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Publications (10 of 148) Show all publications
Sharma, H. S., Feng, L., Chen, L., Huang, H., Tian, Z. R., Nozari, A., . . . Sharma, A. (2023). Cerebrolysin Attenuates Exacerbation of Neuropathic Pain, Blood-spinal Cord Barrier Breakdown and Cord Pathology Following Chronic Intoxication of Engineered Ag, Cu or Al (50-60 nm) Nanoparticles. Neurochemical Research, 48, 1864-1888
Open this publication in new window or tab >>Cerebrolysin Attenuates Exacerbation of Neuropathic Pain, Blood-spinal Cord Barrier Breakdown and Cord Pathology Following Chronic Intoxication of Engineered Ag, Cu or Al (50-60 nm) Nanoparticles
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2023 (English)In: Neurochemical Research, ISSN 0364-3190, E-ISSN 1573-6903, Vol. 48, p. 1864-1888Article in journal (Refereed) Published
Abstract [en]

Neuropathic pain is associated with abnormal sensations and/or pain induced by non-painful stimuli, i.e., allodynia causing burning or cold sensation, pinching of pins and needles like feeling, numbness, aching or itching. However, no suitable therapy exists to treat these pain syndromes. Our laboratory explored novel potential therapeutic strategies using a suitable composition of neurotrophic factors and active peptide fragments-Cerebrolysin (Ever Neuro Pharma, Austria) in alleviating neuropathic pain induced spinal cord pathology in a rat model. Neuropathic pain was produced by constrictions of L-5 spinal sensory nerves for 2-10 weeks period. In one group of rats cerebrolysin (2.5 or 5 ml/kg, i.v.) was administered once daily after 2 weeks until sacrifice (4, 8 and 10 weeks). Ag, Cu and Al NPs (50 mg/kg, i.p.) were delivered once daily for 1 week. Pain assessment using mechanical (Von Frey) or thermal (Hot-Plate) nociceptive showed hyperalgesia from 2 weeks until 10 weeks progressively that was exacerbated following Ag, Cu and Al NPs intoxication in nerve lesioned groups. Leakage of Evans blue and radioiodine across the blood-spinal cord barrier (BSCB) is seen from 4 to 10 weeks in the rostral and caudal cord segments associated with edema formation and cell injury. Immunohistochemistry of albumin and GFAP exhibited a close parallelism with BSCB leakage that was aggravated by NPs following nerve lesion. Light microscopy using Nissl stain exhibited profound neuronal damages in the cord. Transmission electron microcopy (TEM) show myelin vesiculation and synaptic damages in the cord that were exacerbated following NPs intoxication. Using ELISA spinal tissue exhibited increased albumin, glial fibrillary acidic protein (GFAP), myelin basic protein (MBP) and heat shock protein (HSP 72kD) upregulation together with cytokines TNF-alpha, IL-4, IL-6, IL-10 levels in nerve lesion that was exacerbated following NPs intoxication. Cerebrolysin treatment significantly reduced hyperalgesia and attenuated BSCB disruption, edema formation and cellular changes in nerve lesioned group. The levels of cytokines were also restored near normal levels with cerebrolysin treatment. Albumin, GFAP, MABP and HSP were also reduced in cerebrolysin treated group and thwarted neuronal damages, myelin vesiculation and cell injuries. These neuroprotective effects of cerebrolysin with higher doses were also effective in nerve lesioned rats with NPs intoxication. These observations suggest that cerebrolysin actively protects spinal cord pathology and hyperalgesia following nerve lesion and its exacerbation with metal NPs, not reported earlier.

