Neurotoxicity Research

, Volume 20, Issue 3, pp 215–225 | Cite as

Protective Effect of Curcumin and its Combination with Piperine (Bioavailability Enhancer) Against Haloperidol-Associated Neurotoxicity: Cellular and Neurochemical Evidence

  • Mahendra Bishnoi
  • Kanwaljit Chopra
  • Lu Rongzhu
  • Shrinivas K. Kulkarni


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.


Apoptosis Caspase-3 Curcumin Haloperidol NF-kappaB Tardive dyskinesia 



The study was supported by the UGC grant under Centre with Potential for Excellence in Biomedical Sciences (CPEBS).


  1. Aggarwal BB (2000) Tumor necrosis factors receptor associated signalling molecules and their role in activation of apoptosis, JNK and NF-kappaB. Ann Rheum D 59(Suppl 1):6–16CrossRefGoogle Scholar
  2. Aggarwal BB, Shishodia S (2004) Suppression of the nuclear factor-kappaB activation pathway by spice-derived phytochemicals: reasoning for seasoning. Ann N Y Acad Sci 1030:434–441PubMedCrossRefGoogle Scholar
  3. Aggarwal BB, Shishodia S, Ashikawa K, Bharti AC (2002) The role of TNF and its family members in inflammation and cancer: lessons from gene deletion. Curr Drug Targets Inflamm Allergy 1(4):327–341PubMedCrossRefGoogle Scholar
  4. Araujo CAC, Leon LL (2001) Biological activities of Curcuma longa L. Mem Inst Oswaldo Cruz 6(5):723–728CrossRefGoogle Scholar
  5. Arends MJ, Morris RG, Wyllie AH (1990) Apoptosis. The role of the endonuclease. Am J Pathol 136:593–608PubMedGoogle Scholar
  6. Atal CK, Dubey RK, Singh JJ (1985) Biochemical basis of enhanced drug bioavailability by piperine: evidence that piperine is a potent inhibitor of drug metabolism. Pharmacol Exp Ther 232:258–262Google Scholar
  7. Babior BM, Kipner RS, Cerutte JT (1973) Biological defense mechanism. The production by leukocytes of superoxide, a potential bacterial agent. J Clin Investig 52:741–744PubMedCrossRefGoogle Scholar
  8. Balasubramanyam M, Koteswari AA, Kumar RS, Monickaraj SF, Maheswari JU, Mohan V (2003) Curcumin induced inhibition of cellular reactive oxygen species generation: novel therapeutic implications. J Biosci 28:715–721PubMedCrossRefGoogle Scholar
  9. Bishnoi M, Chopra K, Kulkarni SK (2007a) Possible anti-oxidant and neuroprotective mechanisms of zolpidem in attenuating typical anti-psychotic-induced orofacial dyskinesia—a biochemical and neurochemical study. Prog Neuropsychopharmacol Biol Psychiatry 31(5):1130–1138PubMedCrossRefGoogle Scholar
  10. Bishnoi M, Kumar A, Chopra K, Kulkarni SK (2007b) Comparative neurochemical changes associated with chronic administration of typical and atypical neuroleptics: implications in tardive dyskinesia. Indian J Exp Biol 45(2):175–179PubMedGoogle Scholar
  11. Bishnoi M, Chopra K, Kulkarni SK (2008a) Protective effect of Curcumin, the active principle of turmeric (Curcuma longa) in haloperidol-induced orofacial dyskinesia and associated behavioural, biochemical and neurochemical changes in rat brain. Pharmacol Biochem Behav 88:511–520PubMedCrossRefGoogle Scholar
  12. Bishnoi M, Chopra K, Kulkarni SK (2008b) Activation of striatal inflammatory mediators and caspase-3 is central to haloperidol-induced orofacial dyskinesia. Eur J Pharmacol 590(1–3):241–245PubMedCrossRefGoogle Scholar
