The rationale for activated protein C treatment in perinatal white matter injury.
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Anti-Inflammatory Agents↗
Biomedical subjects
Kursad Genc
Publications and source records attributed to Kursad Genc.
Activated protein C: possible therapeutic implications for multiple sclerosis.
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Enzyme Activation↗
Endothelial nitric oxide-mediated Nrf2 activation as a novel mechanism for vascular and neuroprotection by erythropoietin in experimental subarachnoid hemorrhage.
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Animals↗
Erythropoietin downregulates bax and DP5 proapoptotic gene expression in neonatal hypoxic-ischemic brain injury.
BACKGROUND: Perinatal asphyxia is an important cause of neonatal mortality and subsequent serious sequelae such as motor and cognitive deficits and seizures. The ameliorative effect of erythropoietin (Epo) on experimental hypoxic-ischemic brain injury in neonatal rats has been recently reported. Recent studies also confirm the antiapoptotic effect of Epo in a variety of in vitro and in vivo neuronal injury models including hypoxic-ischemic brain injury. However, molecular mechanisms of Epo protection and antiapoptotic effect in this model are unclear. Epo may exert its antiapoptotic effect via the differential regulation of the expression of genes involved in the apoptotic process. OBJECTIVES: Thus, in the present study, we studied the effects of systemically administered Epo on antiapoptotic (bcl-2, bcl-XL), proapoptotic (bax and DP5) gene expression following hypoxic-ischemic brain injury in neonatal rats. METHODS: Seven- day-old Wistar rat pups were divided into three groups: control group (n=15), saline-treated group (n=17), and Epo-treated group (n=18). Rat pups were subjected to left carotid artery occlusion followed by 2.5 h of hypoxic exposure. Epo-treated group received an intraperitoneal injection of recombinant human Epo at a dose of 1,000 units/kg, saline-treated group received an intraperitoneal injection of saline at the same volume of Epo. Forty-eight hours after hypoxia, 3 animals in each group were killed for histopathological evaluation. To detect DNA fragmentation in cell nuclei, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling reaction was applied. Bcl-2 and bax protein expression were also analyzed with immunohistochemistry. For reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, rats were sacrificed 4, 12, and 24 h after hypoxia. Bcl-2, bcl-XL, bax, and DP5 mRNA expression were analyzed by RT-PCR. RESULTS: Epo significantly prevented hypoxia-ischemia-induced bax and DP5 mRNA upregulation in brain tissue. Epo did not show any effect on bcl-XL transcription altered by injury. However, Epo reversed injury-induced downregulation in bcl-2 transcription. Modulating effects of Epo on bcl-2 and bax protein expression were also revealed by immunohistochemistry. CONCLUSIONS: These results suggest that Epo exerts a neuroprotective effect against hypoxic-ischemic brain injury, at least partially, via the differential regulation of the expression of genes involved in apoptotic process.
Animals↗
RNA interference in neuroscience.
One of the most exciting findings in recent years has been the discovery of RNA interference (RNAi). RNAi is an important system that allows sequence-specific gene silencing through targeted degradation of mRNA by cognate double-stranded RNA (dsRNA). RNAi plays a role in endogenous cellular processes, such as developmental control and heterochromatin formation, and serves as an antiviral defense mechanism. Recent findings suggest that RNAi and related pathways are involved in protecting the genome against instabilities caused by transposons and repetitive sequences. Several rapidly developing RNAi methodologies provide a new approach for elucidation of gene functions. RNAi technology is also currently being evaluated as a potentially useful method to develop highly specific dsRNA-based gene-silencing therapeutics. In this paper, we review the use of RNAi in neuroscience research and as a possible therapeutic tool for treatment of neurological diseases.
Animals↗
Hyperbilirubinemic serum is cytotoxic and induces apoptosis in murine astrocytes.
BACKGROUND: High levels of unconjugated bilirubin can be neurotoxic and gliotoxic. However, the effect of serum from patients with neonatal indirect hyperbilirubinemia on astrocyte viability has never been investigated. OBJECTIVES: In the present study, we searched for the possible toxic effect of hyperbilirubinemic serum on murine astrocytes. METHODS: Heat-inactivated patient serum was added to astrocyte cultures at different concentrations varying from 1 to 20%, and cultures were incubated for 24, 48, and 72 h. Sera from healthy infants without hyperbilirubinemia were used as controls. Cytotoxicity was evaluated according to the release of lactate dehydrogenase in the culture medium. Apoptotic cell death was determined by anti-single-strand DNA immunostaining. RESULTS: The results of the present study show that hyperbilirubinemic serum induces cytotoxicity and apoptotic astrocyte death in a concentration- and time-dependent manner. CONCLUSIONS: We conclude that serum from patients with neonatal indirect hyperbilirubinemia is cytotoxic to murine astrocytes.