Place, publisher, year, edition, pages
Springer Nature, 2023
Keywords
Neuropathic pain, Engineered Nanoparticles, Blood-spinal cord barrier, Neuronal injury, Cerebrolysin, Neuroprotection
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:uu:diva-501746 (URN)10.1007/s11064-023-03861-8 (DOI)000922448200001 ()36719560 (PubMedID)
Funder
Uppsala University
Available from: 2023-05-22 Created: 2023-05-22 Last updated: 2023-05-22Bibliographically approved
Niu, F., Sharma, A., Wang, Z., Feng, L., Muresanu, D. F., Sahib, S., . . . Sharma, H. S. (2022). Nanodelivery of oxiracetam enhances memory, functional recovery and induces neuroprotection following concussive head injury. In: Hari Shanker Sharma & Aruna Sharma (Ed.), Nanomedicine and Neuroprotection in Brain Diseases: (pp. 139-230). Amsterdam: Elsevier
Open this publication in new window or tab >>Nanodelivery of oxiracetam enhances memory, functional recovery and induces neuroprotection following concussive head injury
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2022 (English)In: Nanomedicine and Neuroprotection in Brain Diseases / [ed] Hari Shanker Sharma & Aruna Sharma, Amsterdam: Elsevier, 2022, p. 139-230Chapter in book (Other academic)
Abstract [en]

Military personnel are the most susceptible to concussive head injury (CHI) caused by explosion, blast or missile or blunt head trauma. Mild to moderate CHI could induce lifetime functional and cognitive disturbances causing significant decrease in quality of life. Severe CHI leads to instant death and lifetime paralysis. Thus, further exploration of novel therapeutic agents or new features of known pharmacological agents are needed to enhance quality of life of CHI victims.

Previous reports from our laboratory showed that mild CHI induced by weight drop technique causing an impact of 0.224N results in profound progressive functional deficit, memory impairment and brain pathology from 5h after trauma that continued over several weeks of injury.

In this investigation we report that TiO2 nanowired delivery of oxiracetam (50 mg/kg, i.p.) daily for 5 days after CHI resulted in significant improvement of functional deficit on the 8th day. This was observed using Rota Rod treadmill, memory improvement assessed by the time spent in finding hidden platform under water. The motor function improvement is seen in oxiracetam treated CHI group by placing forepaw on an inclined mesh walking and foot print analysis for stride length and distance between hind feet. TiO2-nanowired oxiracetam also induced marked improvements in the cerebral blood flow, reduction in the BBB breakdown and edema formation as well as neuroprotection of neuronal, glial and myelin damages caused by CHI at light and electron microscopy on the 7th day after 5 days TiO2 oxiracetam treatment. Adverse biochemical events such as upregulation of CSF nitrite and nitrate, IL-6, TNF-a and p-Tau are also reduced significantly in oxiracetam treated CHI group. On the other hand post treatment of 100mg/kg dose of normal oxiracetam in identical conditions after CHI is needed to show slight but significant neuroprotection together with mild recovery of memory function and functional deficits on the 8th day. These observations are the first to point out that nanowired delivery of oxiracetam has superior neuroprotective ability in CHI. These results indicate a promising clinical future of TiO2 oxiracetam in treating CHI patients for better quality of life and neurorehabilitation, not reported earlier.

Place, publisher, year, edition, pages
Amsterdam: Elsevier, 2022
Series
Progress in Brain Research, ISSN 0079-6123 ; 265
Keywords
Concussive head injury, Oxiracetam, TiO2 nanowired delivery, Blood-brain barrier, Brain edema, Brain pathology, Neuroprotection, Functional deficit
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-468826 (URN)10.1016/bs.pbr.2021.06.004 (DOI)000750009700005 ()34560921 (PubMedID)978-0-323-90162-8 (ISBN)
Funder
NIH (National Institute of Health), R01 AG02867AstraZeneca
Available from: 2022-03-02 Created: 2022-03-02 Last updated: 2022-10-31Bibliographically approved
Sharma, H. S., Muresanu, D. F., Castellani, R. J., Nozari, A., Vicente Lafuente, J., Buzoianu, A. D., . . . Sharma, A. (2021). Alzheimer's disease neuropathology is exacerbated following traumatic brain injury: Neuroprotection by co-administration of nanowired mesenchymal stem cells and cerebrolysin with monoclonal antibodies to amyloid beta peptide. In: Sharma, HS; Sharma, A (Ed.), Nanomedicine and neuroprotection in brain diseases: (pp. 1-97). Elsevier BV
Open this publication in new window or tab >>Alzheimer's disease neuropathology is exacerbated following traumatic brain injury: Neuroprotection by co-administration of nanowired mesenchymal stem cells and cerebrolysin with monoclonal antibodies to amyloid beta peptide
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2021 (English)In: Nanomedicine and neuroprotection in brain diseases / [ed] Sharma, HS; Sharma, A, Elsevier BV , 2021, p. 1-97Chapter in book (Refereed)
Abstract [en]

