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Sökning: WFRF:(Patnaik Ranjana)

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2.
  • Sharma, Hari S., et al. (författare)
  • Nano-Drug Delivery and Neuroprotection in Spinal Cord Injury
  • 2009
  • Ingår i: Journal of Nanoscience and Nanotechnology. - 1533-4880 .- 1533-4899. ; 9:8, s. 5014-5037
  • Tidskriftsartikel (refereegranskat)abstract
    • Recently nano-drug delivery to the central nervous system (CNS) has been shown to be more effective than the parent compound by itself. An increased availability of the drug for longer periods to the brain or spinal cord and/or a decrease in the drug metabolism altogether could lead to potentiation of the pharmacological activity of the nano-delivered compounds. However, it is still unclear whether the nanocarriers used to deliver the drugs may itself has any potential neurotoxic activity. Although, nanodrug-delivery appears to be a quite promising therapeutic tool for the future clinical therapy, its advantages and limitations for the routine use of patients still needs to be elucidated. Our laboratory is engaged to study a plethora of potential neuroprotective novel compounds delivered to the CNS using nanowiring techniques following brain or spinal cord trauma. Our investigations show that nanowired drugs, if delivered locally following spinal cord injury achieve better neuroprotection than the parent compounds. This effect of nano-drug delivery appears to be very selective in nature. Thus, a clear differentiation based on the compounds used for nano-drug delivery can be seen on various pathological parameters in spinal cord injury. These observations suggest that nanowiring may itself do not induce neuroprotection, but enhance the neuroprotective ability of compounds after trauma. This review describes some recent advances in nano-drug delivery to the CNS in relation to novel neuroprotective strategies with special emphasis on spinal cord trauma based on our own observations and recent findings from our laboratory investigations.
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3.
  • Lafuente, Jose Vicente, et al. (författare)
  • Diabetes Exacerbates Nanoparticles Induced Brain Pathology
  • 2012
  • Ingår i: CNS & Neurological Disorders. - : Bentham Science Publishers Ltd.. - 1871-5273 .- 1996-3181. ; 11:1, s. 26-39
  • Forskningsöversikt (refereegranskat)abstract
    • 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.
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4.
  • Menon, Preeti K., et al. (författare)
  • Intravenous Administration of Functionalized Magnetic Iron Oxide Nanoparticles Does Not Induce CNS Injury in the Rat : Influence of Spinal Cord Trauma and Cerebrolysin Treatment
  • 2017
  • Ingår i: Nanomedicine In Central Nervous System Injury And Repair. - : Elsevier. - 9780128123812 ; , s. 47-63
  • Bokkapitel (refereegranskat)abstract
    • 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.
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6.
  • Muresanu, Dafin F., et al. (författare)
  • Diabetes exacerbates brain pathology following a focal blast brain injury : New role of a multimodal drug cerebrolysin and nanomedicine
  • 2020
  • Ingår i: Neuropharmacology of Neuroprotection. - : ELSEVIER. - 9780128208137 ; 258, s. 285-367
  • Bokkapitel (refereegranskat)abstract
    • Blast brain injury (bBI) is a combination of several forces of pressure, rotation, penetration of sharp objects and chemical exposure causing laceration, perforation and tissue losses in the brain. The bBI is quite prevalent in military personnel during combat operations. However, no suitable therapeutic strategies are available so far to minimize bBI pathology. Combat stress induces profound cardiovascular and endocrine dysfunction leading to psychosomatic disorders including diabetes mellitus (DM). This is still unclear whether brain pathology in bBI could exacerbate in DM. In present review influence of DM on pathophysiology of bBI is discussed based on our own investigations. In addition, treatment with cerebrolysin (a multimodal drug comprising neurotrophic factors and active peptide fragments) or H-290/51 (a chain-breaking antioxidant) using nanowired delivery of for superior neuroprotection on brain pathology in bBI in DM is explored. Our observations are the first to show that pathophysiology of bBI is exacerbated in DM and TiO2-nanowired delivery of cerebrolysin induces profound neuroprotection in bBI in DM, not reported earlier. The clinical significance of our findings with regard to military medicine is discussed.
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7.
  • Muresanu, Dafin Fior, et al. (författare)
  • Exacerbation of blood-brain barrier breakdown, edema formation, nitric oxide synthase upregulation and brain pathology after heat stroke in diabetic and hypertensive rats. Potential neuroprotection with cerebrolysin treatment
  • 2019
  • Ingår i: New Therapeutic Strategies for Brain Edema and Cell Injury. - : Elsevier. - 9780128167540 ; , s. 83-102
  • Bokkapitel (refereegranskat)abstract
    • There is a growing trend of hypertension among military and civilian populations due to lifetime stressful situations. If hypertension is uncontrolled it leads to development of diabetes and serious neurological complications. Most of the World populations live in temperate zone across the World. Thus, a possibility exists that these hypertensive and diabetic people may have external heat as potential risk factors for brain damage. We have seen brain edema and brain damage following exposure to heat stress at 38 degrees C for 4h. A possibility exists that heat exposure in diabetic-hypertensive (DBHY) cases exacerbates exacerbation of brain pathology and edema formation. This hypothesis is examined in a rat model. The role of nitric oxide (NO) in exacerbation of HS-induced brain pathology was also evaluated using nitric oxide synthase (NOS) immunoreactivity. Hypertensive rats (produced by two-kidney one clip (2K1C) method) were made diabetic with streptozotocine (50 mg/kg, i.p./day for 3 days) treatment. After 6 weeks, DBHY rats show 20-30 mM/L Blood Glucose and hypertension (180-200 mmHg). Subjection of these rats to 4h HS resulted in six- to eightfold higher BBB breakdown, brain edema formation and brain pathology. At this time, neuronal or inducible NOS expression was four- to sixfold higher in DBHY rats compared to controls. Interestingly, iNOS expression was higher than nNOS in DBHY rats. Cerebrolysin in high doses (10-mL/kg, i.v. instead of 5-mL/kg) induced significant neuroprotection and downregulation of nNOS and iNOS in DBHY animals whereas normal animals need only 5-mL/kg doses for this purpose. Our observations demonstrate that co-morbidly factors exacerbate brain damage in HS through NOS expression and require double dose of cerebrolysin for neuroprotection as compared to normal rats, not reported earlier.
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8.
  • Muresanu, Dafin Fior, et al. (författare)
  • Hypertension Associated With Silica Dust Intoxication Aggravates Brain Pathology Following Traumatic Brain Injury : New Roles of Neurotrophic Factors
  • 2017
  • Ingår i: The journal of head trauma rehabilitation. - 0885-9701 .- 1550-509X. ; 32:6, s. E68-E69
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • 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.
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10.