Animals↗
Erythropoietin increases glutathione peroxidase enzyme activity and decreases lipid peroxidation levels in hypoxic-ischemic brain injury in neonatal rats.
BACKGROUND: We have previously shown that erythropoietin (Epo) exerts neuroprotective effects in the Rice-Vannucci model of neonatal hypoxic-ischemic brain injury. However, the mechanisms of Epo protection in this model are still unclear. OBJECTIVES: In the present study, we studied the effects of systemically administered Epo on lipid peroxidation levels and antioxidant enzyme (superoxide dismutase and glutathione peroxidase) activities following hypoxic-ischemic brain injury in neonatal rats. METHODS: Seven-day-old Wistar rat pups were subjected to left carotid artery occlusion followed by 2.5 h of hypoxic exposure. Brain lipid peroxidation levels and antioxidant enzyme activities were measured in the injured hemispheres 24 h after the hypoxic-ischemic insult. RESULTS: Hypoxic-ischemic injury significantly increased the thiobarbituric acid-reactive substance levels in the injured hemispheres as compared to the control group. In addition, glutathione peroxidase activity was significantly elevated in Epo-treated animals compared to saline-treated animals and the control group. CONCLUSIONS: These results suggest that Epo exerts neuroprotective effects against hypoxic-ischemic brain injury at least partially via the modulation of antioxidant enzyme activity.
Animals↗
Erythropoietin improves long-term spatial memory deficits and brain injury following neonatal hypoxia-ischemia in rats.
It is well known that neonatal hypoxic-ischemic brain injury leads to mental retardation and deficits in cognitive abilities such as learning and memory in human beings. The ameliorative effect of erythropoietin (Epo) on experimental hypoxic-ischemic brain injury in neonatal rats has been recently reported. However, the effect of Epo on cognitive abilities in the hypoxic-ischemic brain injury model is unknown. The aim of this study is to investigate the effects of Epo on learning-memory, behavior and neurodegeneration induced by hypoxia-ischemia. Seven days old Wistar Albino rat pups have been used in the study (n = 28). Experimental groups in the study were: (1) saline-treated hypoxia-ischemia group, (2) Epo-treated (i.p., 1000 U/kg) hypoxia-ischemia group, (3) sham-operated group, (4) control group. In hypoxia-ischemia groups, left common carotid artery was ligated permanently on the seventh postnatal day. Two hours after the procedure, hypoxia (92% nitrogen and 8% oxygen) was induced for 2.5 h. Epo was administered as a single dose immediately after the hypoxia period. When pups were 22 days old, learning experiments were performed using Morris water maze. On the 20th week, when brain development is accepted to be complete, learning experiments were repeated. Rats were then perfused and brains removed for macroscopic and microscopic evaluation. Epo treatment immediately after hypoxic-ischemic insult significantly improved long-term neurobehavioral achievements when tested during the subsequent phase of brain maturation and even into adulthood. Histopathological evaluation demonstrated that Epo also significantly diminished brain injury and spared hippocampal CA1 neurons. In conclusion, Epo administrated as a single dose immediately after neonatal hypoxic-ischemic insult provides benefit over a prolonged period in the still developing rat brain. Since the wide use of Epo in premature newborns, this agent may be potentially beneficial in treating asphyxial brain damage in the perinatal period.
Analysis of Variance↗
Erythropoietin and the nervous system.
Erythropoietin (Epo) is a hematopoietic growth factor and cytokine which stimulates erythropoiesis. In recent years, Epo has been shown to have important nonhematopoietic functions in the nervous system. Nonerythropoietic actions of Epo include a critical role in the development, maintenance, protection and repair of the nervous system. A wide variety of experimental studies have shown that Epo and its receptor are expressed in the nervous system and Epo exerts remarkable neuroprotection in cell culture and animal models of nervous system disorders. In this review, we summarize the current knowledge on the neurotrophic and neuroprotective properties of Epo, the mechanisms by which Epo produces neuroprotection and the signal transduction systems regulated by Epo in the nervous system.