Military personnel are prone to traumatic brain injury (TBI) that is one of the risk factors in developing Alzheimer's disease (AD) at a later stage. TBI induces breakdown of the bloodbrain barrier (BBB) to serum proteins into the brain and leads to extravasation of plasma amyloid beta peptide (A beta P) into the brain fluid compartments causing AD brain pathology. Thus, there is a need to expand our knowledge on the role of TBI in AD. In addition, exploration of the novel roles of nanomedicine in AD and TBI for neuroprotection is the need of the hour. Since stem cells and neurotrophic factors play important roles in TBI and in AD, it is likely that nanodelivery of these agents exert superior neuroprotection in TBI induced exacerbation of AD brain pathology. In this review, these aspects are examined in details based on our own investigations in the light of current scientific literature in the field. Our observations show that TBI exacerbates AD brain pathology and TiO2 nanowired delivery of mesenchymal stem cells together with cerebrolysin-a balanced composition of several neurotrophic factors and active peptide fragments, and monoclonal antibodies to amyloid beta protein thwarted the development of neuropathology following TBI in AD, not reported earlier.

Place, publisher, year, edition, pages
Elsevier BV, 2021
Series
Progress in Brain Research, ISSN 0079-6123 ; 265
Keywords
Alzheimer's disease, Traumatic brain injury, Brain pathology, Mesenchymal stem cells, Cerebrolysin, Nanowired delivery, Nanomedicine
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-468962 (URN)10.1016/bs.pbr.2021.04.008 (DOI)000750009700002 ()34560919 (PubMedID)978-0-323-90162-8 (ISBN)
Available from: 2022-03-04 Created: 2022-03-04 Last updated: 2022-03-04Bibliographically approved
Sharma, H. S., Muresanu, D. F., Sahib, S., Tian, Z. R., Vicente Lafuente, J., Buzoianu, A. D., . . . Sharma, A. (2021). Cerebrolysin restores balance between excitatory and inhibitory amino acids in brain following concussive head injury: Superior neuroprotective effects of TiO2 nanowired drug delivery. In: Sharma, HS; Sharma, A (Ed.), Brain protection strategies and nanomedicine: (pp. 211-267). Elsevier BV
Open this publication in new window or tab >>Cerebrolysin restores balance between excitatory and inhibitory amino acids in brain following concussive head injury: Superior neuroprotective effects of TiO2 nanowired drug delivery
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2021 (English)In: Brain protection strategies and nanomedicine / [ed] Sharma, HS; Sharma, A, Elsevier BV , 2021, p. 211-267Chapter in book (Refereed)
Abstract [en]

