Department of Clinical Pharmacology, China Medical University, No. 92 Beier Road, Heping District, Shenyang 110001, People's Republic of China.
Neurochem Res. 2012 Nov;37(11):2524-40. doi: 10.1007/s11064-012-0837-7. Epub 2012 Jul 28.
Bipolar disorder I and II are affective disorders with mood changes between depressive and manic (bipolar I) or hypomanic (bipolar II) periods. Current therapy of these conditions is chronic treatment with one or more of the anti-bipolar drugs, Li(+) ('lithium'), carbamazepine and valproic acid. The pathophysiology of bipolar disorder is multifactorial and far from clear. Recent data on the dependence of normal brain function on neuronal-astrocytic interactions raise the possibility of astrocytic involvement. We will discuss our previously published and new results on effects of chronic treatment of primary cultures of normal mouse astrocytes with any of three conventional anti-bipolar drugs. The focus will be on several drug-induced events in relation to therapeutic effects of the drugs, such as myo-inositol uptake, intracellular pH and alkalinization, drug-induced modulation of glutamatergic activity in astrocytes and release of astrocytic 'gliotransmitters'. Finally, we will discuss the importance of phospholipase A2 (PLA(2)) and arachidonic acid cascade in drug-treated astrocytes, partly based on Dr. Barneda Cuirana's published thesis. All three drugs cause gradual intracellular alkalinization through different mechanisms. Alkalinization inhibit myo-inositol uptake, resulting in reduced inositolphosphate/phospholipid signaling. Accordingly, transmitter-induced increase in free intracellular Ca(2+) (Ca(2+)) becomes inhibited, aborting release of astrocytic 'gliotransmitters'. The reduction of "gliotransmitter" effects on neurons may have therapeutic effects in mania. Alkalinization also up-regulates expression of cPLA(2), an enzyme releasing arachidonic acid, and triggered arachidonic acid cascade and production, but perhaps not release, of prostaglandins. Whenever tested, identical effects were observed in freshly isolated astrocytes, but not neurons, from carbamazepine-treated healthy animals.
双相情感障碍 I 型和 II 型是情感障碍，其情绪在抑郁和躁狂（双相情感障碍 I 型）或轻躁狂（双相情感障碍 II 型）之间变化。目前这些疾病的治疗是慢性治疗，使用一种或多种抗双相情感障碍药物，Li(+)（'锂'）、卡马西平和丙戊酸。双相情感障碍的病理生理学是多因素的，远未明确。最近关于正常大脑功能依赖神经元-星形胶质细胞相互作用的数据提出了星形胶质细胞参与的可能性。我们将讨论我们以前发表的和关于三种常规抗双相情感障碍药物对正常小鼠星形胶质细胞原代培养物慢性治疗的新结果。重点将放在与药物治疗效果相关的几种药物诱导事件上，例如肌醇摄取、细胞内 pH 值和碱化、药物诱导的星形胶质细胞谷氨酸能活性的调制以及星形胶质细胞“神经胶质递质”的释放。最后，我们将讨论基于 Barneda Cuirana 博士发表的论文，磷脂酶 A2 (PLA2) 和花生四烯酸级联在药物处理的星形胶质细胞中的重要性。这三种药物通过不同的机制导致逐渐的细胞内碱化。碱化抑制肌醇摄取，导致磷酸肌醇/磷脂信号减少。因此，递质诱导的细胞内游离 Ca2+([Ca2+]i)增加被抑制，终止星形胶质细胞“神经胶质递质”的释放。“神经胶质递质”对神经元作用的减少可能在躁狂症中具有治疗效果。碱化还上调 cPLA2 的表达，cPLA2 是释放花生四烯酸的酶，并触发花生四烯酸级联和产生，但可能不是释放前列腺素。在对健康动物用卡马西平治疗后的新鲜分离的星形胶质细胞和神经元进行测试时，观察到了相同的效果。
