Pathogenesis of Neurodegenerative Diseases and the Effect of Natural Products on Nitric Oxide Production Implicating in These Diseases

一氧化氮(nitric oxide, NO)是一種氣態的自由基，有三種NO生成酵素(NO synthase, NOS)可以將L-arginine轉變成NO。NO具有多種生理功能，它是一種神經傳遞物質，可以調節glutamate釋放和調整N-methyl-D-aspartate(NMDA)受體之神經傳遞功能；由內皮細胞衍生出之NO藉由與guanylyl cyclase作用而擔任一種血管鬆弛因子；NO在發炎性細胞激素或細菌內毒素所引發的發炎反應中扮演重要的角色；NO更參與多種急性或慢性中樞神經退化性疾病之致病機制。僅管各種中樞神經退化性疾病的致病機制不同，NO在其中都扮演著樞紐的角色。在病理情況下，glutamate與NMDA受體結合，增加神經元內鈣離子濃度而活化neuronal NOS(nNOS)，或是發炎性細胞激素與細菌內毒素所間介的訊息途徑引發膠細胞之inducible NOS(iNOS)表現，皆會使細胞產生NO。NO與其更具有毒性的代謝產物，peroxynitrite(ONOO(上标 -))會直接破壞細胞膜完整性或間接地經由損害粒線體功能而造成DNA斷裂、脂質過氧化、和蛋白質硝基化。這一些作用接著活化caspase-cascade或poly-(ADP-ribose) polymerrase(PARP)，最後導致細胞凋亡或壞死。大量的研究致力於由天然物篩選NOS抑制劑以做為神經元保護藥物。在此，我們將已發表之有關天然物作用在NO/NOS訊息途徑包括：阻斷iNOS表現、降低nNOS活性、干擾nNOS上游訊息、清除ONOO(上标 -)、或抑制tyrosine硝基化等論文做一摘要討論。這一些天然物可能提供我們將來用於中樞神經退化性疾病之預防或治療。

關鍵字

一氧化氮；急性神經退化；神經毒性；氧化壓力；發炎；粒線體功能異常；天然物

並列摘要

Nitric oxide (NO) is a free radical synthesized from L-arginine by three isoforms of NO synthase (NOS). NO is involved in a wide range of physiological functions. It functions as neurotransmitter by modulating the release of glutamate and the neurotransmission of N-methyl-D-aspartate (NMDA) receptor, as neuro-endothelial-derived relaxing factor through the action on guanylyl cyclase (sGC), and as inflammatory molecule in response to proinflammatory cytokines or bacterial endotoxin. NO is also implicated in multiple pathological conditions such as acute and chronic neurodegenerative. In spite of the different mechanisms of pathogenesis for these neurodegenerative diseases, NO may play a pivotal role in the pathological conditions of these diseases. Under pathological conditions, NO is produced either from activated neuronal NOS (nNOS) in neuron or inducible NOS (iNOS) in glial cells by increased intracellular calcium concentration through glutamate-NMDA receptor interaction or by inflammatory cytokinemediated signaling pathway, respectively. NO and its toxic metabolite peroxynitrite (ONOO) directly injure membrane integrity or impair mitochondrial function leading to DNA break, lipid peroxidation, and protein nitrosylation. These events consequently activate caspase-cascade or poly-(ADP-ribose) polymerase 1 (PARP) resulting in apoptotic or necrotic cell death. Much effort is devoted to search the specific inhibitors of NOS from natural resource as neuroprotectants. We summarized here the reported natural products that target NO/NOS pathway by blocking iNOS expression, attenuating the activity of nNOS, disturbing upstream signaling of nNOS, scavenging ONOO(superscript -), or inhibiting tyrosine nitration. These natural products may offer possible therapeutics to prevent and/or to treat these neurodegenerative diseases.

並列關鍵字

Nitric oxide ； Acute neurodegeneration ； Neurotoxicity ； Oxidative stress ； Inflammation ； Mitochondrial dysfunction ； Natural products

國際替代計量

Pathogenesis of Neurodegenerative Diseases and the Effect of Natural Products on Nitric Oxide Production Implicating in These Diseases

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