Concussive head injury (CHI) often associated with military personnel, soccer players and related sports personnel leads to serious clinical situation causing lifetime disabilities. About 3-4 k head injury per 100 k populations are recorded in the United States since 2000-2014. The annual incidence of concussion has now reached to 1.2% of population in recent years. Thus, CHI inflicts a huge financial burden on the society for rehabilitation. Thus, new efforts are needed to explore novel therapeutic strategies to treat CHI cases to enhance quality of life of the victims. CHI is well known to alter endogenous balance of excitatory and inhibitory amino acid neurotransmitters in the central nervous system (CNS) leading to brain pathology. Thus, a possibility exists that restoring the balance of amino acids in the CNS following CHI using therapeutic measures may benefit the victims in improving their quality of life. In this investigation, we used a multimodal drug Cerebrolysin (Ever NeuroPharma, Austria) that is a well-balanced composition of several neurotrophic factors and active peptide fragments in exploring its effects on CHI induced alterations in key excitatory (Glutamate, Aspartate) and inhibitory (GABA, Glycine) amino acids in the CNS in relation brain pathology in dose and time-dependent manner. CHI was produced in anesthetized rats by dropping a weight of 114.6 g over the right exposed parietal skull from a distance of 20 cm height (0.224 N impact) and blood-brain barrier (BBB), brain edema, neuronal injuries and behavioral dysfunctions were measured 8, 24, 48 and 72 h after injury. Cerebrolysin (CBL) was administered (2.5, 5 or 10 mL/kg, i.v.) after 4-72 h following injury. Our observations show that repeated CBL induced a dose-dependent neuroprotection in CHI (5-10 mL/kg) and also improved behavioral functions. Interestingly when CBL is delivered through TiO2 nanowires superior neuroprotective effects were observed in CHI even at a lower doses (2.5-5 mL/kg). These observations are the first to demonstrate that CBL is effectively capable to attenuate CHI induced brain pathology and behavioral disturbances in a dose dependent manner, not reported earlier.

Place, publisher, year, edition, pages
Elsevier BV, 2021
Series
Progress in Brain Research, ISSN 0079-6123 ; 266
Keywords
Concussive head injury, Cerebrolysin, Head injury in military, Blood-brain barrier, Brain edema, Neuronal injury, Glutamate, Aspartate, Glycine, GABA, Neuroprotection, Nanowired delivery
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-468961 (URN)10.1016/bs.pbr.2021.06.016 (DOI)000750010200007 ()34689860 (PubMedID)978-0-323-98927-5 (ISBN)
Available from: 2022-03-04 Created: 2022-03-04 Last updated: 2022-03-04Bibliographically approved
Sharma, A., Muresanu, D. F., Patnaik, R., Menon, P. K., Tian, Z. R., Sahib, S., . . . Sharma, H. S. (2021). Histamine H3 and H4 receptors modulate Parkinson's disease induced brain pathology: Neuroprotective effects of nanowired BF-2649 and clobenpropit with anti-histamine-antibody therapy. In: Sharma, HS; Sharma, A (Ed.), Brain protection strategies and nanomedicine: (pp. 1-73). Elsevier BV
Open this publication in new window or tab >>Histamine H3 and H4 receptors modulate Parkinson's disease induced brain pathology: Neuroprotective effects of nanowired BF-2649 and clobenpropit with anti-histamine-antibody therapy
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2021 (English)In: Brain protection strategies and nanomedicine / [ed] Sharma, HS; Sharma, A, Elsevier BV , 2021, p. 1-73Chapter in book (Refereed)
Abstract [en]

Military personnel deployed in combat operations are highly prone to develop Parkinson's disease (PD) in later lives. PD largely involves dopaminergic pathways with hallmarks of increased alpha synuclein (ASNC), and phosphorylated tau (p-tau) in the cerebrospinal fluid (CSF) precipitating brain pathology. However, increased histaminergic nerve fibers in substantia nigra pars Compacta (SNpc), striatum (STr) and caudate putamen (CP) associated with upregulation of Histamine H3 receptors and downregulation of H4 receptors in human cases of PD is observed in postmortem cases. These findings indicate that modulation of histamine H3 and H4 receptors and/or histaminergic transmission may induce neuroprotection in PD induced brain pathology. In this review effects of a potent histaminergic H3 receptor inverse agonist BF-2549 or clobenpropit (CLBPT) partial histamine H4 agonist with H3 receptor antagonist, in association with monoclonal anti-histamine antibodies (AHmAb) in PD brain pathology is discussed based on our own observations. Our investigation shows that chronic administration of conventional or TiO2 nanowired BF 2649 (1 mg/kg, i.p.) or CLBPT (1 mg/kg, i.p.) once daily for 1 week together with nanowired delivery of HAmAb (25 mu L) significantly thwarted ASNC and p-tau levels in the SNpC and STr and reduced PD induced brain pathology. These observations are the first to show the involvement of histamine receptors in PD and opens new avenues for the development of novel drug strategies in clinical strategies for PD, not reported earlier.