  • Muresanu, Dafin F., et al. (författare)
  • 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 Cord
  • 2015
  • Ingår i: Molecular Neurobiology. - : Springer Science and Business Media LLC. - 0893-7648 .- 1559-1182. ; 52:2, s. 837-845
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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11.
  • Niu, Feng, et al. (författare)
  • Co-administration of TiO2-nanowired DL-3-n-butylphthalide (DL-NBP) and mesenchymal stem cells enhanced neuroprotection in Parkinson's disease exacerbated by concussive head injury
  • 2020
  • Ingår i: Neuropharmacology of Neuroprotection. - : ELSEVIER. - 9780128208137 ; , s. 101-155
  • Bokkapitel (refereegranskat)abstract
    • DL-3-n-butylphthalide (DL-NBP) is a powerful antioxidant compound with profound neuroprotective effects in stroke and brain injury. However, its role in Parkinson's disease (PD) is not well known. Traumatic brain injury (TBI) is one of the key factors in precipitating PD like symptoms in civilians and particularly in military personnel. Thus, it would be interesting to explore the possible neuroprotective effects of NBP in PD following concussive head injury (CHI). In this chapter effect of nanowired delivery of NBP together with mesenchymal stem cells (MSCs) in PD with CHI is discussed based on our own investigations. It appears that CHI exacerbates PD pathophysiology in terms of p-tau, alpha-synuclein (ASNC) levels in the cerebrospinal fluid (CSF) and the loss of TH immunoreactivity in substantia niagra pars compacta (SNpc) and striatum (STr) along with dopamine (DA), dopamine decarboxylase (DOPAC). And homovanillic acid (HVA). Our observations are the first to show that a combination of NBP with MSCs when delivered using nanowired technology induces superior neuroprotective effects in PD brain pathology exacerbated by CHI, not reported earlier.
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12.
  • Niu, Feng, et al. (författare)
  • Nanodelivery of oxiracetam enhances memory, functional recovery and induces neuroprotection following concussive head injury
  • 2021
  • Ingår i: Progress in Brain Research. - Amsterdam : Elsevier. - 0079-6123 .- 1875-7855. ; 265, s. 139-230, s. 139-230
  • Tidskriftsartikel (refereegranskat)abstract
    • 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 0.224 N results in profound progressive functional deficit, memory impairment and brain pathology from 5 h 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 100 mg/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.
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13.
  • Ozkizilcik, Asya, et al. (författare)
  • Timed Release of Cerebrolysin Using Drug-Loaded Titanate Nanospheres Reduces Brain Pathology and Improves Behavioral Functions in Parkinson's Disease
  • 2018
  • Ingår i: Molecular Neurobiology. - : HUMANA PRESS INC. - 0893-7648 .- 1559-1182. ; 55:1, s. 359-369
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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14.
  • Pandey, Anand Kumar, et al. (författare)
  • Quercetin in hypoxia-induced oxidative stress : novel target for neuroprotection
  • 2012
  • Ingår i: New Perspectives of Central Nervous System Injury and Neuroprotection. - : Elsevier. - 9780123869869 ; , s. 107-146
  • Bokkapitel (refereegranskat)abstract
    • 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.
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15.
  • Patnaik, Ranjana, et al. (författare)
  • Histamine H3 Inverse Agonist BF 2649 or Antagonist with Partial H4 Agonist Activity Clobenpropit Reduces Amyloid Beta Peptide-Induced Brain Pathology in Alzheimer's Disease
  • 2018
  • Ingår i: Molecular Neurobiology. - : Humana Press. - 0893-7648 .- 1559-1182. ; 55:1, s. 312-321
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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16.
  • Sahib, Seaab, et al. (författare)
  • Cerebrolysin enhances spinal cord conduction and reduces blood-spinal cord barrier breakdown, edema formation, immediate early gene expression and cord pathology after injury
  • 2020. - 1
  • Ingår i: Neuropharmacology of Neuroprotection. - Amsterdam : Elsevier. - 9780128208137 - 9780128208144 ; , s. 397-438
  • Bokkapitel (refereegranskat)abstract
    • Spinal cord evoked potentials (SCEP) are good indicators of spinal cord function in health and disease. Disturbances in SCEP amplitudes and latencies during spinal cord monitoring predict spinal cord pathology following trauma. Treatment with neuroprotective agents preserves SCEP and reduces cord pathology after injury. The possibility that cerebrolysin, a balanced composition of neurotrophic factors improves spinal cord conduction, attenuates blood-spinal cord barrier (BSCB) disruption, edema formation, and cord pathology was examined in spinal cord injury (SCI). SCEP is recorded from epidural space over rat spinal cord T9 and T12 segments after peripheral nerves stimulation. SCEP consists of a small positive peak (MPP), followed by a prominent negative peak (MNP) that is stable before SCI. A longitudinal incision (2mm deep and 5mm long) into the right dorsal horn (T10 and T11 segments) resulted in an immediate long-lasting depression of the rostral MNP with an increase in the latencies. Pretreatment with either cerebrolysin (CBL 5mL/kg, i.v. 30min before) alone or TiO2 nanowired delivery of cerebrolysin (NWCBL 2.5mL/kg, i.v.) prevented the loss of MNP amplitude and even enhanced further from the pre-injury level after SCI without affecting latencies. At 5h, SCI induced edema, BSCB breakdown, and cell injuries were significantly reduced by CBL and NWCBL pretreatment. Interestingly this effect on SCEP and cord pathology was still prominent when the NWCBL was delivered 2min after SCI. Moreover, expressions of c-fos and c-jun genes that are prominent at 5h in untreated SCI are also considerably reduced by CBL and NWCBL treatment. These results are the first to show that CBL and NWCBL enhanced SCEP activity and thwarted the development of cord pathology after SCI. Furthermore, NWCBL in low doses has superior neuroprotective effects on SCEP and cord pathology, not reported earlier. The functional significance and future clinical potential of CBL and NWCBL in SCI are discussed.
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17.
  • Sahib, Seaab, et al. (författare)
  • Nanodelivery of traditional Chinese Gingko Biloba extract EGb-761 and bilobalide BN-52021 induces superior neuroprotective effects on pathophysiology of heat stroke
  • 2021
  • Ingår i: Progress in Brain Research. - : Elsevier. - 0079-6123 .- 1875-7855. ; 265, s. 249-315, s. 249-315
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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19.
  • Sharma, Aruna, et al. (författare)
  • Cold Environment Exacerbates Brain Pathology and Oxidative Stress Following Traumatic Brain Injuries : Potential Therapeutic Effects of Nanowired Antioxidant Compound H-290/51
  • 2018
  • Ingår i: Molecular Neurobiology. - : Humana Press. - 0893-7648 .- 1559-1182. ; 55:1, s. 276-285
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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21.