Animals↗
Analysis of cytotoxic T lymphocyte antigen-4 (CTLA-4) exon 1 polymorphism in patients with type 1 diabetes mellitus in a Turkish population.
Recent studies have described linkage and association between cytotoxic T-lymphocyte antigen-4 (CTLA-4) gene polymorphism and type 1 diabetes mellitus (DM1) in some ethnic populations, but not others. This finding suggests that CTLA-4 gene association with DM1 may be influenced by the racial composition of the population. Thus, it is important to study the polymorphism of the CTLA-4 gene in different ethnic groups. In this case-control association study, the CTLA-4 gene exon 1 A/G polymorphism was analyzed in 48 children with DM1 and 80 healthy controls using polymerase chain reaction-restriction fragment length polymorphism analysis. The possible interaction of the CTLA-4 gene polymorphism with the presence of established genetic markers (HLA-DR genotyping) was also evaluated in 29 patients. The results of the present study do not suggest an association of the known polymorphism in exon 1 of the CTLA-4 gene with DM1 in this Turkish population, and G-allele containing CTLA-4 genotypes were not preferentially associated with age at clinical presentation or with presence of other genetic (HLA-DR3 or -DR4) markers of DM1.
Adolescent↗
Erythropoietin as a novel neuroprotectant.
PURPOSE: To provide an overview of the current knowledge on neuroprotective properties of Erythropoietin (Epo), mechanisms by which Epo produces neuroprotection, and signaling pathways regulated by Epo in the nervous system. METHODS: The Medline database was searched for articles on the neuroprotective properties of Epo. Experimental and clinical studies were systematically reviewed. RESULTS: In addition to promoting the survival, proliferation, and differentiation of immature erythroid cells, Epo and the Epo receptor (EpoR) have recently been shown to exist and function in the nervous system. The Epo/EpoR system plays a critical role in neurodevelopment and neuroprotection. Epo ameliorates or prevents neuronal injury by neuroprotective, anti-apoptotic, anti-inflammatory, anti-oxidant, angiogenic, neurogenic and neurotrophic effects in cell culture and animal models of neurological diseases. The clinical effectiveness of recombinant human Epo in ischemic stroke in human patients has also been reported recently. CONCLUSION: Recent studies suggest that Epo is a potential novel neurotherapeutic agent and further clinical studies are warranted.
Animals↗
Selective inhibition of nitric oxide in hypoxic-ischemic brain model in newborn rats: is it an explanation for the protective role of erythropoietin?
Erythropoietin (Epo) exerts neuroprotection against neuronal death induced by ischemia and hypoxia in vitro and in vivo. Recent studies suggest that the neuroprotective effects of Epo may depend upon different mechanisms, including the inhibition of nitric oxide (NO). We recently demonstrated that Epo exerts neuroprotection in a model of neonatal hypoxic-ischemic brain damage. In the present study, we directly determined whether systemic administration of recombinant Epo modulates cerebral NO production in a neonatal rat model of hypoxic-ischemic brain injury. Seven-day-old Wistar rat pups were subjected to left carotid artery occlusion followed by 2.5 h of hypoxic exposure. Brain nitrite levels were evaluated in both hemispheres (carotid ligated or nonligated) by Griess reagent 72 h after the hypoxic-ischemic insult. Our results show that hypoxic-ischemic insult results a significant increase in NO production as compared with NO levels in hypoxic hemispheres and control animals. A single dose of Epo treatment (1,000 U/kg i.p.) significantly decreased NO overproduction in the hypoxic-ischemic hemisphere, whereas no significant change appeared in hypoxia alone or in controls. These data suggest that the selective inhibitory effect of Epo on NO overproduction could have a neuroprotective effect in neonatal hypoxic-ischemic brain injury.
Animals↗
Bilirubin is cytotoxic to rat oligodendrocytes in vitro.
High levels of unconjugated bilirubin can be neurotoxic and gliotoxic. However, the effect of bilirubin on oligodendrocyte viability has never been investigated. In the present study, we searched the possible toxic effect of bilirubin on differentiated rat oligodendrocytes. Bilirubin was added to oligodendrocyte cultures at different concentrations varied between 10 and 100 microM, and cultures were incubated for different times (24, 48 and 72 h). Cell viability was evaluated by trypan blue exclusion. The results showed that bilirubin decreased oligodendroglial cell viability in a concentration and time-dependent manner. Bilirubin induced apoptotic cell death as revealed by TUNEL staining and poly(ADP-ribose) polymerase cleavage. We found that bilirubin induced inducible nitric oxide synthase (NOS) mRNA expression in rat oligodendrocytes. Bilirubin also increased oligodendroglial nitrite production in a concentration-dependent manner and NOS inhibitor partly blocked bilirubin-induced cytotoxicity. These results suggest that bilirubin induces cytotoxicity, at least partly, via the induction of nitric oxide production in oligodendrocytes.