Place, publisher, year, edition, pages
Elsevier BV, 2021
Series
Progress in Brain Research, ISSN 0079-6123 ; 266
Keywords
Parkinson's disease, Histamine, Alpha synuclein, Phosphorylated tau, BF-2549, Clobenpropit, Anti-histamine antibodies, Dopamine, Brain pathology, Neuroprotection
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:uu:diva-468967 (URN)10.1016/bs.pbr.2021.06.003 (DOI)000750010200002 ()34689857 (PubMedID)978-0-323-98927-5 (ISBN)
Available from: 2022-03-04 Created: 2022-03-04 Last updated: 2022-03-04Bibliographically approved
Sharma, A., Wiklund, L. & Sharma, H. S. (2021). Manganese nanoparticles induce blood-brain barrier disruption, cerebral blood flow reduction, edema formation and brain pathology associated with cognitive and motor dysfunctions. In: Sharma, HS Sharma, A (Ed.), NANOMEDICINE AND NEUROPROTECTION IN BRAIN DISEASES: (pp. 385-406). ELSEVIER ACADEMIC PRESS INC
Open this publication in new window or tab >>Manganese nanoparticles induce blood-brain barrier disruption, cerebral blood flow reduction, edema formation and brain pathology associated with cognitive and motor dysfunctions
2021 (English)In: NANOMEDICINE AND NEUROPROTECTION IN BRAIN DISEASES / [ed] Sharma, HS Sharma, A, ELSEVIER ACADEMIC PRESS INC , 2021, p. 385-406Chapter in book (Refereed)
Abstract [en]

Nanoparticles affect blood-brain barrier (BBB) and brain edema formation resulting in sensory-motor dysfunction. Exposure of Mn nanoparticles from industrial sources in humans could target basal ganglia resulting in Parkinson's disease. In present investigation, Mn exposure on brain pathology in a rat model was examined. Rats received Mn nanoparticles (30-40nm size) in a dose of 10 or 20mg/kg, i.p. once daily for 7 days and behavioral dysfunctions on Rota Rod performance, inclined plane angle and grid-walking tests as well as gait performances were examined. In addition, BBB breakdown to Evans blue and radioiodine, brain edema formation and neural injuries were also evaluated. Mn nanoparticles treated rats exhibited cognitive and motor dysfunction on the 8th day. At this time, BBB disruption, reduction in cerebral blood flow (CBF), brain edema formation and brain pathology were most marked in the sensory-motor cortex, hippocampus, caudate putamen, cerebellum and thalamus followed by hypothalamus, pons, medulla and spinal cord. In these brain areas, neuronal injuries using Nissl staining was clearly seen. These effects of Mn nanoparticle are dose dependent. These results are the first to demonstrate that Mn nanoparticles induce selective brain pathology resulting in cognitive and motor dysfunction, not reported earlier.

Place, publisher, year, edition, pages
ELSEVIER ACADEMIC PRESS INC, 2021
Series
Progress in Brain Research, ISSN 0079-6123 ; 265
Keywords
Mn nanoparticles, Blood-brain barrier, Cerebral blood flow, Brain edema, Brain pathology
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:uu:diva-468825 (URN)10.1016/bs.pbr.2021.06.015 (DOI)000750009700010 ()34560926 (PubMedID)978-0-323-90162-8 (ISBN)
Available from: 2022-03-02 Created: 2022-03-02 Last updated: 2022-03-02Bibliographically approved
Sharma, H. S., Vicente Lafuente, J., Feng, L., Muresanu, D. F., Menon, P. K., Castellani, R. J., . . . Sharma, A. (2021). Methamphetamine exacerbates pathophysiology of traumatic brain injury at high altitude. Neuroprotective effects of nanodelivery of a potent antioxidant compound H-290/51. In: Sharma, HS; Sharma, A (Ed.), Brain protection strategies and nanomedicine: (pp. 123-193). Elsevier BV
Open this publication in new window or tab >>Methamphetamine exacerbates pathophysiology of traumatic brain injury at high altitude. Neuroprotective effects of nanodelivery of a potent antioxidant compound H-290/51
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2021 (English)In: Brain protection strategies and nanomedicine / [ed] Sharma, HS; Sharma, A, Elsevier BV , 2021, p. 123-193Chapter in book (Refereed)
Abstract [en]