  • Sharma, Aruna, et al. (författare)
  • Concussive head injury exacerbates neuropathology of sleep deprivation : Superior neuroprotection by co-administration of TiO2-nanowired cerebrolysin, alpha-melanocyte-stimulating hormone, and mesenchymal stem cells
  • 2020
  • Ingår i: Neuropharmacology of Neuroprotection. - : ELSEVIER. - 9780128208137 ; , s. 1-77
  • Bokkapitel (refereegranskat)abstract
    • Sleep deprivation (SD) is common in military personnel engaged in combat operations leading to brain dysfunction. Military personnel during acute or chronic SD often prone to traumatic brain injury (TBI) indicating the possibility of further exacerbating brain pathology. Several lines of evidence suggest that in both TBI and SD alpha-melanocyte-stimulating hormone (alpha-MSH) and brain-derived neurotrophic factor (BDNF) levels decreases in plasma and brain. Thus, a possibility exists that exogenous supplement of alpha-MSH and/or BDNF induces neuroprotection in SD compounded with TBI. In addition, mesenchymal stem cells (MSCs) are very portent in inducing neuroprotection in TBI. We examined the effects of concussive head injury (CHI) in SD on brain pathology. Furthermore, possible neuroprotective effects of alpha-MSH, MSCs and neurotrophic factors treatment were explored in a rat model of SD and CHI. Rats subjected to 48h SD with CHI exhibited higher leakage of BBB to Evans blue and radioiodine compared to identical SD or CHI alone. Brain pathology was also exacerbated in SD with CHI group as compared to SD or CHI alone together with a significant reduction in alpha-MSH and BDNF levels in plasma and brain and enhanced level of tumor necrosis factor-alpha (TNF-alpha). Exogenous administration of alpha-MSH (250 mu g/kg) together with MSCs (1 x 10(6)) and cerebrolysin (a balanced composition of several neurotrophic factors and active peptide fragments) (5mL/kg) significantly induced neuroprotection in SD with CHI. Interestingly, TiO2 nanowired delivery of alpha-MSH (100 mu g), MSCs, and cerebrolysin (2.5mL/kg) induced enhanced neuroprotection with higher levels of alpha-MSH and BDNF and decreased the TNF-alpha in SD with CHI. These observations are the first to show that TiO2 nanowired administration of alpha-MSH, MSCs and cerebrolysin induces superior neuroprotection following SD in CHI, not reported earlier. The clinical significance of our findings in light of the current literature is discussed.
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22.
  • Sharma, Aruna, et al. (författare)
  • 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
  • 2021
  • Ingår i: Brain protection strategies and nanomedicine. - : Elsevier BV. - 9780323989275 ; 266, s. 1-73
  • Bokkapitel (refereegranskat)abstract
    • 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.
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23.
  • Sharma, Aruna, et al. (författare)
  • Mild traumatic brain injury exacerbates Parkinson's disease induced hemeoxygenase-2 expression and brain pathology : Neuroprotective effects of co-administration of TiO2 nanowired mesenchymal stem cells and cerebrolysin
  • 2020
  • Ingår i: Neuropharmacology of Neuroprotection. - : ELSEVIER. - 9780128208137 ; , s. 157-231
  • Bokkapitel (refereegranskat)abstract
    • Mild traumatic brain injury (mTBI) is one of the leading predisposing factors in the development of Parkinson's disease (PD). Mild or moderate TBI induces rapid production of tau protein and alpha synuclein (ASNC) in the cerebrospinal fluid (CSF) and in several brain areas. Enhanced tau-phosphorylation and ASNC alters the molecular machinery of the brain leading to PD pathology. Recent evidences show upregulation of constitutive isoform of hemeoxygenase (HO-2) in PD patients that correlates well with the brain pathology. mTBI alone induces profound upregulation of HO-2 immunoreactivity. Thus, it would be interesting to explore whether mTBI exacerbates PD pathology in relation to tau, ASNC and HO-2 expression. In addition, whether neurotrophic factors and stem cells known to reduce brain pathology in TBI could induce neuroprotection in PD following mTBI. In this review role of mesenchymal stem cells (MSCs) and cerebrolysin (CBL), a well-balanced composition of several neurotrophic factors and active peptide fragments using nanowired delivery in PD following mTBI is discussed based on our own investigation. Our results show that mTBI induces concussion exacerbates PD pathology and nanowired delivery of MSCs and CBL induces superior neuroprotection. This could be due to reduction in tau, ASNC and HO-2 expression in PD following mTBI, not reported earlier. The functional significance of our findings in relation to clinical strategies is discussed.
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24.
  • Sharma, Aruna, et al. (författare)
  • Neuroprotective effects of 5-HT3 receptor antagonist ondansetron on morphine withdrawal induced brain edema formation, blood-brain barrier dysfunction, neuronal injuries, glial activation and heat shock protein upregulation in the brain
  • 2019
  • Ingår i: New Therapeutic Strategies for Brain Edema and Cell Injury. - : Elsevier. - 9780128167540 ; , s. 209-228
  • Bokkapitel (refereegranskat)abstract
    • Morphine withdrawal response is associated with brain edema formation, blood-brain barrier (BBB) disruption, activation of glial cells and heat shock protein (HSP 72kDa) responses in the CNS. Thus, exploration of suitable therapeutic measures is the need of the hour to induce neuroprotection in morphine withdrawal cases. There are reports that 5-HT3-receptor antagonists ondansetron attenuate some of the behavioral changes in morphine-withdrawal symptoms. However, brain protection in morphine withdrawal using pharmacological approaches is still not well known. In present investigation, effect of ondansetron the potent 5-HT3 receptor antagonist on brain edema formation BBB disruption, glial activation and/or HSP response following morphine withdrawal was examined. Rats received ondansetron (1mg or 2mg/kg, s.c) or saline once daily from 2 days before morphine administration (10 mg/kg, s.c. once daily for 10 days) that continued up to 2days after its withdrawal (day 13th). Cessation of morphine on day 11th results in withdrawal symptoms and BBB breakdown to proteins in the cerebral cortex, hippocampus, cerebellum, thalamus, hypothalamus, brain stem and spinal cord along with activation of glial fibrillary acidic protein (GFAP) and HSP immunoreactivity. In these animals brain edema and neurotoxicity are prominent on day 13th as compared to controls. Ondansetron treatment significantly reduced withdrawal symptoms on the day 13th in a dose dependent manner and attenuated BBB breakdown, edema formation, GFAP and HSP expression and neuronal injuries. These observations are the first to show that ondansetron is neuroprotective following morphine withdrawal indicating an important role of 5-HT3 receptors in psychostimulants abuse.
