Neurochemistry international
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The present study investigated oxidative damage and neuroprotective effect of the antiparkinsonian drug, L-deprenyl in neuronal death produced by intranigral infusion of a potent mitochondrial complex-I inhibitor, rotenone in rats. Unilateral stereotaxic intranigral infusion of rotenone caused significant decrease of striatal dopamine levels as measured employing HPLC-electrochemistry, and loss of tyrosine hydroxylase immunoreactivity in the perikarya of ipsilateral substantia nigra (SN) neurons and their terminals in the striatum. Rotenone-induced increases in the salicylate hydroxylation products, 2,3- and 2,5-dihydroxybenzoic acid indicators of hydroxyl radials in mitochondrial P2 fraction were dose-dependently attenuated by L-deprenyl. ⋯ The rotenone-induced elevated activities of cytosolic antioxidant enzymes superoxide dismutase and catalase showed further significant increase following L-deprenyl. Our findings suggest that unilateral intranigral infusion of rotenone reproduces neurochemical, neuropathological and behavioral features of PD in rats and L-deprenyl can rescue the dopaminergic neurons from rotenone-mediated neurodegeneration in them. These results not only establish oxidative stress as one of the major causative factors underlying dopaminergic neurodegeneration as observed in Parkinson's disease, but also support the view that deprenyl is a potent free radical scavenger and an antioxidant.
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Hypoxia is a common cause of cell death and is implicated in many disease processes including stroke and chronic degenerative disorders. In response to hypoxia, cells express a variety of genes which allow adaptation to altered metabolic demands, decreased oxygen demands, and the removal of irreversibly damaged cells. Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that regulates the adaptive response to hypoxia in cells. ⋯ Epo responds to ischemia in an early stage, whereas VEGF and BNIP3 accumulate in cells at later times after ischemia. This suggests the possibility that BH3-only proteins might be one of the major downstream effectors of HIF-1alpha in hypoxic cell death. These findings open the possibility that the hypoxia-regulated pro-apoptotic protein BNIP3 enters the nucleus and could interact with other proteins involved in DNA structure, transcription or mRNA splicing after focal brain ischemia.
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The function of muscarinic acetylcholine receptors expressed in oligodendrocytes and in myelin has remained largely undetermined. Here we present evidence that incubation of oligodendrocyte progenitors, deprived of growth factor, with the acetylcholine analog carbachol significantly reduced cell death by apoptosis and blocked caspase-3 cleavage. This protective effect was reversed by atropine, a muscarinic acetylcholine receptor antagonist, as well as by specific inhibitors of intracellular signaling molecules, including phosphatidylinositol 3-kinase (Wortmannin and LY294002), Akt (Akt inhibitor III) and Src-like tyrosine kinases (PP2), but not by the mitogen-activated protein kinase kinase inhibitor, PD98059. ⋯ The Src-like tyrosine kinase inhibitor, PP2, also reduced carbachol stimulation of extracellular signal-regulated kinases 1/2 and cAMP-response element binding protein in a dose-dependent manner. Furthermore, carbachol increased tyrosine-phosphorylation of Fyn, a member of the Src-like tyrosine kinases. These results indicate that muscarinic acetylcholine receptors play an important role in oligodendrocyte progenitor survival through transduction pathways involving activation of Src-like tyrosine kinases and phosphatidylinositol 3-kinase/Akt.
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1-{3-[2-(1-Benzothiophen-5-yl)ethoxy]propyl}-3-azetidinol maleate (T-817MA), a novel neurotrophic agent, protects against amyloid-beta peptide- or hydrogen peroxide-induced neuronal death. The exact mechanism of the neuroprotection is not known. This study examines the effects of T-817MA on oxidative stress-induced cytotoxicity in primary rat cortical neurons. ⋯ In addition, the agent reduced SNP-induced increase in mitochondrial reactive oxygen species (ROS) production. The effects of T-817MA on SNP-induced decrease in cell viability and SNP-induced increase in mitochondrial ROS production were blocked by cycloheximide. These results suggest that T-817MA improves SNP-induced mitochondrial dysfunction in cortical neurons in a newly synthesized protein-mediated mechanism and this effect contributes to its neuroprotective effect.
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Preconditioning (PC) is a phenomenon in which a brief ischemic insult induces tolerance against a subsequent severe ischemic insult. Recent studies showed that cerebral ischemia in adult rat upregulates progenitor cell proliferation in the hippocampal dentate gyrus. We presently evaluated whether PC can also stimulate progenitor cell proliferation in rat brain. ⋯ Furthermore, cerebral mRNA expression of the growth factors IGF1, FGF2, TGFbeta1, EGF and PDGF-A was significantly elevated after PC. Thus, we show that the beneficial effects of PC extend beyond providing neuroprotection during the acute phase after ischemia. Induction of growth factor expression and neurogenesis by PC might be a positive adaptation for an efficient repair and plasticity in the event of an ischemic insult.