Military personnel are often exposed to high altitude (HA, ca. 4500-5000 m) for combat operations associated with neurological dysfunctions. HA is a severe stressful situation and people frequently use methamphetamine (METH) or other psychostimulants to cope stress. Since military personnel are prone to different kinds of traumatic brain injury (TBI), in this review we discuss possible effects of METH on concussive head injury (CHI) at HA based on our own observations. METH exposure at HA exacerbates pathophysiology of CHI as compared to normobaric laboratory environment comparable to sea level. Increased blood-brain barrier (BBB) breakdown, edema formation and reductions in the cerebral blood flow (CBF) following CHI were exacerbated by METH intoxication at HA. Damage to cerebral microvasculature and expression of beta catenin was also exacerbated following CHI in METH treated group at HA. TiO2-nanowired delivery of H-290/51 (150 mg/kg, i.p.), a potent chain-breaking antioxidant significantly enhanced CBF and reduced BBB breakdown, edema formation, beta catenin expression and brain pathology in METH exposed rats after CHI at HA. These observations are the first to point out that METH exposure in CHI exacerbated brain pathology at HA and this appears to be related with greater production of oxidative stress induced brain pathology, not reported earlier.

Place, publisher, year, edition, pages
Elsevier BV, 2021
Series
Progress in Brain Research, ISSN 0079-6123 ; 266
Keywords
High altitude, Brain pathology, Methamphetamine, Traumatic brain injury, Brain edema, Cerebral blood flow, Antioxidant, Nanowired delivery, H-290/51, Military medicine
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:uu:diva-468965 (URN)10.1016/bs.pbr.2021.06.008 (DOI)000750010200005 ()34689858 (PubMedID)978-0-323-98927-5 (ISBN)
Available from: 2022-03-04 Created: 2022-03-04 Last updated: 2022-03-04Bibliographically approved
Sharma, A., Wiklund, L. & Sharma, H. S. (2021). Nanodelivery of traditional Chinese Gingko Biloba extract EGb-761 and bilobalide BN-52021 induces superior neuroprotective effects on pathophysiology of heat stroke. In: Sharma, HS Sharma, A (Ed.), NANOMEDICINE AND NEUROPROTECTION IN BRAIN DISEASES: (pp. 249-315). ELSEVIER ACADEMIC PRESS INC
Open this publication in new window or tab >>Nanodelivery of traditional Chinese Gingko Biloba extract EGb-761 and bilobalide BN-52021 induces superior neuroprotective effects on pathophysiology of heat stroke
2021 (English)In: NANOMEDICINE AND NEUROPROTECTION IN BRAIN DISEASES / [ed] Sharma, HS Sharma, A, ELSEVIER ACADEMIC PRESS INC , 2021, p. 249-315Chapter in book (Refereed)
Abstract [en]

Military personnel often exposed to high summer heat are vulnerable to heat stroke (HS) resulting in abnormal brain function and mental anomalies. There are reasons to believe that leakage of the blood-brain barrier (BBB) due to hyperthermia and development of brain edema could result in brain pathology. Thus, exploration of suitable therapeutic strategies is needed to induce neuroprotection in HS. Extracts of Gingko Biloba (EGb-761) is traditionally used in a variety of mental disorders in Chinese traditional medicine since ages. In this chapter, effects of TiO2 nanowired EGb-761 and BN-52021 delivery to treat brain pathologies in HS is discussed based on our own investigations. We observed that TiO2 nanowired delivery of EGb-761 or TiO2 BN-52021 is able to attenuate more that 80% reduction in the brain pathology in HS as compared to conventional drug delivery. The functional outcome after HS is also significantly improved by nanowired delivery of EGb-761 and BN-52021. These observations are the first to suggest that nanowired delivery of EGb-761 and BN-52021 has superior therapeutic effects in HS not reported earlier. The clinical significance in relation to the military medicine is discussed.

