Lan Martin J, Yuan Peixiong, Chen Guang, Manji Husseini K
Laboratory of Molecular Pathophysiology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
J Mol Neurosci. 2008 Jun;35(2):225-34. doi: 10.1007/s12031-008-9056-8. Epub 2008 Apr 25.
Valproate (Depakote) remains an effective medication for the prevention and treatment of seizures in epilepsy and of mood symptoms in bipolar disorder. Both of these disorders are severe and debilitating, and both warrant further medication options as well as a better understanding of the side effects associated with their current treatments. Although a number of molecular and cellular processes have been found to be altered by valproate, the medication's therapeutic mechanism has not been fully elucidated. In this paper, peroxisome proliferator-activated receptor (PPAR) signaling was examined to determine valproate's effects on this transcriptional regulatory system in neuronal tissue. PPAR signaling has been found to affect a number of biochemical processes, including lipid metabolism, cellular differentiation, insulin sensitivity, and cell survival. When primary neuronal cultures were treated with valproate, a significant decrease in PPARgamma signaling was observed. This effect was demonstrated through a change in nuclear quantities of PPARgamma receptor and decreased DNA binding of the receptor. Valproate also caused gene expression changes and a change to the peroxisome biochemistry consistent with a decrease of PPARgamma signaling. These biochemical changes may have functional consequences for either valproate's therapeutic mechanism or for its neurological side effects and merit further investigation.
丙戊酸盐（德巴金）仍然是预防和治疗癫痫发作以及双相情感障碍情绪症状的有效药物。这两种疾病都很严重且使人衰弱，都需要更多的药物选择以及对当前治疗相关副作用有更好的了解。尽管已发现丙戊酸盐会改变许多分子和细胞过程，但其治疗机制尚未完全阐明。在本文中，研究了过氧化物酶体增殖物激活受体（PPAR）信号传导，以确定丙戊酸盐对神经元组织中这种转录调节系统的影响。已发现PPAR信号传导会影响许多生化过程，包括脂质代谢、细胞分化、胰岛素敏感性和细胞存活。当用丙戊酸盐处理原代神经元培养物时，观察到PPARγ信号传导显著降低。这种效应通过PPARγ受体核数量的变化和受体DNA结合的减少得以证明。丙戊酸盐还导致基因表达变化以及与PPARγ信号传导减少一致的过氧化物酶体生物化学变化。这些生化变化可能对丙戊酸盐的治疗机制或其神经副作用产生功能影响，值得进一步研究。
