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

Targeting essential cellular pathways that determine neuronal and vascular survival can foster a successful therapeutic platform for the treatment of a wide variety of degenerative disorders in the central nervous system. In particular, oxidative cellular injury can precipitate several nervous system disorders that may either be acute in nature, such as during cerebral ischemia, or more progressive and chronic, such as during Alzheimer disease. Apoptotic injury in the brain proceeds through two distinct pathways that ultimately result in the early externalization of membrane phosphatidylserine (PS) residues and the late induction of genomic DNA fragmentation. Degradation of DNA may acutely impact cellular survival, while the exposure of membrane PS residues can lead to microglial phagocytosis of viable cells, cellular inflammation, and thrombosis in the vascular system. Through either independent or common pathways, the Wingless/Wnt pathway and the serine-threonine kinase Akt serve central roles in the maintenance of cellular integrity and the prevention of the phagocytic disposal of cells "tagged" by PS exposure. By selectively governing the activity of specific downstream substrates that include GSK-3beta, Bad, and beta-catenin, Wnt and Akt serve to foster neuronal and vascular survival and block the induction of programmed cell death. Novel to Akt is its capacity to protect cells from phagocytosis through the direct modulation of membrane PS exposure. Intimately linked to the activation of Wnt signaling and Akt is the maintenance of mitochondrial membrane potential and the regulation of Bcl-xL, mitochondrial energy metabolism, and cytochrome c release that can lead to specific cysteine protease activation.
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PMID:Targeting WNT, protein kinase B, and mitochondrial membrane integrity to foster cellular survival in the nervous system. 1502 10

Recent data provides evidence that new neurons are born in cerebral ischemia. Although ultimate evidence for their functional importance is lacking, correlational data suggest that they contribute to recovery. Therefore, the underlying mechanisms of neurogenesis are interesting as a basis for pharmacological enhancement of the phenomenon. Neurogenesis is a multistep process that includes proliferation of precursor cells, migration of the newborn cells to the site of lesion, differentiation, integration into neuronal circuits, and survival. All these steps rely on gene transcription. However, only preliminary data about the specific transcriptional control of neurogenesis in cerebral ischemia have been obtained so far. To promote this investigation, we review currently available information on six pathways (Notch, Wnt/beta-catenin, NF-kappaB, signal transducers and activators of transcription (STA) 3, HIF-1, and cyclic AMP response element-binding protein [CREB]) that have been shown to regulate transcription in neurogenesis and that have been implicated in cerebral ischemia. With the exception of CREB, direct involvement in postischemic neurogenesis is quite conjectural and much more must be learned to draw practical conclusions.
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PMID:Transcriptional regulation of neurogenesis: potential mechanisms in cerebral ischemia. 1742 98

17beta-Estradiol (E2) has been implicated to be neuroprotective in a variety of neurodegenerative disorders, although the mechanism remains poorly understood. The current study sheds light on this issue by demonstrating that low physiological levels of E2 protects the hippocampus CA1 against global cerebral ischemia by preventing elevation of dickkopf-1 (Dkk1), an antagonist of the Wnt/beta-catenin signaling pathway, which is a principal mediator of neurodegeneration in cerebral ischemia and Alzheimer's disease. E2 inhibition of Dkk1 elevation correlated with a reduction of phospho-beta-catenin and elevation of nuclear beta-catenin levels, as well as enhancement of Wnt-3, suggesting E2 activation of the Wnt/beta-catenin signaling pathway. In agreement, the beta-catenin downstream prosurvival factor, survivin, was induced by E2 at 24 and 48 h after cerebral ischemia, an effect observed only in surviving neurons because degenerating neurons lacked survivin expression. E2 suppression of Dkk1 elevation was found to be caused by attenuation of upstream c-Jun N-terminal protein kinase (JNK)/c-Jun signaling, as E2 attenuation of JNK/c-Jun activation and a JNK inhibitor significantly blocked Dkk1 induction. Tau hyperphosphorylation has been implicated to have a prodeath role in Alzheimer's disease and cerebral ischemia, and E2 attenuates tau hyperphosphorylation. Our study demonstrates that tau hyperphosphorylation is strongly induced after global cerebral ischemia, and that E2 inhibits tau hyperphosphorylation by suppressing activation of the JNK/c-Jun/Dkk1 signaling pathway. Finally, exogenous Dkk1 replacement via intracerebroventricular administration completely reversed E2-induced neuroprotection, nuclear beta-catenin induction, and phospho-tau attenuation, further suggesting that E2 inhibition of Dkk1 is a critical mechanism underlying its neuroprotective and phospho-tau regulatory effects after cerebral ischemia.
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PMID:Role of Dickkopf-1, an antagonist of the Wnt/beta-catenin signaling pathway, in estrogen-induced neuroprotection and attenuation of tau phosphorylation. 1871 1

