Cheng Lili, Lumb Michael, Polgár László, Mudge Anne W
MRC Laboratory for Molecular Cell Biology and Department of Biology, UCL, Gower Street London, WC1E 6BT, UK.
Mol Cell Neurosci. 2005 Jun;29(2):155-61. doi: 10.1016/j.mcn.2004.12.003.
The mood stabilizing drugs commonly used to treat bipolar disorder--lithium, valproic acid (VPA), and carbamazepine (CBZ)--limit the frequency of swings to either manic or depressive states. We previously showed that these drugs all have a common action on cultured neurons, which can be reversed by the addition of either inositol or specific inhibitors of the enzyme prolyl oligopeptidase (PO). Inhibition of PO activity is reported to enhance phosphoinositide (PIns) signaling consistent with the suggestion that mood stabilizers inhibit PIns signaling. We now report that VPA directly inhibits recombinant PO activity, which would have the opposite effect on PIns signaling. This unexpected result suggests a model that could explain the dual action of VPA in stabilizing mood: we propose that euthymic mood is dependent on stable PIns signaling and that VPA may limit mood swings to mania by decreasing PIns signaling, and that it may limit mood swings to depression by inhibiting PO and thus increasing PIns signaling.
常用于治疗双相情感障碍的心境稳定剂——锂盐、丙戊酸（VPA）和卡马西平（CBZ）——可限制躁狂或抑郁状态的发作频率。我们之前表明，这些药物对培养的神经元均有共同作用，添加肌醇或脯氨酰寡肽酶（PO）的特异性抑制剂可逆转这种作用。据报道，抑制PO活性可增强磷酸肌醇（PIns）信号传导，这与心境稳定剂抑制PIns信号传导的观点一致。我们现在报告，VPA可直接抑制重组PO活性，这对PIns信号传导会产生相反的作用。这一意外结果提示了一个可以解释VPA稳定心境双重作用的模型：我们提出，正常心境依赖于稳定的PIns信号传导，VPA可能通过降低PIns信号传导来限制躁狂发作，并且可能通过抑制PO从而增加PIns信号传导来限制抑郁发作。