  13. Burger MBE, Fachineto R, Alves A, Callegari L, Rocha JBT (2005) Acute reserpine and sub-chronic haloperidol treatments change synaptosomal brain glutamate uptake and elicit orofacial dyskinesia in rats. Brain Res 1031(2):202–210PubMedCrossRefGoogle Scholar
  14. Burkhardt C, Kelly JP, Lim YH, Filley CM, Parker WD (1993) Neuroleptic medications inhibit complex II of the electron transport chain. Ann Neurol 33:512–517PubMedCrossRefGoogle Scholar
  15. Cara DB, Dusticier N, Forni C, Lievens JC, Daszuta A (2001) Serotonin depletion produces long lasting increase in striatal glutamatergic transmission. J Neurochem 78:240–248PubMedCrossRefGoogle Scholar
  16. Cho JW, Lee KS, Kim CW (2007) Curcumin attenuates the expression of IL-1beta, IL-6, and TNF-alpha as well as cyclin E in TNF-alpha-treated HaCaT cells; NF-kappaB and MAPKs as potential upstream targets. Int J Mol Med 19(3):469–474PubMedGoogle Scholar
  17. Church WH (2005) Column chromatography analysis of brain tissue: an advanced laboratory exercise for neuroscience majors. J Undergrad Neurosci Educ 3(2):A36–A41Google Scholar
  18. Cosi C, Waget A, Rollet K, Tesori V, Newman-Tancredi A (2005) Clozapine, ziprasidone and aripiprazole but not haloperidol protect against kainic acid-induced lesion of the striatum in mice, in vivo: role of 5-HT1A receptor activation. Brain Res 1043(1–2):32–41PubMedCrossRefGoogle Scholar
  19. Coyle JT, Puttfarcken P (1993) Oxidative stress, glutamate, and neurodegenerative disorders. Science 262(5134):689–695PubMedCrossRefGoogle Scholar
  20. Creese I, Burt D, Snyder SH (1976) Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 192:481–483PubMedCrossRefGoogle Scholar
  21. Cummings TJ, Walker PD (1996) Serotonin depletion exacerbates changes in striatal gene expression following quinolinic acid injection. Brain Res 743(1–2):240–248PubMedCrossRefGoogle Scholar
  22. De Leon J, Susce MT, Pan RM, Koch WH, Wedlund PJ (2005) Polymorphic variations in GSTM1, GSTT1, PgP, CYP2D6, CYP3A5, and dopamine D2 and D3 receptors and their association with tardive dyskinesia in severe mental illness. J Clin Psychopharmacol 25(5):448–456PubMedCrossRefGoogle Scholar
  23. Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 82:70–77Google Scholar
  24. Garcea G, Jones DJ, Singh R, Dennison AR, Farmer PB, Sharma RA, Steward WP, Gescher AJ, Berry DP (2004) Detection of curcumin and its metabolites in hepatic tissue and portal blood of patients following oral administration. Br J Cancer 90:1011–1015PubMedCrossRefGoogle Scholar
  25. Guerin-Marchand C, Sénéchal H, Pelletier C, Fohrer H, Olivier R, David B, Berthon B (2001) H2O2 impairs inflammatory mediator release from immunologically stimulated RBL-2H3 cells through a redox-sensitive, calcium-dependent mechanism. Inflamm Res 150:341–349CrossRefGoogle Scholar
  26. Guthmann F, Wissel H, Schachtrup C, Tölle A, Rüdiger M, Spener F, Rüstow B (2005) Inhibition of TNFalpha in vivo prevents hyperoxia-mediated activation of caspase 3 in type II cells. Respir Res 6:10PubMedCrossRefGoogle Scholar
