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.
BACKGROUND
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.


OBJECTIVE
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.
Beijing HuiLongGuan Hospital, Peking University, Beijing, China; Institute of Chinese Integrative Medicine, Beijing HuiLongGuan Hospital, Peking University, Beijing, China.
Hui Mei
HM
An
Beijing HuiLongGuan Hospital, Peking University, Beijing, China; Institute of Chinese Integrative Medicine, Beijing HuiLongGuan Hospital, Peking University, Beijing, China.
Yun Long
YL
Tan
Beijing HuiLongGuan Hospital, Peking University, Beijing, China; Institute of Chinese Integrative Medicine, Beijing HuiLongGuan Hospital, Peking University, Beijing, China.
Jing
J
Shi
Beijing HuiLongGuan Hospital, Peking University, Beijing, China; Institute of Chinese Integrative Medicine, Beijing HuiLongGuan Hospital, Peking University, Beijing, China.
Zhiren
Z
Wang
Institute of Chinese Integrative Medicine, Beijing HuiLongGuan Hospital, Peking University, Beijing, China.
Meng Han
MH
Lv
Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
Jair C
JC
Soares
Institute of Mental Health, Peking University, Beijing, China.
Dongfeng
D
Zhou
Beijing HuiLongGuan Hospital, Peking University, Beijing, China; Institute of Chinese Integrative Medicine, Beijing HuiLongGuan Hospital, Peking University, Beijing, China. Electronic address: yangfd200@126.com.
Fude
F
Yang
Beijing HuiLongGuan Hospital, Peking University, Beijing, China; Institute of Chinese Integrative Medicine, Beijing HuiLongGuan Hospital, Peking University, Beijing, China; Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, Texas, USA. Electronic address: xiang.y.zhang@uth.tmc.edu.
Xiang Yang
XY
Zhang
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000009:adverse effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000378:metabolism; D020441:Ginkgo biloba; D006220:Haloperidol / Q000009:adverse effects*; D007274:Injections, Intraperitoneal; D008297:Male; D008409:Mastication / Q000187:drug effects; D010936:Plant Extracts / Q000008:administration & dosage / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D024502:alpha-Tocopherol / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D000096983:Ginkgo Extract
D000975:Antioxidants; D014150:Antipsychotic Agents; D006220:Haloperidol; D010936:Plant Extracts; D019253:Proto-Oncogene Proteins c-bcl-2; D024502:alpha-Tocopherol; D051028:bcl-2-Associated X Protein; C494828:Bax protein, rat; C063170:Ginkgo biloba extract; D000096983:Ginkgo Extract
Alpha-tocopherol; Bax/Bcl-2; Ginkgo biloba leaf extract (EGb761); Tardive dyskinesia