| Summary: | 碩士 === 國防醫學院 === 生理學研究所 === 85 === β-amyloid peptide (PAP) or its active residue (25-35 fragment) , the major component of the senile plaques in senile dementia, has been reported to be neurotoxic in vitro and in vivo extensively. Although the path-physiological mechanisms underlying βAP25-35-induced neurodegeneration are still not clear, the increased intracellular calcium following βAP25-35 application has been considered to serve as a critical trigger to initiate this type of neuronal damage. Since the major effect of βAP25-35 is to destabilize intacellular calcium homeostasis leading to an increase of intracellular calcium, this should raise a possibility that the over- activation of nitric oxide synthase (NOS) following βAP25-35 application may be a possible pathogenesis involved in βAP25-35-induced neurodegeneration. This study adresses the issue whether the activation of NOS is involved in βAP25-35-induced neurodegeneration in cultured rat cerebral neurons by examining LDH release, NO formation, and neuronal morphology simultaneously. The employment of βAP25-35 alone failed to induce significant enhancement in neurodegeneration and NO. In contrast, βAP25-35 can cause a concentration -dependent augmentation in βAP25-35- induced neurodegeneration and NO if sufficient levels of glutamate were concurrently provided to cultured neurons. Furthemiore, this augmented relationship between βAP25-35-induced neurodegeneration and NO was positively correlated. The magnitudes of the βAP25-35-induced neurodegeneration and NO can be considerably attenuated by the inhibitor of the neuronal constitutive NOS or the inducible NOS, but not by the inhibitor of guanylyl cyclase. The employment of inhibitors of NMDA, AMPA, Kainate receptors shows that only inhibitor of NMDA receptor apparently attenuated βAP25-35-induced neurodegenerarion and NO production. Taken together, these results raise the possibility that the overactivation of NOS by βAP25-35 in the presence of sufficient levels of glutamate contributes an important role making neurons more vulnerable to surrounding excitotoxic insults, implicated in the senile dementia.
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