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25.
  • Sharma, Aruna, et al. (författare)
  • 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 Disease
  • 2017
  • Ingår i: Nanomedicine In Central Nervous System Injury And Repair. - : Elsevier. - 9780128123812 ; , s. 123-165
  • Bokkapitel (refereegranskat)abstract
    • 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.
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26.
  • Sharma, Aruna, et al. (författare)
  • Size- and Age-Dependent Neurotoxicity of Engineered Metal Nanoparticles in Rats
  • 2013
  • Ingår i: Molecular Neurobiology. - : Springer Science and Business Media LLC. - 0893-7648 .- 1559-1182. ; 48:2, s. 386-396
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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27.
  • Sharma, Aruna, et al. (författare)
  • 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 Ondansetron
  • 2015
  • Ingår i: Molecular Neurobiology. - : Springer Science and Business Media LLC. - 0893-7648 .- 1559-1182. ; 52:2, s. 867-881
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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28.
  • Sharma, Aruna, et al. (författare)
  • Spinal Cord Injury at Hot Environment Exacerbates Blood-spinal Cord Barrier Disruption, Edema Formation and Cellular Damages. Effective Treatment With a Multimodal Drug Cerebrolsyi
  • 2017
  • Ingår i: The journal of head trauma rehabilitation. - 0885-9701 .- 1550-509X. ; 32:6, s. E68-E68
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • 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.
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29.
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30.
  • Sharma, Hari Shanker, et al. (författare)
  • 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
  • 2021
  • Ingår i: Progress in Brain Research. - : Elsevier. - 0079-6123 .- 1875-7855. ; 265, s. 1-97, s. 1-97
  • Tidskriftsartikel (refereegranskat)abstract
    • 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 blood-brain barrier (BBB) to serum proteins into the brain and leads to extravasation of plasma amyloid beta peptide (ΑβP) 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.
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31.
  • Sharma, Hari Shanker, et al. (författare)
  • Cardiac Arrest Alters Regional Ubiquitin Levels in Association with the Blood-Brain Barrier Breakdown and Neuronal Damages in the Porcine Brain
  • 2015
  • Ingår i: Molecular Neurobiology. - : Springer Science and Business Media LLC. - 0893-7648 .- 1559-1182. ; 52:2, s. 1043-1053
  • Tidskriftsartikel (refereegranskat)abstract
    • The possibility that ubiquitin expression is altered in cardiac arrest-associated neuropathology was examined in a porcine model using immunohistochemical and biochemical methods. Our observations show that cardiac arrest induces progressive increase in ubiquitin expression in the cortex and hippocampus in a selective and specific manner as compared to corresponding control brains using enzyme-linked immunoassay technique (enzyme-linked immunosorbent assay (ELISA)). Furthermore, immunohistochemical studies showed ubiquitin expression in the neurons exhibiting immunoreaction in the cytoplasm and karyoplasm of distorted or damaged cells. Separate Nissl and ubiquitin staining showed damaged and distorted neurons and in the same cortical region ubiquitin expression indicating that ubiquitin expression after cardiac arrest represents dying neurons. The finding that methylene blue treatment markedly induced neuroprotection following identical cardiac arrest and reduced ubiquitin expression strengthens this view. Taken together, our observations are the first to show that cardiac arrest enhanced ubiquitin expression in the brain that is related to the magnitude of neuronal injury and the finding that methylene blue reduced ubiquitin expression points to its role in cell damage, not reported earlier.
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32.
  • Sharma, Hari S., et al. (författare)
  • Cerebrolysin Attenuates Heat Shock Protein (HSP 72 KD) Expression in the Rat Spinal Cord Following Morphine Dependence and Withdrawal : Possible New Therapy for Pain Management
  • 2011
  • Ingår i: Current Neuropharmacology. - 1570-159X .- 1875-6190. ; 9:1, s. 223-235
  • Tidskriftsartikel (refereegranskat)abstract
    • The possibility that pain perception and processing in the CNS results in cellular stress and may influence heat shock protein (HSP) expression was examined in a rat model of morphine dependence and withdrawal. Since activation of pain pathways result in exhaustion of growth factors, we examined the influence of cerebrolysin, a mixture of potent growth factors (BDNF, GDNF, NGF, CNTF etc,) on morphine induced HSP expression. Rats were administered morphine (10 mg/kg, s.c. /day) for 12 days and the spontaneous withdrawal symptoms were developed by cessation of the drug administration on day 13(th) that were prominent on day 14(th) and continued up to day 15(th) (24 to 72 h periods). In a separate group of rats, cerebrolysin was infused intravenously (5 ml/kg) once daily from day one until day 15(th). In these animals, morphine dependence and withdrawal along with HSP immunoreactivity was examined using standard protocol. In untreated group mild HSP immunoreaction was observed during morphine tolerance, whereas massive upregulation of HSP was seen in CNS during withdrawal phase that correlated well with the withdrawal symptoms and neuronal damage. Pretreatment with cerebrolysin did not affect morphine tolerance but reduced the HSP expression during this phase. Furthermore, cerebrolysin reduced the withdrawal symptoms on day 14(th) to 15(th). Taken together these observations suggest that cellular stress plays an important role in morphine induced pain pathology and exogenous supplement of growth factors, i.e. cerebrolysin attenuates HSP expression in the CNS and induce neuroprotection. This indicates a new therapeutic role of cerebrolysin in the pathophysiology of drugs of abuse, not reported earlier.
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33.
  • Sharma, Hari Shanker, et al. (författare)
  • Co-Administration of TiO2 Nanowired Mesenchymal Stem Cells with Cerebrolysin Potentiates Neprilysin Level and Reduces Brain Pathology in Alzheimer's Disease
  • 2018
  • Ingår i: Molecular Neurobiology. - : Humana Press. - 0893-7648 .- 1559-1182. ; 55:1, s. 300-311
  • Tidskriftsartikel (refereegranskat)abstract
    • Neprilysin (NPL), the rate-limiting enzyme for amyloid beta peptide (A beta P), appears to play a crucial role in the pathogenesis of Alzheimer's disease (AD). Since mesenchymal stem cells (MSCs) and/or cerebrolysin (CBL, a combination of neurotrophic factors and active peptide fragments) have neuroprotective effects in various CNS disorders, we examined nanowired delivery of MSCs and CBL on NPL content and brain pathology in AD using a rat model. AD-like symptoms were produced by intraventricular (i.c.v.) administration of A beta P (1-40) in the left lateral ventricle (250 ng/10 mu l, once daily) for 4 weeks. After 30 days, the rats were examined for NPL and A beta P concentrations in the brain and related pathology. Co-administration of TiO2-nanowired MSCs (10(6) cells) with 2.5 ml/kg CBL (i.v.) once daily for 1 week after 2 weeks of A beta P infusion significantly increased the NPL in the hippocampus (400 pg/g) from the untreated control group (120 pg/g; control 420 +/- 8 pg/g brain) along with a significant decrease in the A beta P deposition (45 pg/g from untreated control 75 pg/g; saline control 40 +/- 4 pg/g). Interestingly, these changes were much less evident when the MSCs or CBL treatment was given alone. Neuronal damages, gliosis, and myelin vesiculation were also markedly reduced by the combined treatment of TiO2, MSCs, and CBL in AD. These observations are the first to show that co-administration of TiO2-nanowired CBL and MSCs has superior neuroprotective effects in AD probably due to increasing the brain NPL level effectively, not reported earlier.