  27. Hoehle SI, Pfeiffer E, Solyom AM, Metzler M (2006) Metabolism of curcuminoids in tissue slices and subcellular fractions from rat liver. J Agric Food Chem 54:756–764PubMedCrossRefGoogle Scholar
  28. Jarskog LF, Selinger ES, Lieberman JA, Gilmore JH (2004) Apoptotic proteins in the temporal cortex in schizophrenia: high Bax/Bcl-2 ratio without caspase-3 activation. Am J Psychiatry 161:109–115PubMedCrossRefGoogle Scholar
  29. Jarskog LF, Gilmore JH, Glantz LA, Gable KL, German TT, Tong RI, Lieberman JA (2007) Caspase-3 activation in rat frontal cortex following treatment with typical and atypical antipsychotics. Neuropsychopharmacology 32:95–102PubMedCrossRefGoogle Scholar
  30. Kikumori T, Kambe F, Nagaya T, Funahashi H, Seo H (2001) Thyrotrophin modifies activation of nuclear factor kappaB by tumor necrosis factor-alpha in rat thyroid cell line. Biochem J 354:573–579PubMedCrossRefGoogle Scholar
  31. Lambert JD, Hong J, Kim DH, Mishin VM, Yang CS (2004) Piperine enhances the bioavailability of the tea polyphenol (−)-epigallocatechin-3-gallate in mice. J Nutr 134(8):1948–1952PubMedGoogle Scholar
  32. Lerer B, Segman RH, Fangerau H, Daly AK, Basile VS, Cavallaro R, Aschauer HN, McCreadie RG, Ohlraun S, Ferrier N, Masellis M, Verga M, Scharfetter J, Rietschel M, Lovlie R, Levy UH, Meltzer HY, Kennedy JL, Steen VM, Macciardi F (2002) Pharmacogenetics of tardive dyskinesia: combined analysis of 780 patients supports association with dopamine D3 receptor gene Ser9Gly polymorphism. Neuropsychopharmacology 27(1):105–119PubMedCrossRefGoogle Scholar
  33. Liñares D, Taconis M, Maña P, Correcha M, Fordham S, Staykova M, Willenborg DO (2006) Neuronal nitric oxide synthase plays a key role in CNS demyelination. J Neurosci 26(49):12672–12681PubMedCrossRefGoogle Scholar
  34. Liou YJ, Lai IC, Lin MW, Bai YM, Lin CC, Liao DL, Chen JY, Lin CY, Wang YC (2006) Haplotype analysis of endothelial nitric oxide synthase (NOS3) genetic variants and tardive dyskinesia in patients with schizophrenia. Pharmacogenet Genomics 16(3):151–157PubMedGoogle Scholar
  35. Lohr JB, Kuezenski R, Niculescu AB (2003) Oxidative mechanisms and tardive dyskinesia. CNS drugs 17(1):47–62PubMedCrossRefGoogle Scholar
  36. Lowry OH (1951) Protein measurements with the Folin-phenol reagent. J Biol Chem 193:265–275PubMedGoogle Scholar
  37. Madhavan L, Freed WJ, Anantharam V, Kanthasamy AG (2003) 5-Hydroxytryptamine 1A receptor activation protects against N-methyl-d-aspartate-induced apoptotic cell death in striatal and mesencephalic cultures. J Pharmacol Exp Ther 304(3):913–923PubMedCrossRefGoogle Scholar
  38. Mahakunakorn P, Tohda M, Murakami Y, Matsumoto K, Watanabe H, Vajaragupta O (2003) Cytoprotective and cytotoxic effects of curcumin: dual action on H2O2-induced oxidative cell damage in NG108-15 cells. Biol Pharm Bull 26:725–728PubMedCrossRefGoogle Scholar
  39. Müller DJ, Shinkai T, De Luca V, Kennedy JL (2004) Clinical implications of pharmacogenomics for tardive dyskinesia. Pharmacogenomics J 4(2):77–87PubMedCrossRefGoogle Scholar