Neural progenitor cells (NPCs) have the potential to survive brain ischemia and participate in neurogenesis after stroke. However, it is not clear how survival responses are initiated in NPCs. Using embryonic mouse NPCs and the in vitro oxygen and glucose deprivation (OGD) model, we found that angiopoietin-1 (Ang1) could prevent NPCs from OGD-induced apoptosis, as evidenced by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and annexin V labeling. Ang1 significantly elevated tunica intima endothelial kinase 2 (Tie2) autophosphorylation level, suggesting the existence of functional Tie2 receptors on NPCs. NPCs under OGD conditions exhibited reduction of Akt phosphorylation, decrease of the Bcl-2/Bax ratio, activation of caspase-3, cleavage of PARP, and downregulation of beta-catenin and nestin. Ang1 reversed the above changes concomitantly with significant rising of survival rates of NPCs under OGD, but all these effects of Ang1 could be blocked by either soluble extracellular domain of Tie2 Fc fusion protein (sTie2Fc) or the phosphoinositide 3-kinase (PI3K) inhibitor 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one (LY294002). Our findings suggest the existence of an Ang1-Tie2-PI3K signaling axis that is essential in initiation of survival responses in NPCs against cerebral ischemia and hypoxia.
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PMID:An Ang1-Tie2-PI3K axis in neural progenitor cells initiates survival responses against oxygen and glucose deprivation. 1940 99

Beta-catenin, a transcription factor, plays a critical role in cell survival and degradation after stroke. In this study, we examined changes of expression in beta-catenin in the hippocampal CA1 region of the gerbil following 5 min of transient cerebral ischemia. We observed neuronal damage using cresyl violet staining, neuronal nuclei immunohistochemistry and Fluro-Jade B immunofluorescence. Four days after ischemia-reperfusion (I-R), most of pyramidal cells in the CA1 region were damaged. In addition, early damage in dendrites was detected 1 day after I-R by immunohistochemical staining for microtubule-associated protein 2 (MAP-2), and MAP-2 immunoreactivity was hardly detected in the CA1 region 4 days after I-R. We found that beta-catenin (a synapse-enriched cell adhesion molecule) was well expressed in dendrites before I-R. Its immunoreactivity was well colocalized with MAP-2. Chronological change of beta-catenin immunoreactivity was novelty in the present study. Twelve hours after I-R, its immunoreactivity was decreased in the stratum radiatum of the CA1 region, however, its immunoreactivity was increased 1 and 2 days after I-R, and decreased sharply 4 days after I-R. However, we did not find any change in beta-catenin immunoreactivity in the CA2 and CA3 region. In brief, we suggest that early change of beta-catenin expression in the stratum pyramidale of ischemic hippocampal CA1 region is associated with early dendrite damage following transient cerebral ischemia.
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PMID:Reduced beta-catenin expression in the hippocampal CA1 region following transient cerebral ischemia in the gerbil. 2350 94