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34.
  • Sharma, Hari Shanker, et al. (författare)
  • Cocaine-Induced Breakdown of the Blood–Brain Barrier and Neurotoxicity
  • 2009
  • Ingår i: International review of neurobiology. - 0074-7742 .- 2162-5514. ; 88, s. 297-334
  • Forskningsöversikt (refereegranskat)abstract
    • Role of cocaine in influencing blood-brain barrier (BBB) function is still unknown. Available evidences suggest that cocaine administration results in acute hyperthermia and alterations in brain serotonin metabolism. Since hyperthermia is capable to induce the breakdown of the BBB either directly or through altered serotonin metabolism, a possibility exists that cocaine may induce neurotoxicity by causing BBB disruption. This hypothesis is discussed in this review largely based on our own laboratory investigations. Our observations in rats demonstrate that cocaine depending on the dose and routes of administration induces profound hyperthermia, increased plasma and brain serotonin levels leading to BBB breakdown and brain edema formation. Furthermore, cocaine was able to enhance cellular stress as seen by upregulation of heat shock protein (HSP 72 kD) expression and resulted in marked neuronal and glial cell damages at the time of the BBB dysfunction. Taken together, these observations are the first to suggest that cocaine-induced BBB disruption is instrumental in precipitating brain pathology. The possible mechanisms of cocaine-induced BBB breakdown and neurotoxicity are discussed.
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35.
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36.
  • Sharma, Hari Shanker, et al. (författare)
  • Development of in vivo drug-induced neurotoxicity models
  • 2014
  • Ingår i: Expert Opinion on Drug Metabolism & Toxicology. - : Informa Healthcare. - 1742-5255 .- 1744-7607. ; 10:12, s. 1637-1661
  • Forskningsöversikt (refereegranskat)abstract
    • Introduction: Neurotoxicity caused by diverse psychostimulant drugs, for example, methamphetamine, 3,4-methylenedioxy-methamphetamine, cocaine or morphine is a cause of concern to human populations especially the young generation across the world. These recreational drugs affect brain function severely leading to addiction and brain pathology. Use of psychostimulants may induce breakdown of the blood-brain barrier to serum proteins resulting in adverse brain microenvironment, edema cell injury or eventually neuronal death. Thus, there is an urgent need to find out detailed mechanisms of psychostimulants-induced neurotoxicity in vivo models for suitable therapeutic strategies to induce neuroprotection and also to help de-addiction in clinical situations. Areas covered: In this review, psychostimulants drugs-induced neurotoxicity is discussed in view of recent literature and the financial burden it may pose on our society due to rehabilitation and de-addiction. Furthermore, experimental evidences of drug-induced neuroprotection are also discussed. Expert opinion: Use of in vivo models of neurotoxicity caused by psychostimulants is discussed based on author's own research and to find suitable drugs that could induce neuroprotection including nanodelivery. Furthermore, novel therapeutic agents for de-addiction and reducing neurotoxicity following psychostimulants administration are presented.
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37.
  • Sharma, Hari Shanker, et al. (författare)
  • Diabetes Aggravates Nanoparticles Induced Breakdown of the Blood-Brain Barrier Permeability, Brain Edema Formation, Alterations in Cerebral Blood Flow and Neuronal Injury : An Experimental Study Using Physiological and Morphological Investigations in the Rat
  • 2010
  • Ingår i: Journal of Nanoscience and Nanotechnology. - : American Scientific Publishers. - 1533-4880 .- 1533-4899. ; 10:12, s. 7931-7945
  • Tidskriftsartikel (refereegranskat)abstract
    • The possibility that diabetes aggravates nanoparticles induced blood brain barrier (BBB) break-down, edema formation and brain pathology was examined in a rat model. Engineered nanoparticles from metals Ag and Cu (50-60 mn) were administered (50 mg/kg, i.p.) once daily for 7 days in normal and streptozotocine induced diabetic rats. On the 8th day, BBB permeability to Evans blue and radioactive iodine (I-131-sodium) was examined in 16 brain regions. In these brain regions alterations in regional CBF was also evaluated using radiolabelled (I-125) carbonized microspheres (o.d. 15 +/- 6 mu m). Regional brain edema and Na+, K+ and Cl- ion analysis were done in 8 selected brain regions. Histopathology was used to detect neuronal damage employing Nissl staining. Nanoparticles treatment in diabetic rats showed much more profound disruption of the BBB to Evans blue albumin (EBA) and radioiodine in almost all the 16 regions examined as compared to the normal animals. In these diabetic animals reduction in regional cerebral blood flow (CBF) was more pronounced than in normal rats. Edema development as seen using water content and increase in Na+ and a decrease in K+ ion were most marked in diabetic rats as compared to normal rats after nanoparticles treatment. Cell changes in the regions of BBB disruptions were also exacerbated in diabetic rats compared to normal group after nanoparticles treatment. Taken together, these observations are the first to show that diabetic rats are more susceptible to nanoparticles induced cerebrovascular reactions in the brain and neuronal damage. The possible mechanisms and significance of the present findings are discussed.
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38.
