The Neuroprotective Mechanism of PMC and TMPZ in a Transient Focal Ischemia/Reperfusion Rat Model

• Main Authors: Jiing-harn Lin, 林璟含
• Other Authors: Joen-Rong Sheu
• Format: Others
• Language: zh-TW
• Published: 2005
• Online Access: http://ndltd.ncl.edu.tw/handle/57598012048803557866

碩士 === 臺北醫學大學 === 藥理學研究所 === 93 === Stroke is one of the leading causes of mortality and　morbidity world-wide. Although our knowledge concerning　the molecular and cellular　pathophysiology of brain injury　after focal ischemia has advanced greatly, the development　of new treatment drugs for acute ischemic stroke has not　progressed as rapidly. One strategy for treating acute stroke patients is the development of neuroprotective　drugs. Unfortunately, clinical trials using various preclinically　neuroprotective drugs for stroke have proven　unsuccessful. Because the middle cerebral artery is the vessel mostly affected by cerebral occlusion in ischemic stroke, so the middle cerebral　artelry occlusion (MCAO) of rodents provides an excellent　model that is relevant to ischemic stroke in　human. PMC (2, 2, 5, 7, 8-pentamethyl-6-hydroxychromane) is an analogue of α-tocopherol and has potent free radical scavenging activity. It is known to inhibit platelet aggregation and inhibit the activation of cytokine-induced NF-κB (nuclear factor-κB). TMPZ (2, 3, 5, 6-tetramethylpyrazine) is extracted from the root of Ligusticum wallichii, a common herb used in traditional Chinese medicine. TMPZ has antiplatelet and vasodilation activity. It is shown to improve changes in microcirculation of patients with acute cerebral thrombosis. In this study we evaluated the protective effects of PMC and TMPZ in a cerebral ischemia-reperfusion injury model in rats, and the further inhibitory effects on generation of inflammatory response and expression of apoptosis. We test the effects of PMC and TMPZ in transient focal cerebral ischemia and reperfusion rat modal. PMC and TMPZ (20 mg/kg ip.) markedly attenuated the infarct volume about 60 % and 59.3 % respectively at 24 hours after middle cerebral artery occlusion. Subsequently, we examined the neuropreotective mechanisms of PMC and TMPZ in the molecular and cellular　pathophysiology of brain injury　after focal ischemia. By the data of western and immunofluorescent analysis, we found that pretreatment of PMC and TMPZ may significantly reduce the expression of iNOS, nitrotyrosine, HIF-1αand caspase-3. By reverse transcription-polymerase chain reaction analysis, PMC and TMPZ also suppressed the expression of TNF-αmRNA. Moreover, we prove the directly antioxidant effect of PMC, but not TMPZ in the test of lipid peroxidation in rats brain homogenates. According to these findings, PMC and TMPZ have neuroprotective effects against cerebral ischemia and reperfusion injury. Moreover, the beneficial results may due to the reduction of iNOS, peroxynitrite, the suppression of pro-inflammatoy cytokine TNF-α and the inhibition of apoptotic of caspase-3 and HIF-1α. However, the exact mechanisms of their neuroprotective effects at further signal transduction of cellular level need to be clarified in the future.