Place, publisher, year, edition, pages
ELSEVIER ACADEMIC PRESS INC, 2021
Series
Progress in Brain Research, ISSN 0079-6123 ; 265
Keywords
Heat stroke, Brain edema, Hyperthermia, Gingko Biloba, EGb-761, Nanowired delivery, Neuroprotection, Blood-brain barrier, Brain pathology
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-468827 (URN)10.1016/bs.pbr.2021.06.007 (DOI)000750009700007 ()34560923 (PubMedID)978-0-323-90162-8 (ISBN)
Available from: 2022-03-02 Created: 2022-03-02 Last updated: 2022-03-02Bibliographically approved
Sharma, H. S., Vicente Lafuente, J., Muresanu, D. F., Sahib, S., Tian, Z. R., Menon, P. K., . . . Sharma, A. (2021). Neuroprotective effects of insulin like growth factor-1 on engineered metal nanoparticles Ag, Cu and Al induced blood-brain barrier breakdown, edema formation, oxidative stress, upregulation of neuronal nitric oxide synthase and brain pathology. In: Sharma, HS; Sharma, A (Ed.), Brain protection strategies and nanomedicine: (pp. 97-121). Elsevier BV
Open this publication in new window or tab >>Neuroprotective effects of insulin like growth factor-1 on engineered metal nanoparticles Ag, Cu and Al induced blood-brain barrier breakdown, edema formation, oxidative stress, upregulation of neuronal nitric oxide synthase and brain pathology
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2021 (English)In: Brain protection strategies and nanomedicine / [ed] Sharma, HS; Sharma, A, Elsevier BV , 2021, p. 97-121Chapter in book (Refereed)
Abstract [en]

Military personnel are vulnerable to environmental or industrial exposure of engineered nanoparticles (NPs) from metals. Long-term exposure of NPs from various sources affect sensory-motor or cognitive brain functions. Thus, a possibility exists that chronic exposure of NPs affect blood-brain barrier (BBB) breakdown and brain pathology by inducing oxidative stress and/or nitric oxide production. This hypothesis was examined in the rat intoxicated with Ag, Cu or Al (50-60nm) nanoparticles (50 mg/kg, i.p. once daily) for 7 days. In these NPs treated rats the BBB permeability, brain edema, neuronal nitric oxide synthase (nNOS) immunoreactivity and brain oxidants levels, e.g., myeloperoxidase (MP), malondialdehyde (MD) and glutathione (GT) was examined on the 8th day. Cu and Ag but not Al nanoparticles increased the MP and MD levels by twofold in the brain although, GT showed 50% decline. At this time increase in brain water content and BBB breakdown to protein tracers were seen in areas exhibiting nNOS positive neurons and cell injuries. Pretreatment with insulin like growth factor-1 (IGF-1) in high doses (1 mu g/kg, i.v. but not 0.5 mu g/kg daily for 7 days) together with NPs significantly reduced the oxidative stress, nNOS upregulation, BBB breakdown, edema formation and cell injuries. These novel observations demonstrate that (i) NPs depending on their metal constituent (Cu, Ag but not Al) induce oxidative stress and nNOS expression leading to BBB disruption, brain edema and cell damage, and (ii) IGF-1 depending on doses exerts powerful neuroprotection against nanoneurotoxicity, not reported earlier.

