| 1. |
- Muresanu, Dafin Fior, et al.
(författare)
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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
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Ingår i: New Therapeutic Strategies for Brain Edema and Cell Injury. - : Elsevier. - 9780128167540 ; , s. 83-102
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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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| 2. |
- Ozkizilcik, Asya, et al.
(författare)
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Timed Release of Cerebrolysin Using Drug-Loaded Titanate Nanospheres Reduces Brain Pathology and Improves Behavioral Functions in Parkinson's Disease
- 2018
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Ingår i: Molecular Neurobiology. - : HUMANA PRESS INC. - 0893-7648 .- 1559-1182. ; 55:1, s. 359-369
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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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| 3. |
- Sharma, Hari Shanker, et al.
(författare)
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Neuroprotective effects of cerebrolysin, a combination of different active fragments of neurotrophic factors and peptides on the whole body hyperthermia-induced neurotoxicity : modulatory roles of co-morbidity factors and nanoparticle intoxication
- 2012
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Ingår i: International review of neurobiology. - 0074-7742 .- 2162-5514. ; 102, s. 249-276
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Tidskriftsartikel (refereegranskat)abstract
- Military personals are often exposed to adverse environmental circumstances, for example, heat stress during peacekeeping or combat operations in summer months or in desert areas leading to disturbed mental functions. The suitable therapeutic strategies to treat heat-induced mental anomalies are still not worked out. Thus, exploration of suitable therapeutic strategies to minimize heat-induced abnormal brain function is needed in suitable animal models. Previous works from our laboratory show that rats exposed to whole body hyperthermia (WBH) for 4 h at 38 °C exhibited profound neuronal, glial, and axonal damages in the cerebral cortex, hippocampus, cerebellum, thalamus, and hypothalamus in a specific manner at light microscopy. Electron microscopy further revealed endothelial cell membrane damage, that is, breakdown of the blood-brain barrier (BBB) after WBH in the brain areas showing cellular damages. These observations indicate that breakdown of the BBB is instrumental in hyperthermia-induced brain injury. Pretreatment with cerebrolysin (2.5 ml or 5 ml/kg, i.v. 30 min before WBH), a mixture of various neurotropic factors and active peptide fragments significantly attenuated BBB disruption and brain damage following heat exposure in a dose-dependent manner. Furthermore, repeated administration of cerebrolysin (5 ml/kg, i.v.) starting from 30 min to 1h after but not after 1.5 or 2 h WBH markedly reduced the BBB disruption and neurotoxicity. Taken together our observations suggest that cerebrolysin if administered within 1 h after WBH in suitable doses induce marked reduction in neurotoxicity. This indicated that cerebrolysin has potential therapeutic value to treat heat stress victims to prevent mental dysfunction in future clinical settings.
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