  • Sharma, Hari S., et al. (författare)
  • Exacerbation of Brain Pathology After Partial Restraint in Hypertensive Rats Following SiO2 Nanoparticles Exposure at High Ambient Temperature
  • 2013
  • Ingår i: Molecular Neurobiology. - : Springer Science and Business Media LLC. - 0893-7648 .- 1559-1182. ; 48:2, s. 368-379
  • Forskningsöversikt (refereegranskat)abstract
    • This investigation examines the possibility that exposure to silica dust of hypertensive individuals may exacerbate brain pathology and sensory motor dysfunction at high environmental temperature. Hypertension was produced in rats (200-250 g) by two-kidney one clip (2K1C) method, and in these animals, SiO2 nanoparticles (NPs; 50 to 60 nm) were administered at 50 mg/kg, i.p. daily for 1 week. On the 8th day, these rats were subjected to partial restraint in a Perspex box for 4 h either at room temperature (21 A degrees C) or at 33 A degrees C in a biological oxygen demand incubator (wind velocity, 2.6 cm/s; relative humidity, 65 to 67 %). In these animals, behavioral functions, blood-brain barrier (BBB) permeability to Evans blue albumin (EBA) and radioiodine (([131]-)Iodine), brain water content and neuronal injuries were determined. Hypertensive rats subjected to 4 h restraint at room temperature did not exhibit BBB dysfunction, brain edema, neural injury, or alterations in rotarod or inclined plane angle performances. However, when these hypertensive rats were subjected to restraint at 33 A degrees C, breakdown of the cortical BBB (EBA, +38 %; radioiodine, +56 %), brain water (+0.88 %), neuronal damages (+18 %), and behavioral impairment were exacerbated. Interestingly, SiO2 exposure to these rats further exacerbated BBB breakdown (EBA, 280 %; radioiodine, 350 %), brain edema (4 %), and neural injury (30 %) after identical restraint depending on the ambient temperature. SiO2 treatment also induced brain pathology and alteration in behavioral functions in normotensive rats after restraint at high temperature. These observations clearly show that hypertension significantly enhances restraint-induced brain pathology, and behavioral anomalies particularly at high ambient temperature and SiO2 intoxication further exacerbated these brain pathologies and cognitive dysfunctions.
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39.
  • Sharma, Hari Shanker, et al. (författare)
  • Exacerbation of Methamphetamine Neurotoxicity in Cold and Hot Environments : Neuroprotective Effects of an Antioxidant Compound H-290/51
  • 2015
  • Ingår i: Molecular Neurobiology. - : Springer Science and Business Media LLC. - 0893-7648 .- 1559-1182. ; 52:2, s. 1023-1033
  • Tidskriftsartikel (refereegranskat)abstract
    • In this study, we examined the influence of cold and hot environments on methamphetamine (METH) neurotoxicity in both drug-naive rats and animals previously exposed to different types of nanoparticles (NPs). Since METH induces oxidative stress, we also examined how a potential chain-breaking antioxidant H-290/51 (Astra-Zeneca, Molndal, Sweden) affects METH-induced neurotoxicity. Exposure of drug-naive rats to METH (9 mg/kg, s.c.) at 4, 21, or 34 A degrees C for 3 h resulted in breakdown of the blood-brain barrier (BBB), brain edema, and neuronal injuries, which all differed in severity depending upon ambient temperatures. The changes were moderate at 21 A degrees C, 120-180 % larger at 34 A degrees C, and almost absent at 4 A degrees C. In rats chronically treated with NPs (SiO2, Cu, or Ag; 50-60 nm, 50 mg/kg, i.p. for 7 days), METH-induced brain alterations showed a two- to fourfold increase at 21 A degrees C, a four- to sixfold increase at 34 A degrees C, and three- to fourfold increase at 4 A degrees C. SiO2 exposure showed the most pronounced METH-induced brain pathology at all temperatures followed by Ag and Cu NPs. Pretreatment with a potent antioxidant compound H-290/51 (50 mg/kg, p.o., 30 min before METH) significantly reduced brain pathology in naive animals exposed to METH at 21 and 34 A degrees C. In NPs-treated animals, however, attenuation of METH-induced brain pathology occurred only after repeated exposure of H-290/51 (-30 min, 0 min, and +30 min). These observations are the first to show that NPs exacerbate METH-induced brain pathology in both cold and hot environments and demonstrate that timely intervention with antioxidant H-290/51 could have neuroprotective effects.
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40.
  • Sharma, Hari Shanker, et al. (författare)
  • Histaminergic Receptors Modulate Spinal Cord Injury-Induced Neuronal Nitric Oxide Synthase Upregulation and Cord Pathology : New Roles of Nanowired Drug Delivery for Neuroprotection
  • 2017
  • Ingår i: Nanomedicine In Central Nervous System Injury And Repair. - : Elsevier. - 9780128123812 ; , s. 65-98
  • Bokkapitel (refereegranskat)abstract
    • The possibility that histamine influences the spinal cord pathophysiology following trauma through specific receptor-mediated upregulation of neuronal nitric oxide synthase (nNOS) was examined in a ratmodel. A focal spinal cord injury (SCI) was inflicted by a longitudinal incision into the right dorsal horn of the T10-11 segments. The animals were allowed to survive 5h. The SCI significantly induced breakdown of the blood-spinal cord barrier to protein tracers, reduced the spinal cord blood flowat 5h, and increased the edema formation and massive upregulation of nNOS expression. Pretreatment with histamine H1 receptor antagonist mepyramine (1mg, 5mg, and 10mg/kg, i.p., 30min before injury) failed to attenuate nNOS expression and spinal cord pathology following SCI. On the other hand, blockade of histamine H2 receptors with cimetidine or ranitidine (1mg, 5mg, or 10mg/kg) significantly reduced these early pathophysiological events and attenuated nNOS expression in a dose-dependent manner. Interestingly, TiO2-naowire delivery of cimetidine or ranitidine (5mg doses) exerted superior neuroprotective effects on SCIinduced nNOS expression and cord pathology. It appears that effects of ranitidine were far superior than cimetidine at identical doses in SCI. On the other hand, pretreatment with histamine H3 receptor agonist a-methylhistamine (1mg, 2mg, or 5mg/kg, i.p.) that inhibits histamine synthesis and release in the central nervous systemthwarted the spinal cord pathophysiology and nNOS expression when used in lower doses. Interestingly, histamine H3 receptor antagonist thioperamide (1mg, 2mg, or 5mg/kg, i.p.) exacerbated nNOS expression and cord pathology after SCI. These novel observations suggest that blockade of histamine H2 receptors or stimulation of histamine H3 receptors attenuates nNOS expression and induces neuroprotection in SCI. Taken together, our results are the first to demonstrate that histamine-induced pathophysiology of SCI is mediated via nNOS expression involving specific histamine receptors.
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41.
  • Sharma, Hari Shanker, et al. (författare)
  • Methamphetamine exacerbates pathophysiology of traumatic brain injury at high altitude. Neuroprotective effects of nanodelivery of a potent antioxidant compound H-290/51
  • 2021
  • Ingår i: Brain protection strategies and nanomedicine. - : Elsevier BV. - 9780323989275 ; 266, s. 123-193
  • Bokkapitel (refereegranskat)abstract
    • 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.
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42.
