title: Protective effect of curcumin and its combination with piperine (bioavailability enhancer) against haloperidol-associated neurotoxicity: cellular and neurochemical evidence.
abstract: Long-term treatment with haloperidol is associated with a number of extrapyramidal side effects, particularly the irregular movements of chorionic type. This limitation presents a marked therapeutic challenge. The present study investigates the molecular etiology of haloperidol neurotoxicity and the role of curcumin, a well-known anti-oxidant, in ameliorating these adverse effects. The redox status of haloperidol-treated brains along with NO, TNF-α, NF-kappaB p65 subunit, caspase-3, and monoamine neurotransmitters were measured in the striatum of rat brain. Chronic treatment with haloperidol (5 mg/kg, i.p., 21 days) produced orofacial dyskinetic movements which were coupled with marked increase in oxidative stress parameters, TNF-α, caspase-3 activity in cytoplasmic lysate and active p65 sub unit of NF-kappaB in nuclear lysates of the striatum. Neurochemically, chronic administration of haloperidol resulted in a significant decrease in the levels of norepinephrine, dopamine, and serotonin. The prototype atypical anti-psychotic, clozapine (10 mg/kg, i.p., 21 days) produced mild oxidative stress but did not alter any other parameters. Interestingly, co-administration of curcumin (25 and 50 mg/kg, i.p., 21 days) dose-dependently prevented all the behavioral, cellular, and neurochemical changes associated with the chronic administration of haloperidol. Curcumin per se (50 mg/kg) did not show any side effects. Co-administration of piperine significantly enhanced the effect of curcumin (25 mg/kg) but not of curcumin (50 mg/kg). Collectively, the data indicated the potential of curcumin as an adjunct to haloperidol treatment and provided initial clues to the underlying molecular mechanisms in haloperidol neurotoxicity. This study also provides a rationale for the combination of piperine and curcumin.
authors.affiliation: Department of Pharmacology, Southern Illinois University-School of Medicine, Springfield, IL 62702, USA. mbishnoi@siumed.edu
authors.forename: Mahendra
authors.initials: M
authors.lastname: Bishnoi
authors.forename: Kanwaljit
authors.initials: K
authors.lastname: Chopra
authors.forename: Lu
authors.initials: L
authors.lastname: Rongzhu
authors.forename: Shrinivas K
authors.initials: SK
authors.lastname: Kulkarni
mesh_terms: D000470:Alkaloids / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D052117:Benzodioxoles / Q000627:therapeutic use*; D053148:Caspase 3 / Q000378:metabolism; D003124:Colorimetry / Q000379:methods; D003474:Curcumin / Q000627:therapeutic use*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018492:Dopamine Antagonists / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination / Q000379:methods; D004797:Enzyme-Linked Immunosorbent Assay; D006220:Haloperidol / Q000009:adverse effects; D007249:Inflammation / Q000209:etiology; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D020258:Neurotoxicity Syndromes / Q000150:complications / Q000209:etiology / Q000517:prevention & control*; D018377:Neurotransmitter Agents / Q000378:metabolism; D010880:Piperidines / Q000627:therapeutic use*; D053284:Polyunsaturated Alkamides / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D013223:Statistics as Topic; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
chemical_list: D000470:Alkaloids; D052117:Benzodioxoles; D016207:Cytokines; D018492:Dopamine Antagonists; D018696:Neuroprotective Agents; D018377:Neurotransmitter Agents; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D017392:Thiobarbituric Acid Reactive Substances; D053148:Caspase 3; D003474:Curcumin; D006220:Haloperidol; C008922:piperine