HS, Elsevier, 2012, p. 23-45Chapter in book (Refereed)
    Abstract [en]

    Central nervous system (CNS) injury is a complex in which numerous neurochemicals and other vasoactive agents actively contribute towards the development of posttraumatic brain pathology and/or repair mechanisms. A focal trauma to the brain or spinal cord releases several endogenous neurodestructive agents within the CNS, resulting in adverse cellular reactions. Our laboratory is engaged in identifying these endogenous neurodestructive signals in the CNS following injury caused by trauma or hyperthermia. Our observations show that serotonin (5-HT), dynorphin A (Dyn A 1-17), nitric oxide synthase (NOS), and tumor necrosis factor-α (TNF-α) could be potential neurodestructive signals in the CNS injury. Thus, neutralization of these agents using monoclonal antibodies directed against 5-HT, NOS, Dyn A (1-17), and TNF-α in vivo will result in marked neuroprotection and enhance neurorepair after trauma. In addition, a suitable combination of monoclonal antibodies, for example, NOS and TNF-α, when applied 60-90 min after trauma, is capable to enhance neuroprotective ability and thwart cell and tissue injury after spinal cord insult. Taken together, our novel observations suggest a potential use of monoclonal antibodies as suitable therapeutic agents in CNS injuries to achieve neuroprotection and/or neurorepair.

  • 48.
    Sharma, H.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Muresanu, D.
    Univ Med & Pharm, Bucharest, Romania.
    Lafuente, J.
    Univ Basque Country, Leioa, Spain.
    Nozari, A.
    Harvard Univ, Cambridge, MA USA.
    Ozkizilcik, A.
    Univ Arkansas, Fayetteville, AR USA.
    Tian, R.
    Univ Arkansas, Fayetteville, AR USA.
    Sharma, A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Pathophysiology of Concussive Head Injury is Exacerbated High Altitude. Neuroprotective Effects of TiO2 Nanodelivery of Cerebrolysin2018In: The journal of head trauma rehabilitation, ISSN 0885-9701, E-ISSN 1550-509X, Vol. 33, no 3, p. E72-E72Article in journal (Other academic)
  • 49.
    Sharma, H.
    et al.
    Uppsala Univ Hsopital, Surg Sci Anesthesiol Intens Care Med, Uppsala, Sweden..
    Nozari, A.
    Massachusetts Gen Hosp, Anesthesiol & Intens Care Med, Boston, MA 02114 USA..
    Muresanu, D.
    Univ Med & Pharm, Clin Neurosci, Cluj Napoca, Romania..
    Moessler, H.
    Ever Neuro Pharma, Drug Dev & Discovery, Oberburgau, Austria..
    Lafuente, J.
    Univ Basque Country, Neurosci, Bilbao, Spain..
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    NANOPARTICLES FROM METALS EXACERBATE CARDIAC ARREST INDUCED BRAIN PATHOLOGY. NEUROPROTECTIVE EFFECTS OF CEREBROLYSIN2016In: Journal of Cerebral Blood Flow and Metabolism, ISSN 0271-678X, E-ISSN 1559-7016, Vol. 36, no Suppl. 1, p. 332-333, article id 476Article in journal (Other academic)
  • 50.
    Sharma, Hari
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Muresanu, Dafin
    Univ Med & Pharm, Cluj Napoca, Romania..
    Lafuente, Jose
    Univ Basque Country, Bilbao, Spain..
    Patnaik, Ranjana
    BHU, Indian Inst Technol, Varanasi, Uttar Pradesh, India..
    Moessler, Herbert
    Ever Neuropharma, Oberburgau, Austria..
    Tian, Z. Ryan
    Univ Arkansas, 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.
    Nanodrug delivery of a multimodal novel drug cerebrolysin reduces engineered nanoparticles induced aggravation of heat stroke induced ubiquitin expression and brain pathology2016In: Brain Injury, ISSN 0269-9052, E-ISSN 1362-301X, Vol. 30, no 5-6, p. 505-506Article in journal (Other academic)
123 1 - 50 of 109
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