The antibipolar drug valproate mimics lithium in stimulating glutamate release and inositol 1,4,5-trisphosphate accumulation in brain cortex slices but not accumulation of inositol monophosphates and bisphosphates
The antibipolar drug valproate mimics lithium in stimulating glutamate release and inositol 1,4,5-trisphosphate accumulation in brain cortex slices but not accumulation of inositol monophosphates and bisphosphates
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DOI：
10.1073/pnas.94.9.4757
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发表时间：
1997-04-29
影响因子：
11.1
通讯作者：
Hokin, LE
中科院分区：
文献类型：
--
作者：
Dixon, JF;Hokin, LE
丙戊酸和锂是有效的抗双相情感障碍药物。我们最近发现锂刺激猴和小鼠大脑皮层脑片中谷氨酸的释放，通过激活N-甲基-D-天冬氨酸受体，增加1，4，5-三磷酸肌醇[Ins（1，4，5）P-3]的积累。我们在此表明，丙戊酸盐的行为与锂相似，在治疗浓度下，它刺激小鼠大脑皮层切片中谷氨酸释放和Ins（1，4，5）P-3蓄积，这两种效应是两种结构无关的抗双相药物的共同特征，这一事实表明这些效应在其抗双相作用中很重要。锂和丙戊酸盐的最大浓度对谷氨酸释放的影响是相加的，表明不同的释放机制，对此进行了讨论，这两种药物对谷氨酸释放的相加作用与这两种药物联合治疗双相患者子集的临床获益一致，例如，快速循环的躁狂抑郁症与锂不同，丙戊酸盐不会增加肌醇单磷酸、肌醇二磷酸或肌醇1，3，4-三磷酸的蓄积。这是反对“肌醇耗竭”假说的额外证据，该假说指出，通过以肌醇单磷酸和某些肌醇多磷酸的形式捕获肌醇，锂通过抑制磷酸肌醇的再合成而产生Ins（1，4，5）P-3信号传导的钝化来发挥其抗躁狂作用。
Valproic acid and lithium are effective antibipolar drugs, We recently showed that lithium stimulated the release of glutamate in monkey and mouse cerebral cortex slices, which, through activation of the N-methyl-D-aspartate receptor, increased accumulation of inositol 1,4,5-trisphosphate [Ins(1,4,5)P-3]. We show here that valproate behaves similarly to lithium in that at therapeutic concentrations it stimulates glutamate release and Ins(1,4,5)P-3 accumulation in mouse cerebral cortex slices, The fact that these two effects are a common denominator for two structurally unrelated antibipolar drugs suggests that these effects are important in their antibipolar action, The effects of maximal concentrations of lithium and valproate on glutamate release are additive, suggesting different mechanisms for release, which are discussed, The additivity of the two drugs on glutamate release is consistent with the clinical benefit of combining the two drugs in the treatment of subsets of bipolar patients, e.g., in rapid cycling manic-depression. Unlike lithium, valproate does not increase accumulation of inositol monophosphates, inositol bisphosphates, or inositol 1,3,4-trisphosphate. This is additional evidence against the ''inositol depletion'' hypothesis, which states that, by trapping inositol in the form of inositol monophosphates and certain inositol polyphosphates, lithium exerts its antimanic action by inhibiting resynthesis of phosphoinositides with resultant blunting of Ins(1,4,5)P-3 signaling.