| Neurovascular diseases threaten severely the people?s health. Studies confirmed that stroke is the leading cause of the disability and the third cause of death. So, to develop the effective drug on stroke has been the important project for researchers in the neurovascular field. Dipfluzine is developed by school of pharmacy, Hebei medical university. It is a flunarizine-like calcium channel blocker, acting on L-type calcium channel. Previous studies found that DIP has neuroprotection on ischemic brain damage, such as the reduction of brain infarct volume, the increase of the cerebral blood flow, ameliaration of the brain edema. Jin et al confirmed that CD95 molecules are activated in rats subjected to transient forebrain ischemia, which mediate the delayed neurons death of the hippocampal CA1 region through initiating cell death signaling transduction pathway.As we know, calcium plays a key role in the brain ischemia/reperfusion damage. Likewise, among the diverse related signaling transduction pathways of apoptosis in T lymphocytes, Ca2+/CaM-Calcineurin-NFATc-CD95 ligand molecular pathway has been highly focused on. The increase of the intracellular calcium activates the serine-threonine phosphatase calcineurin in the cytoplasm through calmodulin (CaM), the latter dephosphorylates the nuclear factors of activated T-cells (NFAT), making it translocate from cytoplasm to nucleus, promoting the gene transcription of CD95 molecules and CD95 ligand-induced apoptosis in T lymphocytes. Although having diverse experimental results and possible other signaling transduction pathways, it is sure that the activation of the Ca2+/CaM-Calcineurin-NFATc-CD95 ligand pathway is the important mechanism of apoptosis in T lymphocytes. So, is the activation of Ca2+/CaM-Calcineurin-NFATc-CD95 ligand pathway the cause of brain ischemia/reperfusion damage? So far, there is little experimental reports on this issue. In hippocampal neurons in vitro, calcineurin/NFAT3-dependent transcription is activated in response to electrical activity or potassium depolarization, which is critically dependent on the calcium entry through L-type voltage-gated calcium channels. Glycogen synthase kinase-3 (GSK-3) can phosphorylate NFATc proteins at specific amino-terminal motifs, promoting its export from the nucleus and antagonizing NFAT-dependent transcription. Uchino et al also found that cyclosporin A and FK506, the inhibitors of calcineurin, could inhibit the focal brain ischemia/reperfusion damage and have neuroprotective effects. These results might suggest that Ca2+/CaM-Calcineurin-NFATc-CD95 ligand pathway may be involved in the brain ischemia/reperfusion damage.Experiments demonstrated that Many factors are known to activate NF-κB, such as reactive oxygen intermediate, calcium overload, and various cytokines. NF-κB regulates the expression of many genes involved in immune and inflammatory responses, such as iNOS, TNF-α etc. Products of the genes that are regulated by NF-κB also cause the activation of NF-κB. The proinflammatory cytokines interleukin-1β and TNF-α both activate and are activated by NF-κB. This type of positive regulatory loop may amplify and perpetuate local inflammatory responses. Recent studies about brain ischemia found that transient activation of NF-κB may be neuroprotective, while more persistent activation of NF-κB can lead to the death of neuronal cells. Shen et al found that NF-κB activation may be mediated by NMDA receptor, non-NMDA receptor, and L-type voltage-gated calcium channel. They also found that NF-κB may be pro-apoptotic following severe global ischemia in rat hippocampus. Recently, our preliminary study also found that DIP downregulates the expression of CD95 molecules in rats subjected to transient forebrain ischemia. However, the relationship between the neuroproteciton by DIP and CD95 molecules; and the gene transcription mechanism of CD95 molecules have not been elucidated.Based on preliminary results and literatures published, we proposed that (1) t...
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