Neurochemistry international
-
A brief ischemic insult induces significant protection against subsequent massive ischemic events. The molecular mechanisms underlying this phenomenon known as preconditioning (PC)-induced ischemic tolerance are not completely understood. Inflammation seen during the acute phase after stroke is known to be detrimental to the neurological outcome. ⋯ Prior PC significantly reduced the post-ischemic increased expression of many inflammatory genes including cytokines, chemokines, adhesion molecules and pro-inflammatory transcription factors, and prevented the infiltration of neutrophils and macrophages in the ipsilateral cortex of rats subjected to focal ischemia. PC also decreased the volume of infarction and neurological dysfunction caused by transient focal ischemia. These studies indicate that prevention of inflammation might be a contributing mechanism by which PC induces protection against focal ischemia.
-
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.
-
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.
-
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.
-
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.