Galili R, Gil-Ad I, Weizman A, Melamed E, Offen D
Department of Neurology, Rabin Medical Center, Tiqva, Israel.
J Neural Transm (Vienna). 2000;107(4):479-90. doi: 10.1007/s007020070089.
Tardive dyskinesia (TD) is one of the major side effects of long term neuroleptic treatment. The pathophysiology of this disabling and commonly irreversible movement disorder is still obscure. The traditional concept of supersensitivity of striatal dopamine receptors as the mechanism involved in the development of TD is not satisfying, and current studies have focused on the role of neuroleptic-induced neuronal toxicity in the development of TD. We performed a series of experiments to gain a better understanding on the mechanisms involved in induction of TD. We have evaluated the direct neurotoxic effect of haloperidol (HP), a widely--used neuroleptic drug, and its three metabolites, in mouse neuronal cultures and in PC-12 cells. We found that the features of HP-induced cell death were apoptotic rather than necrotic, as indicated by different DNA-staining methods and specific caspases inhibitors. Moreover, cotreatment with antioxidants such as vitamin E and N-acetylcysteine (NAC) significantly protected the cultures. Further studies on the mechanisms underlying HP-induced toxicity may lead to the development of new neuroprotective therapeutic strategies.
迟发性运动障碍（TD）是长期使用抗精神病药物治疗的主要副作用之一。这种致残且通常不可逆的运动障碍的病理生理学仍不清楚。将纹状体多巴胺受体超敏作为TD发生机制的传统概念并不令人满意，目前的研究集中在抗精神病药物诱导的神经元毒性在TD发生中的作用。我们进行了一系列实验，以更好地了解TD诱导所涉及的机制。我们评估了广泛使用的抗精神病药物氟哌啶醇（HP）及其三种代谢物在小鼠神经元培养物和PC-12细胞中的直接神经毒性作用。我们发现，不同的DNA染色方法和特异性半胱天冬酶抑制剂表明，HP诱导的细胞死亡特征是凋亡而非坏死。此外，与抗氧化剂如维生素E和N-乙酰半胱氨酸（NAC）共同处理可显著保护培养物。对HP诱导毒性的潜在机制的进一步研究可能会导致新的神经保护治疗策略的发展。
