Ginkgo biloba leaf extract and alpha-tocopherol attenuate haloperidol-induced orofacial dyskinesia in rats: Possible implication of antiapoptotic mechanisms by preventing Bcl-2 decrease and Bax elevation

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• 作者：Hui Mei An^a ; ^b ; ; Yun Long Tan^a ; ^b ; ; Jing Shi^a ; ^b ; Zhiren Wang^a ; ^b ; Meng Han Lv^b ; Jair C. Soares^c ; Dongfeng Zhou^d ; Fude Yang^a ; ^b ; ^{yangfd200@126.com" class="auth_mail" title="E-mail the corresponding author} ; Xiang Yang Zhang^a ; ^b ; ^c ; ^{xiang.y.zhang@uth.tmc.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Ginkgo biloba leaf extract (EGb761) ; Alpha-tocopherol ; Tardive dyskinesia ; Bax/Bcl-2
• 刊名：Phytomedicine
• 出版年：2016
• 出版时间：1 December 2016
• 年：2016
• 卷：23
• 期：13
• 页码：1653-1660
• 全文大小：1177 K

文摘

Tardive dyskinesia (TD) is a serious side effect of long-term administration of typical neuroleptics, such as haloperidol. The pathophysiology of TD remains unclear, but the experimental evidence suggests that free radical-induced neuronal apoptosis in the basal ganglia may play an important role.

Purpose

This study was to investigate changes in Bax and Bcl-2 expression levels in TD-associated brain regions and the effects of the antioxidant EGb761 on Bax and Bcl-2 levels in an animal model of TD.

Methods

Thirty-two rats were randomly divided into four study groups: saline control (saline), haloperidol-alone (haloperidol), EGb761-haloperidol (EGb), and alpha-tocopherol-haloperidol (vitamin E). Rats were treated with daily intraperitoneal haloperidol injections (2 mg/kg/day) for 5 weeks. EGb761 (50 mg/kg/day) and alpha-tocopherol (20 mg/kg/day) were then administered for another 5 weeks during the withdrawal period. Behavioral assessments were performed, and Bax and Bcl-2 protein expression levels were immunohistochemically analyzed in four brain regions, including the prefrontal cortex, striatum, substantia nigra, and globus pallidum.

Results

We found that increased vacuous chewing movements (VCMs) were associated with increased proapoptotic Bax protein expression, decreased antiapoptotic Bcl-2 protein expression, and an increased Bax/Bcl-2 ratio. EGb761 and alpha-tocopherol treatment reversed the increase in VCMs, decreased Bax expression, increased Bcl-2 expression, and decreased the Bax/Bcl-2 ratio.

Conclusions

These results demonstrate that long-term haloperidol administration may affect Bcl-2 protein family expression and promote neuronal apoptosis in the basal ganglia. In combination with their antioxidant capacity, EGb761 and alpha-tocopherol's antiapoptotic effects through Bcl-2 might account for the symptom improvement observed in haloperidol-induced TD rats.