Place, publisher, year, edition, pages
Elsevier BV, 2021
Series
Progress in Brain Research, ISSN 0079-6123 ; 266
Keywords
Nanoparticles, Oxidative stress, Nitric oxide, Cell injury, Insulin like growth factor-1 (IGF-1), Brain edema, Cu, Al, Ag
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-468963 (URN)10.1016/bs.pbr.2021.06.005 (DOI)000750010200004 ()34689867 (PubMedID)978-0-323-98927-5 (ISBN)
Available from: 2022-03-04 Created: 2022-03-04 Last updated: 2022-03-04Bibliographically approved
Sharma, H. S., Muresanu, D. F., Ozkizilcik, A., Sahib, S., Tian, Z. R., Vicente Lafuente, J., . . . Sharma, A. (2021). Superior antioxidant and anti-ischemic neuroprotective effects of cerebrolysin in heat stroke following intoxication of engineered metal Ag and Cu nanoparticles: A comparative biochemical and physiological study with other stroke therapies. In: Sharma, HS; Sharma, A (Ed.), Brain protection strategies and nanomedicine: (pp. 301-348). Elsevier BV
Open this publication in new window or tab >>Superior antioxidant and anti-ischemic neuroprotective effects of cerebrolysin in heat stroke following intoxication of engineered metal Ag and Cu nanoparticles: A comparative biochemical and physiological study with other stroke therapies
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2021 (English)In: Brain protection strategies and nanomedicine / [ed] Sharma, HS; Sharma, A, Elsevier BV , 2021, p. 301-348Chapter in book (Refereed)
Abstract [en]

Military personnel are often exposed to high environmental heat associated with industrial or ambient abundance of nanoparticles (NPs) affecting brain function. We have shown that engineered metal NPs Ag and Cu exacerbate hyperthermia induced brain pathology. Thus, exploration of novel drug therapy is needed for effective neuroprotection in heat stroke intoxicated with NPs. In this investigation neuroprotective effects of cerebrolysin, a balanced composition of several neurotrophic factors and active peptides fragments exhibiting powerful antioxidant and anti-ischemic effects was examined in heat stroke after NPs intoxication. In addition, its efficacy is compared to currently used drugs in post-stroke therapies in clinics. Thus, levertiracetam, pregabalin, topiramat and valproate were compared in standard doses with cerebrolysin in heat stroke intoxicated with Cu or Ag NPs (50-60 nm, 50 mg/kg, i.p./day for 7 days). Rats were subjected to 4 h heat stress (HS) in a biological oxygen demand incubator at 38 degrees C (Relative Humidity 45-47%; Wind velocity 22.4-25.6 cm/s) that resulted in profound increase in oxidants Luminol, Lucigenin, Malondialdehyde and Myeloperoxidase, and a marked decrease in antioxidant Glutathione. At this time severe reductions in the cerebral blood flow (CBF) was seen together with increased blood-brain barrier (BBB) breakdown and brain edema formation. These pathophysiological responses were exacerbated in NPs treated heat-stressed animals. Pretreatment with cerebrolysin (2.5 mL/kg, i.v.) once daily for 3 days significantly attenuated the oxidative stress, BBB breakdown and brain edema and improved CBF in the heat stressed group. The other drugs were least effective on brain pathology following heat stroke. However, in NPs treated heat stressed animals 5 mL/kg conventional cerebrolysin and 2.5 mL/kg nanowired cerebrolysin is needed to attenuate oxidative stress, BBB breakdown, brain edema and to improve CBF. Interestingly, the other drugs even in higher doses used are unable to alter brain pathologies in NPs and heat stress. These observations are the first to demonstrate that cerebrolysin is the most superior antioxidant and anti-ischemic drug in NPs exposed heat stroke, not reported earlier.

Place, publisher, year, edition, pages
Elsevier BV, 2021
Series
Progress in Brain Research, ISSN 0079-6123 ; 266
Keywords
Cerebrolysin, Levetiracetam, Pregabalin, Topiramat, Valproate, Heat stroke, Cerebral blood flow, Brain edema, Heat exposure, Brain pathology, Neuroproetction, Nanoparticles from metals, Ag, Cu toxicity
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-468966 (URN)10.1016/bs.pbr.2021.06.014 (DOI)000750010200009 ()34689862 (PubMedID)978-0-323-98927-5 (ISBN)
Available from: 2022-03-04 Created: 2022-03-04 Last updated: 2022-03-04Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0001-8700-5610

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