Protective effect of curcumin and its combination with piperine (bioavailability enhancer) against haloperidol-associated neurotoxicity: cellular and neurochemical evidence

Neurotox Res. 2011 Oct;20(3):215-25. doi: 10.1007/s12640-010-9229-4. Epub 2010 Nov 13.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaloids / therapeutic use*
  • Analysis of Variance
  • Animals
  • Apoptosis / drug effects
  • Behavior, Animal / drug effects
  • Benzodioxoles / therapeutic use*
  • Caspase 3 / metabolism
  • Colorimetry / methods
  • Curcumin / therapeutic use*
  • Cytokines / metabolism
  • Disease Models, Animal
  • Dopamine Antagonists / adverse effects
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug Therapy, Combination / methods
  • Enzyme-Linked Immunosorbent Assay
  • Haloperidol / adverse effects
  • Inflammation / etiology
  • Male
  • Neuroprotective Agents / therapeutic use*
  • Neurotoxicity Syndromes / complications
  • Neurotoxicity Syndromes / etiology
  • Neurotoxicity Syndromes / prevention & control*
  • Neurotransmitter Agents / metabolism
  • Piperidines / therapeutic use*
  • Polyunsaturated Alkamides / therapeutic use*
  • Rats
  • Rats, Wistar
  • Statistics as Topic
  • Thiobarbituric Acid Reactive Substances / metabolism


  • Alkaloids
  • Benzodioxoles
  • Cytokines
  • Dopamine Antagonists
  • Neuroprotective Agents
  • Neurotransmitter Agents
  • Piperidines
  • Polyunsaturated Alkamides
  • Thiobarbituric Acid Reactive Substances
  • Caspase 3
  • Curcumin
  • Haloperidol
  • piperine