Activation of striatal inflammatory mediators and caspase-3 is central to haloperidol-induced orofacial dyskinesia.
The undesired extrapyramidal movement disorders observed with long term treatment with haloperidol have been associated with striatal neurodegeneration. The present study was designed to investigate the effect of prolonged haloperidol treatment on striatal levels of inflammatory mediators and caspase-3 and to correlate it with orofacial dyskinesia, a movement disorder observed with long term haloperidol treatment. Prolonged administration of haloperidol (1, 2, 5 mg/kg) to rats produced dose-dependent increase in the orofacial dyskinetic movements and induced a marked oxidative stress in the striatum. Lower dose of haloperidol (1 mg/kg) decreased NO levels but did not induce TNF-alpha or NF-kappaB expression. At higher doses (2 and 5 mg/kg), increased levels of total nitric oxide and TNF-alpha in cytoplasmic lysate and active p65 subunit of NF-kappaB in nuclear lysates of rat brain were observed. These doses (2 and 5 mg/kg) also induced an increased expression of caspase-3 protein in striatal cytoplasmic fraction as shown by western blot analysis. Collectively, we conclude that oxidative stress mediated increase in inflammatory mediators may initiate the apoptotic pathway (caspase-3) after chronic haloperidol treatment. All this is well correlated with behavioural development of orofacial dyskinesia.
Bishnoi
Mahendra
M
Centre with Potential for Excellence in Biomedical Sciences (CPEBS), Panjab University, Chandigarh 160014, India.
Chopra
Kanwaljit
K
Kulkarni
Shrinivas K
SK
D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects*; D053148:Caspase 3 / Q000502:physiology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004409:Dyskinesia, Drug-Induced / Q000209:etiology*; D006220:Haloperidol / Q000009:adverse effects*; D018836:Inflammation Mediators / Q000502:physiology*; D008297:Male; D009069:Movement Disorders / Q000209:etiology*; D016328:NF-kappa B / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D014150:Antipsychotic Agents; D018836:Inflammation Mediators; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D053148:Caspase 3; D006220:Haloperidol