Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Auckland, New Zealand.
Neurobiol Dis. 2011 Jan;41(1):96-103. doi: 10.1016/j.nbd.2010.08.024. Epub 2010 Sep 9.
Valproic acid (VPA) is widely used for the treatment of mood disorders and epilepsy, but its mechanism of action is unclear. In vivo and in vitro studies using rodent models have demonstrated that VPA has both neuroprotective and neurotrophic effects. These beneficial effects are, in part, through modulation of glial cell function. Recently, we and others have shown that VPA selectively induces caspase-3 mediated apoptosis in rodent microglial cells. However, the effect of VPA on human microglia has not been tested. In this study, using microglia derived from adult human brains, we demonstrate that VPA does not induce microglial apoptosis as determined by the absence of caspase-3 cleavage. However, VPA does partially decrease the expression of the microglial markers PU.1 and CD45, as well as dramatically reducing microglial phagocytosis. Due to the many roles of microglia in the brain, these VPA-induced alterations in microglial phenotype could potentially have major effects on physiological and pathological actions of these cells.
丙戊酸（VPA）广泛用于治疗情绪障碍和癫痫，但其作用机制尚不清楚。使用啮齿动物模型的体内和体外研究表明，VPA具有神经保护和神经营养作用。这些有益作用部分是通过调节神经胶质细胞功能实现的。最近，我们和其他人已经表明，VPA 选择性诱导啮齿动物小胶质细胞中 caspase-3 介导的细胞凋亡。然而，尚未测试 VPA 对人小胶质细胞的影响。在这项研究中，我们使用源自成人大脑的小胶质细胞证明，VPA 不会诱导小胶质细胞凋亡，因为 caspase-3 裂解不存在。然而，VPA 确实部分降低了小胶质细胞标记物 PU.1 和 CD45 的表达，并显著降低了小胶质细胞的吞噬作用。由于小胶质细胞在大脑中有许多作用，VPA 诱导的小胶质细胞表型改变可能对这些细胞的生理和病理作用产生重大影响。