Analysis of Variance↗
Methamphetamine induces oligodendroglial cell death in vitro.
We investigated whether the psychostimulant methamphetamine (METH) has a cytotoxic effect on oligodendrocytes and which cell-death pathways are involved in the cytotoxic process. METH caused concentration- and time-dependent cytotoxicity in rat oligodendrocyte cultures. METH induced apoptotic cell death and mRNA expression of pro-apoptotic proteins (bax and DP5), but not anti-apoptotic proteins (bcl-2 and bcl-XL). These results suggest that METH induces cytotoxicity in rat oligodendrocytes via the differential regulation of the expression of genes involved in the apoptotic process.
Animals↗
Interferon gamma and lipopolysaccharide upregulate TNF-related apoptosis-inducing ligand expression in murine microglia.
In this study, it is reported that neonatal murine microglia and N9 murine microglial cell line express tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). TRAIL protein and mRNA expression in murine microglia greatly upregulate upon stimulation with interferon gamma (IFNgamma) or lipopolysaccharide (LPS) as revealed by immunoprecipitation-immunoblotting, reverse transcriptase-polymerase chain reaction (RT-PCR) and flow cytometry techniques. IFNgamma and LPS act synergistically to induce TRAIL expression on both translational and transcriptional levels. The upregulated microglial TRAIL in inflammatory conditions may involve in the cytotoxic effect of these cells and play a role in neurodegenerative processes.
Animals↗
Erythropoietin restores glutathione peroxidase activity in 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine-induced neurotoxicity in C57BL mice and stimulates murine astroglial glutathione peroxidase production in vitro.
Recently, we have reported that erythropoietin (Epo) provides neuroprotection in 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP)-induced neurotoxicity in vivo. In the present study, we investigated the effects of single Epo administration on brain antioxidant enzyme (superoxide dismutase (SOD) and glutathion peroxidase (GSHPx)) activities in this model in C57BL/6 mice. We found that MPTP treatment decreased GSHPx activity in both substantia nigra and striatum, and Epo restores nigral GSHPx activity decreased by MPTP. SOD enzyme activity was not significantly changed by MPTP and Epo treatment. Further, Epo stimulated astroglial GSHPx production in neonatal murine astroglial cell culture suggesting that the possible cell source for the stimulation of GSHPx activity by Epo in the MPTP-induced neurotoxicity model are astroglia. In conclusion, modulation of the astroglial antioxidant defense system might be one of the mechanisms by which Epo exerts a beneficial effect in MPTP-induced Parkinsonism.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Erythropoietin prevents motor neuron apoptosis and neurologic disability in experimental spinal cord ischemic injury.
The cytokine erythropoietin (EPO) possesses potent neuroprotective activity against a variety of potential brain injuries, including transient ischemia and reperfusion. It is currently unknown whether EPO will also ameliorate spinal cord injury. Immunocytochemistry performed using human spinal cord sections showed abundant EPO receptor immunoreactivity of capillaries, especially in white matter, and motor neurons within the ventral horn. We used a transient global spinal ischemia model in rabbits to test whether exogenous EPO can cross the blood-spinal cord barrier and protect these motor neurons. Spinal cord ischemia was produced in rabbits by occlusion of the abdominal aorta for 20 min, followed by saline or recombinant human (rHu)-EPO (350, 800, or 1,000 units/kg of body weight) administered intravenously immediately after the onset of reperfusion. The functional neurological status of animals was better for rHu-EPO-treated animals 1 h after recovery from anesthesia, and improved dramatically over the next 48 h. In contrast, saline-treated animals exhibited a poorer neurological score at 1 h and did not significantly improve. Histopathological examination of the affected spinal cord revealed widespread motor neuron injury associated with positive terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling in control but not in rHu-EPO-treated animals. These observations suggest both an acute as well as a delayed beneficial action of rHu-EPO in ischemic spinal cord injury. Because rHu-EPO is currently used widely with an excellent safety profile, clinical trials evaluating its potential to prevent motor neuron apoptosis and the neurological deficits that occur as a consequence of ischemic injury are warranted.
Animals↗