Department of Neuropsychiatry, Division of Neuroscience, Graduate School of Medicine, Mie University, Tsu 514-8507, Japan.
National Hospital Organization Sakakibara Hospital, 777 Sakakibara, Tsu, Mie 514-1292, Japan.
Cells. 2020 Feb 11;9(2):414. doi: 10.3390/cells9020414.
Clozapine (CLZ) is a gold-standard antipsychotic against treatment-refractory schizophrenia, but is one of the most toxic antipsychotic agents. Pharmacological mechanisms of the double-edged sword clinical action of CLZ remain to be clarified. To explore the mechanisms of CLZ, the present study determined the astroglial transmission associated with connexin43 (Cx43), which is the most principal expression in astrocytes and myocardial cells, and expression of Cx43 in primary cultured astrocytes. Both acute and subchronic administrations of CLZ concentration-dependently increased Cx43-associated astroglial release of l-glutamate and d-serine, whereas therapeutic-relevant concentration of CLZ acutely did not affect but subchronically increased astroglial release. In contrast, after the subchronic administration of therapeutic-relevant concentration of valproate (VPA), acute administration of therapeutic-relevant concentration of CLZ drastically increased Cx43-associated astroglial releases. VPA increased Cx43 expression in cytosol fraction without affecting plasma membrane fraction, whereas CLZ increased Cx43 expression in both fractions. Acute administration of therapeutic-relevant concentration of CLZ drastically increased Cx43 expression in the plasma membrane fraction of astrocytes subchronically treated with VPA. The present findings suggest that CLZ-induced the activation of Cx43-associated channel activity and transported Cx43 to plasma membrane, probably contribute to the double-edged sword clinical action of CLZ, such as improvement of cognitive dysfunction and CLZ-induced myocarditis.
氯氮平（CLZ）是一种治疗难治性精神分裂症的金标准抗精神病药物，但也是毒性最大的抗精神病药物之一。CLZ 双刃剑临床作用的药理学机制仍需阐明。为了探讨 CLZ 的作用机制，本研究测定了与缝隙连接蛋白 43（Cx43）相关的星形胶质细胞传递，Cx43 是星形胶质细胞和心肌细胞中表达最主要的蛋白，以及原代培养星形胶质细胞中 Cx43 的表达。急性和亚慢性给予 CLZ 浓度依赖性地增加了 Cx43 相关的星形胶质细胞释放 L-谷氨酸和 D-丝氨酸，而治疗相关浓度的 CLZ 急性给药不影响，但亚慢性给药增加了星形胶质细胞释放。相比之下，在给予治疗相关浓度的丙戊酸钠（VPA）亚慢性给药后，给予治疗相关浓度的 CLZ 急性给药会急剧增加 Cx43 相关的星形胶质细胞释放。VPA 增加了细胞质部分的 Cx43 表达，而不影响质膜部分，而 CLZ 则增加了两个部分的 Cx43 表达。急性给予治疗相关浓度的 CLZ 会急剧增加 VPA 亚慢性处理的星形胶质细胞质膜部分的 Cx43 表达。本研究结果表明，CLZ 诱导 Cx43 相关通道活性的激活，并将 Cx43 转运到质膜，可能有助于 CLZ 的双刃剑临床作用，如改善认知功能障碍和 CLZ 诱导的心肌炎。