  • Sharma, Hari Shanker, et al. (författare)
  • Nanoparticles Exacerbate Both Ubiquitin and Heat Shock Protein Expressions in Spinal Cord Injury : Neuroprotective Effects of the Proteasome Inhibitor Carfilzomib and the Antioxidant Compound H-290/51
  • 2015
  • Ingår i: Molecular Neurobiology. - : Springer Science and Business Media LLC. - 0893-7648 .- 1559-1182. ; 52:2, s. 882-898
  • Tidskriftsartikel (refereegranskat)abstract
    • Increased levels of ubiquitin and heat shock protein (HSP) 72 kD are often seen in spinal cord injury (SCI). However, their roles in cell injury or survival are not well known. Thus, we have investigated the possible relationship between ubiquitin and HSP expressions in relation to cell injury in healthy animals, or following nanoparticle (NP) intoxication in SCI animals. A focal SCI was inflicted on the T10-11 segments over the right dorsal horn; animals were allowed to survive from 5 to 8 h after trauma. Separate groups of rats were exposed to SiO2, Ag, or Cu NPs for 7 days and subjected to SCI on the eighth day. A marked increase in ubiquitin or HSP immunoreactive cells occurred in the T9 to T12 segments 5 h after the injury, which further extended to the T4 and L5 after 8 h of survival. At this time, a marked increase in blood-spinal cord barrier (BSCB) permeability to Evans blue and radioiodine, accompanied by an intense edema formation, was observed. Changes were further exacerbated in NP-treated traumatized rats. The most marked expressions of ubiquitin and HSP in SCI were seen in rats treated with SiO2, followed by Ag, and Cu NPs. Treatment with H-290/51 (50 mg/kg p.o., 30 to 60 min after injury) or carfilzomib (1 mg/kg, i.v., 30 to 60 min after trauma) significantly reduced the ubiquitin or HSP expressions, as well as the BSCB breakdown, the edema formation, and the cell injury in the cord both 5 and 8 h after the injury, in normal animals. However, a double dose of H-290/51 (100 mg/kg) or carfilzomib (2 mg/kg) is needed to reduce cord pathology or ubiquitin and HSP expressions in traumatized animals treated with NPs. H-290/51 showed superior beneficial effects in reducing cord pathology in SCI than carfilzomib. These observations are the first to demonstrate that (i) NP-treated traumatized animals induce a widespread BSCB leakage, edema formation, and cord pathology as well as an overexpression of ubiquitin and HSP, (ii) high doses of antioxidant compounds or proteasome inhibitors are required for neuroprotection in the NP-exposed traumatized group, and (iii) ubiquitin and HSP expressions play a key role in neuronal injury in SCI, not reported earlier.
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43.
  • Sharma, Hari Shanker, et al. (författare)
  • Nanoparticles influence pathophysiology of spinal cord injury and repair
  • 2009
  • Ingår i: Progress in Brain Research. - Amsterdam : Elsevier. - 0079-6123 .- 1875-7855. - 9780444534316 ; 180, s. 155-180
  • Forskningsöversikt (refereegranskat)abstract
    • Spinal cord injury (SCI) is a serious clinical problem for which no suitable therapeutic strategies have been worked out so far. Recent studies suggest that the SCI and its pathophysiological responses could be altered by systemic exposure to nanoparticles. Thus, SCI when made in animals intoxicated with engineered nanoparticles from metals or silica dust worsened the outcome. On the other hand, drugs tagged with titanium (TiO2) nanoparticles or encapsulated in liposomes could enhance their neuroprotective efficacy following SCI. Thus, to expand our knowledge on nanoparticle-induced alterations in the spinal cord pathophysiology further research is needed. These investigations will help to develop new strategies to achieve neuroprotection in SCI, for example, using nanodrug delivery. New results from our laboratory showed that nanoparticle-induced exacerbation of cord pathology following trauma can be reduced when the suitable drugs tagged with TiO2 nanowires were administered into the spinal cord as compared to those drugs given alone. This indicates that nanoparticles depending on the exposure and its usage could induce both neurotoxicity and neuroprotection. This review discusses the potential adverse or therapeutic utilities of nanoparticles in SCI largely based on our own investigations. In addition, possible mechanisms of nanoparticle-induced exacerbation of cord pathology or enhanced neuroprotection following nanodrug delivery is described in light of recently available data in this rapidly emerging field of nanoneurosciences.
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44.
  • Sharma, Hari Shanker, et al. (författare)
  • Nanowired Delivery of Cerebrolysin and Mesenchymal Stem Cells Potentiate Neuroprotection Following Concussive Head Injury
  • 2017
  • Ingår i: The journal of head trauma rehabilitation. - 0885-9701 .- 1550-509X. ; 32:6, s. E67-E68
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • Introduction/Rational: Military personnel are highly vulnerable to concussive head injury (CHI) during combat operations resulting in long-term disability. Since no suitable treatments are available novel therapeutic strategies using combination therapy is needed. Since, stem cells and/or neurotrophic factors are shown to induce neuroprotection in central nervous system (CSN) injuries and nanodelivery of therapeutic agents have superior effects on neuroprotection in brain injury, in this investigation we used nanowired delivery of mesenchymal stem cells (MSCs) together with a multimodal drug cerebrolysin- a powerful combination of various neurotrophic factors and active peptide fragments in CHI to induce neuroprotection in CHI.Method/Approach: CHI was inflicted in rats using a weight drop of 114.6 g on the right parietal skull under Equithesin anesthesia from a 20 cm height causing an impact of 0.224 N and mimic the “counter-coup” phenomenon as seen 48 h after the primary insult. In separate groups, commercially available MSCs (1 million cells) in combination with Cerebrolsyin (2.5 ml/kg; Ever NeuroPharma, Austria) either as such or with TiO2 nanowired formulations were delivered intravenously 4 and 8 after CHI. After 48 h CHI blood-brain barrier (BBB) to Evans blue and radioiodine, brain edema and neuronal injuries were examined.Results/Effects: A focal CHI induced massive breakdown of the BBB to Evans blue albumin and [131]-Iodine and volume swelling at 48 h that was significantly higher in the left hemisphere as compared to the right side. Neuronal damages using Nissl staining was also prominent in the cortex, hippocampus, thalamus and hypothalamus in the left side. Treatment with TiO2 nanowired MSCs and cerebrolysin resulted in significant reduction in brain pathology that was seen in both the right and left hemispheres. Whereas, normal MSCs and cerebrolysin were able to reduce brain pathology largely in the right side only.Conclusions/Limitations: These observations are the first to demonstrate that a combination of nanowired Cerebrolsyin and MSCs synergistically induced efficient neuroprotection in CHI, not reported earlier. It would be interesting to see whether this combination when administered 8 or 12 h after CHI whether neuroprotective effects are still visible at 48 h, a feature currently being investigated in our laboratory.
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45.
