Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The nuclear transcription factor E2F1 plays an important role in modulating neuronal death in response to excitotoxicity and cerebral ischemia. Here, by comparing gene expression in brain cortices from E2F1(+/+) and E2F1(-/-) mice using a custom high-density DNA microarray, we identified a group of putative E2F1 target genes that might be responsible for ischemia-induced E2F1-dependent neuronal death. Neuropilin 1 (NRP-1), a receptor for semaphorin 3A-mediated axon growth cone collapse and retraction, was confirmed to be a direct target of E2F1 based on (i) the fact that the NRP-1 promoter sequence contains an E2F1 binding site, (ii) reactivation of NRP-1 expression in E2F1(-/-) neurons when the E2F1 gene was replaced, (iii) activation of the NRP-1 promoter by E2F1 in a luciferase reporter assay, (iv) electrophoretic mobility gel shift analysis confirmation of the presence of an E2F binding sequence in the NRP-1 promoter, and (v) the fact that a chromatin immunoprecipitation assay showed that E2F1 binds directly to the endogenous NRP-1 promoter. Interestingly, the temporal induction in cerebral ischemia-induced E2F1 binding to the NRP-1 promoter correlated with the temporal-induction profile of NRP-1 mRNA, confirming that E2F1 positively regulates NRP-1 during cerebral ischemia. Functional analysis also showed that NRP-1 receptor expression was extremely low in E2F1(-/-) neurons, which led to the diminished response to semaphorin 3A-induced axonal shortening and neuronal death. An NRP-1 selective peptide inhibitor provided neuroprotection against oxygen-glucose deprivation. Taken together, these findings support a model in which E2F1 targets NRP-1 to modulate axonal damage and neuronal death in response to cerebral ischemia.
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PMID:Neuropilin-1 is a direct target of the transcription factor E2F1 during cerebral ischemia-induced neuronal death in vivo. 1717 35

Neuropilin 2 (NRP2) is a type I transmembrane protein that binds to distinct members of the class III secreted Semaphorin subfamily. NRP2 plays important roles in repulsive axon guidance, angiogenesis and vasculogenesis through partnering with co-receptors such as vascular endothelial growth factor receptors (VEGFRs) during development. Emerging evidence also suggests that NRP2 contributes to injury response and environment changes in adult brains. In this study, we examined the contribution of NRP2 gene to cerebral ischemia-induced brain injury using NRP2 deficient mouse. To our surprise, the lack of NRP2 expression does not affect the outcome of brain injury induced by transient occlusion of the middle cerebral artery (MCAO) in mouse. The cerebral vasculature in terms of the middle cerebral artery anatomy and microvessel density in the cerebral cortex of NRP2 deficient homozygous (NRP2(-/-)) mice are normal and almost identical to those of the heterozygous (NRP2(+/-)) and wild type (NRP2(+/+)) littermates. MCAO (1h) and 24h reperfusion caused a brain infarction of 23% (compared to the contralateral side) in NRP2(-/-) mice, which is not different from those in NRP2(+/- and +/+) mice at 22 and 21%, respectively (n=19, p>0.05). Correspondingly, NRP2(-/-) mouse also showed a similar level of deterioration of neurological functions after stroke compared with their NRP2(+/- and +/+) littermates. Oxygen-glucose-deprivation (OGD) caused a significant neuronal death in NRP2(-/-) cortical neurons, at the level similar to that in NRP(+/+) cortical neurons (72% death in NRP(-/-) neurons vs. 75% death in NRP2(+/+) neurons; n=4; p>0.05). Together, these loss-of-function studies demonstrated that despite of its critical role in neuronal guidance and vascular formation during development, NRP2 expression dose not affect adult brain response to cerebral ischemia.
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PMID:Neuropilin 2 deficiency does not affect cortical neuronal viability in response to oxygen-glucose-deprivation and transient middle cerebral artery occlusion. 2003 91

Membrane rafts, rich in sphingolipids and cholesterol, are membrane microdomains important in neuronal domain-specific signaling events such as during axonal outgrowth and neuronal death. The present study seeks to determine the spatiotemporal association of several axonal guidance signaling molecules with membrane rafts. These molecules are Neuropilin-1 (NRP-1), Fer Kinase, and collapsin response mediator proteins (CRMPs), which are known to have important functions in axonal outgrowth and neuronal death caused by cerebral ischemia. Mice were subjected to sham or a 1h unilateral middle cerebral artery occlusion (MCAO) followed by a time course of reperfusion up to 24h. Brain cortices were separated and membrane rafts were extracted based on their insolubility in Triton X-100 and separation by sucrose gradient fractionation. We demonstrate the early and transient induction of NRP-1 and CRMP-2 in membrane rafts in both ipsilateral and contralateral hemispheres, in contrast to an early, but sustained elevation of Fer kinase and other CRMPs (1, 3, 4, 5) in response to unilateral MCAO. The fact that NRP1/Fer kinase/CRMP-2 co-localize in membrane rafts early during ischemic injury suggests that the membrane rafts may form a scaffold to support and initiate NRP1/Fer/CRMP-2-mediated signal transduction in neuronal damage response during ischemia-reperfusion. Further understanding of the time-specific and membrane domain-specific protein-protein interaction may lead to the identification of therapeutic targets for stroke.
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PMID:Transient and bilateral increase in Neuropilin-1, Fer kinase and collapsin response mediator proteins within membrane rafts following unilateral occlusion of the middle cerebral artery in mouse. 2049 26