- 學位論文
結合鋰鹽與4-苯基丁酸降低缺氧/再灌氧所誘發神經細胞內質網壓力及細胞凋亡之研究
Lithium Combined with 4-Phenylbutyrate Attenuates Hypoxia/Reoxygenation - Induced Neuronal Endoplasmic Reticulum Stress and Apoptosis
摘要
缺血性中風(ischemic stroke)是目前造成死亡和長期殘疾的主要原因。因此，神經保護劑的研發，用來對抗缺血性腦損傷一直是一個重要的治療策略，來減少缺血性中風的發病率和死亡率。有越來越多的證據證實，鋰鹽對缺血性中風具有神經保護的作用。然而，鋰鹽的投藥在臨床上對缺血性神經傷害的治療效果卻十分有限。內質網（Endoplasmic reticulum, ER）壓力已經被認為和腦缺血的病理過程有關聯。因此，以內質網為治療標的或許可以提供一種治療策略以阻絕腦缺血引起的病理過程。為了提高鋰鹽的神經保護效用，我們假定內質網壓力所導致的細胞凋亡(Apoptosis)訊息傳導之調控，是缺血性神經細胞死亡的決定因子。在本研究中，我們証明了以一種低分子量的化學伴護因子(Chemical chaperon)，4-苯基丁酸(4-phenylbutyrate, 4-PBA)的投藥，與鋰鹽相結合，可以保護神經細胞免於缺氧或者再灌氧(Hypoxia/reoxygenation, H/ R)的損傷。同時，我們的數據也顯示，4-苯基丁酸與鋰鹽的混合投藥，可以抑制內質網壓力造成下游細胞凋亡訊息傳導的活化，包含PARP和凋亡蛋白酶3(caspase 3)的活化。而這種保護作用可能與激活PI3K/Akt的細胞生存傳導途徑和GSK3β的抑制有關。因此，鋰鹽和4-苯基丁酸的混合投藥，或許可以在腦缺血的治療上發揮協同作用，從而可能具有在臨床上治療缺血性中風的潛在應用價值。
並列摘要
Ischemic stroke is currently a major cause of death and long-lasting disability. Consequently, developing of neuroprotective agents against ischemia-induced brain damage has been an important therapeutic strategy to reduce the mortality and morbidity associated with ischemia stroke. There is growing evidence that lithium is neuroprotective against ischemia stroke. However, lithium administration provides limited benefit of ischemia neurological outcome in clinical. Endoplasmic reticulum (ER) stress has been implicated in the pathology of cerebral ischemia. Therefore, targeting the ER may provide a therapeutic approach for blocking the pathological process induced by cerebral ischemia. To enhance the neuroprotective actions of lithium, we hypothesized that the regulation of ER stress-mediated apoptotic signaling is an important determinant of ischemic neuronal death. In the present study, we demonstrated that the administration of 4-phenylbutyrate (4-PBA), a low molecular weight chemical chaperon, combined with lithium protected the neuronal cell from hypoxia/reoxygenation (H/R) injury. Our data also showed that 4-PBA combined with lithium inhibited the activation of downstream ER-stress-induced apoptotic signaling including PARP and caspase 3 activation. This protective effect may include activation of the PI3K/Akt cell survival pathway and inhibition of GSK3β. Thus, lithium and 4-PBA may exert synergistic effects in treatment of cerebral ischemia and thus may have potential clinical value for the treatment of ischemia stroke.