  • Sharma, Hari Shanker, et al. (författare)
  • 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
  • 2021
  • Ingår i: Progress in Brain Research. - : Elsevier. - 0079-6123 .- 1875-7855. ; 266, s. 97-121, s. 97-121
  • Tidskriftsartikel (refereegranskat)abstract
    • 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 (50–60 nm) 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 μg/kg, i.v. but not 0.5 μg/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.
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46.
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47.
  • Sharma, Hari Shanker, et al. (författare)
  • Pathophysiology of Blood-Brain Barrier in Brain Injury in Cold and Hot Environments : Novel Drug Targets for Neuroprotection
  • 2016
  • Ingår i: CNS & Neurological Disorders. - : Bentham Science Publishers Ltd.. - 1871-5273 .- 1996-3181. ; 15:9, s. 1045-1071
  • Forskningsöversikt (refereegranskat)abstract
    • The blood-brain barrier (BBB) plays a pivotal role in the maintenance of central nervous system function in health and disease. Thus, in almost all neurodegenerative, traumatic or metabolic insults BBB breakdown occurs, allowing entry of serum proteins into the brain fluid microenvironment with subsequent edema formation and cellular injury. Accordingly, pharmacological restoration of BBB function will lead to neurorepair. However, brain injury which occurs following blast, bullet wounds, or knife injury appears to initiate different sets of pathophysiological responses. Moreover, other local factors at the time of injury such as cold or elevated ambient temperatures could also impact the final outcome. Obviously, drug therapy applied to different kinds of brain trauma occurring at either cold or hot environments may respond differently. This is largely due to the fact that internal defense mechanisms of the brain, gene expression, release of neurochemicals and binding of drugs to specific receptors are affected by external ambient temperature changes. These factors may also affect BBB function and development of edema formation after brain injury. In this review, the effects of seasonal exposure to heat and cold on traumatic brain injury using different models i.e., concussive brain injury and cerebral cortical lesion, on BBB dysfunction in relation to drug therapy are discussed. Our observations clearly suggest that closed head injury and open brain injury are two different entities and the external hot or cold environments affect both of them remarkably. Thus, effective pharmacological therapeutic strategies should be designed with these views in mind, as military personnel often experience blunt or penetrating head injuries in either cold or hot environments.
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48.
  • Sharma, Hari Shanker, et al. (författare)
  • Pathophysiology of blood-brain barrier in brain tumor. : Novel therapeutic advances using nanomedicine
  • 2020
  • Ingår i: Novel Therapeutic Advances In Glioblastoma. - LONDON ENGLAND : Elsevier. - 9780128211144 ; , s. 1-66
  • Bokkapitel (refereegranskat)abstract
    • Glioblastoma Multiforme (GBM) is one the most common intracranial tumors discovered by Burns (1800) and Abernethy (1804) based on gross morphology of the autopsied material and referred to as "medullary sarcoma" and later "fungus medullare" (Abernethy, 1804; Burns, 1800). Virchow in 1863 was the first German pathologist using histomorphological techniques discovered that GBM is a tumor of glial origin. Virchow (1863/65) also then used the term Glioma for the first time and classified as low-grade glioma and high-grade glioma very similar to that of today according to World health organization (WHO) classification (Jellinger, 1978; Virchow, 1863/65). After almost >50 years of this discovery, Baily and Cushing (1926) based on modern neuropathological tools provide the classification of gliomas that is still valid today (Baily & Cushing, 1926). Although, our knowledge about development of gliomas has advanced through development of modern cellular and molecular biological tools (Gately, McLachlan, Dowling, & Philip, 2017; Omuro & DeAngelis, 2013), therapeutic advancement of GBM still requires lot of efforts for the benefit of patients. This review summarizes new developments on pathophysiological aspects of GBM and novel therapeutic strategies to enhance quality of life of patients. These novel therapeutic approaches rely on enhanced penetration of drug therapy into the tumor tissues by use of nanomedicine for both the diagnostic and therapeutic purposes, referred to as "theranostic nanomedicine" (Alphandery, 2020; Zhao, van Straten, Broekman, Preat, & Schiffelers, 2020). Although, the blood-brain barrier (BBB) is fenestrated around the periphery of the tumor tissues, the BBB is still tight within the deeper tissues of the tumor. Thus, drug delivery is a challenge for gliomas and requires new therapeutic advances (Zhao et al., 2020). Associated edema development around tumor tissues is another factor hindering therapeutic effects (Liu, Mei, & Lin, 2013). These factors are discussed in details using novel therapeutic advances in gliomas.
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49.
  • Sharma, Hari Shanker, et al. (författare)
  • Silicon dioxide nanoparticles (SiO2, 40-50 nm) exacerbate pathophysiology of traumatic spinal cord injury and deteriorate functional outcome in the rat : An experimental study using pharmacological and morphological approaches
  • 2009
  • Ingår i: Journal of Nanoscience and Nanotechnology. - : American Scientific Publishers. - 1533-4880 .- 1533-4899. ; 9:8, s. 4970-4980
  • Tidskriftsartikel (refereegranskat)abstract
    • Silicon (SiO2) nanoparticles or silica dust is quite common form of exposure to soldiers engaged in gulf war that may influence their health and brain function. It is quite likely that traumatic injuries to the CNS may be influenced by exposure to these nanoparticles. However, the details of silicon nanoparticles on human health functions are still unknown. In this investigation we examined the effects of chronic silicon dioxide nanoparticles (SiO2, 40-50 nm) exposure on spinal cord injury (SCI) induced alterations on the functional outcome and the cord pathology in a rat model. Since nanoparticles induce oxidative stress, the influence of an antioxidant compound H-290/51 was also examined in these nanoparticles treated injured rats as well. Rats treated with SiO2 for 7 days did not show any significant alteration in behaviour on rota rod performances or on capacity angle tests. However, subjection of these nanoparticles exposed rats to SCI resulted in a profound deterioration in motor functions compared to normal rats with SCI. The magnitude of blood-spinal cord barrier (BSCB) disruption to Evans blue and radioiodine tracers and edema formation was much more aggravated following SCI in nanoparticles treated animals compared to untreated traumatized rats. Pretreatment with H-290/51 (50 mg/kg, p.o.) 30 min before SCI in nanoparticle treated rats did not alter spinal cord pathology or functional outcome, however, this dose of the compound was very effective in reducing pathophysiology of SCI in normal animals. These observations are the first to suggest that exposure of nanoparticles enhances the sensitivity of CNS to injuries and alter the effect of neuroprotective drugs.
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50.
  • Sharma, Hari Shanker, et al. (författare)
  • 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
  • 2021
  • Ingår i: Progress in Brain Research. - : Elsevier. - 0079-6123 .- 1875-7855. ; 266, s. 301-348, s. 301-348
  • Tidskriftsartikel (refereegranskat)abstract
    • 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 °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.
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