Ishida Miki, Ichikawa Ryuya, Ohbuchi Katsuya, Oizumi Hiroaki, Miyamoto Yuki, Yamauchi Junji
Laboratory of Molecular Neuroscience and Neurology, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan.
Tsumura Research Laboratories, Tsumura & Co., Ibaraki, 200-1192, Japan.
Sci Rep. 2025 Apr 8;15(1):12049. doi: 10.1038/s41598-025-97308-5.
Tardive dyskinesia involves involuntary movements of body parts and is often observed in individuals taking antipsychotics for extended periods. Initial treatment strategies include reducing medication dosage, switching medications, or using drugs to suppress symptoms. One of the therapeutic targets for tardive dyskinesia is vesicular monoamine transporter-2 (VMAT-2, also known as solute carrier family 18 member A2 [SLC18A2]), which functions as an energy-dependent transporter of monoamines. The therapeutic drugs are used during adulthood, when neurons are maturing. For the first time, we report that treatment with a chemical VMAT-2 inhibitor reduces neuronal process elongation, a phenomenon commonly observed during development. Treatment with the inhibitors reserpine or tetrabenazine decreased process elongation in primary cortical neurons, and similar results were obtained in N1E-115 neuronal model cells undergoing process elongation. Knockdown of VMAT-2 using clustered regularly interspaced short palindromic repeat (CRISPR)/Cas13-fitted guide RNA also reduced process elongation. However, treatment with reserpine or tetrabenazine did not affect the morphology of mature processes. Notably, treatment with hesperetin, a citrus flavonoid with neuroprotective effects, was able to restore the reduced process elongation induced by these inhibitors or VMAT-2 knockdown. The underlying molecular mechanism appeared to involve neuronal differentiation-related Akt kinase signaling. These results suggest that VMAT-2, as a drug target for tardive dyskinesia, plays a key role in process elongation and that some inhibitory effects of VMAT-2-targeted drugs on its elongation may be mitigated by co-administering a neuroprotective molecule.
迟发性运动障碍涉及身体部位的不自主运动，常在长期服用抗精神病药物的个体中观察到。初始治疗策略包括减少药物剂量、更换药物或使用药物抑制症状。迟发性运动障碍的治疗靶点之一是囊泡单胺转运体2（VMAT - 2，也称为溶质载体家族18成员A2 [SLC18A2]），它作为单胺的能量依赖性转运体发挥作用。这些治疗药物在成年神经元成熟时使用。我们首次报告，用化学VMAT - 2抑制剂治疗会减少神经元突起伸长，这是发育过程中常见的现象。用利血平或丁苯那嗪抑制剂治疗可减少原代皮层神经元的突起伸长，在经历突起伸长的N1E - 115神经元模型细胞中也获得了类似结果。使用成簇规律间隔短回文重复序列（CRISPR）/Cas13适配的引导RNA敲低VMAT - 2也减少了突起伸长。然而，用利血平或丁苯那嗪治疗并不影响成熟突起的形态。值得注意的是，用具有神经保护作用的柑橘类黄酮橙皮素治疗能够恢复由这些抑制剂或VMAT - 2敲低诱导的减少的突起伸长。潜在的分子机制似乎涉及与神经元分化相关的Akt激酶信号传导。这些结果表明，VMAT - 2作为迟发性运动障碍的药物靶点，在突起伸长中起关键作用，并且通过共同施用神经保护分子可能减轻针对VMAT - 2的药物对其伸长的一些抑制作用。
