| Summary: | 碩士 === 臺北醫學大學 === 藥理學研究所 === 92 === Stroke is the state of ischemia that localized tissue is unable to maintain physiological condition due to obstruction or rupture of blood vessels in the brain. According to the pathological mechanisms, stroke is classified into two main types, ischemic and hemorrhagic stroke. Ischemic strokes are caused by blood clots that form and obstruct a blood vessel. Ischemic strokes are caused in part by atherosclerosis which is the process of abnormal lipid deposit around the vessel wall. Ischemic strokes are subtyped to thrombotic and embolic strokes according to where the blood clot forms and where it causes obstruction. Hemorrhagic stroke is defined as the rupturing of cranial blood vessels caused in part by aneurysm or arteriovenous malformation.
Various drugs have been intensively researched in many animal experiments and clinical trials for the treatment of stroke including sodium, potassium and calcium channel blockers, NMDA (N-methyl-D-aspartate), and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole) anta-gonists, magnesium, ?-aminobutyric acid agonist, free radical scavengers, anti-adhesion molecule therapy, matrix metalloproteinase inhibitors and therapeutic hypothermia.
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 inhibitory effects on generation of free radicals and chemotaxis in human neutrophils.
Volumes of cerebral infarct decreased when rats were pretreated with 20 mg/kg PMC or TMPZ. However, the neurological deficits didn’t change after drug treatment. Respiratory bursts of neutrophils induced by PMA (Phorbol 12-myristate-13-acetate) or fMLP (N-formyl-Met-Leu-Phe) were inhibited by PMC (4-12 μM) pretreatments. Similarly, TMPZ (100-500 μM) pretreatment inhibited respiratory bursts induced by PMA and fMLP, respectively. PMC at 12-60 μM inhibited neutrophil chemotaxis stimulated by LTB4 but not by fMLP. Besides, TMPZ at 100-500 μM inhibited neutrophil chemotaxis stimulated by LTB4 and fMLP. Moreover, immunohistochemical staining showed that the accumulation of peroxynitrite in cerebrum with infarct was reduced by PMC or TMPZ pretreatment.
According to the findings, PMC and TMPZ have protective effects against cerebral infarction. However, the exact mechanisms of their protective effects at cellular level need to be clarified in the future.
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