  40. Naidu PS, Singh A, Kulkarni SK (2003) Quercetin, a bioflavonoid attenuated haloperidol induced orofacial dyskinesia. Neuropharmacology 44:1100–1106PubMedCrossRefGoogle Scholar
  41. Pan MH, Huang TM, Lin JK (1999) Biotransformation of curcumin through reduction and glucuronidation in mice. Drug Metab Dispos 27:486–494PubMedGoogle Scholar
  42. Polydoro M, Schroder N, Lima MN, Caldana F, Laranja DC, Bromberg E, Roesler R, Quevedo J, Moreira JC, Dal-Pizzol F (2004) Haloperidol- and clozapine-induced oxidative stress in the rat brain. Pharmacol Biochem Behav 78(4):751–756PubMedCrossRefGoogle Scholar
  43. Post A, Holsboer F, Behl C (1998) Induction of NF-KB activity during haloperidol-induced oxidative toxicity in clonal hippocampal cells: suppression of NF-KB and neuroprotection by antioxidants. J Neurosci 15:8236–8246Google Scholar
  44. Post A, Rücker M, Ohl F, Uhr M, Holsboer F, Almeida OF, Michaelidis TM (2002) Mechanisms underlying the protective potential of alpha-tocopherol (vitamin E) against haloperidol-associated neurotoxicity. Neuropsychopharmacology 26(3):397–407PubMedCrossRefGoogle Scholar
  45. Priyadarsini K, Maity D, Naik G (2003) Role of phenolic O–H and methylene hydrogen on the free radical reactions and antioxidant activity of curcumin. Free Radic Biol Med 35:475–484PubMedCrossRefGoogle Scholar
  46. Qin ZH, Chen RW, Wang Y, Nakai M, Chuang DM, Chase TN (1999) Nuclear factor KB nuclear translocation upregulates c-Myc and p53 expression during NMDA receptor apoptosis. J Neurosci 19:4023–4033PubMedGoogle Scholar
  47. Quiles JL, Mesa MD, Ramirez-Tortosa CL, Aguilera CM, Battino M, Gil A, Ramirez-Tortosa MC (2002) Curcuma longa extract supplementation reduces oxidative stress and attenuates aortic fatty streak development in rabbits. Arterioscler Thromb Vasc Biol 22(7):1225–1231PubMedCrossRefGoogle Scholar
  48. Rajeswari A (2006) Curcumin protects mouse brain from oxidative stress caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Eur Rev Med Pharmacol Sci 10(4):157–161PubMedGoogle Scholar
  49. Ramos AJ, Rubio MD, Defagot C, Hischberg L, Villar MJ, Brusco A (2004) The 5HT1A receptor agonist, 8-OH-DPAT, protects neurons and reduces astroglial reaction after ischemic damage caused by cortical devascularization. Brain Res 1030(2):201–220PubMedCrossRefGoogle Scholar
  50. Rauscher FM, Sanders RA, Watkins JB (2000) Effects of piperine on antioxidant pathways in tissues from normal and streptozotocin-induced diabetic rats. J Biochem Mol Toxicol 14(6):329–334PubMedCrossRefGoogle Scholar
  51. Reinke A, Martins MR, Lima MS, Moreira JC, Dal-Pizzol F, Quevedo J (2004) Haloperidol and clozapine, but not olanzapine, induces oxidative stress in rat brain. Neurosci Lett 372(1–2):157–160PubMedCrossRefGoogle Scholar
  52. Reynolds GP, Templeman LA, Zhang ZJ (2005) The role of 5-HT2C receptor polymorphisms in the pharmacogenetics of antipsychotic drug treatment. Prog Neuropsychopharmacol Biol Psychiatry 29(6):1021–1028PubMedCrossRefGoogle Scholar
  53. Sagara Y (1998) Induction of reactive oxygen species in neurons by haloperidol. J Neurochem 71:1002–1012PubMedCrossRefGoogle Scholar
  54. Saldaña M, Bonastre M, Aguilar E, Marin C (2006) Role of nigral NF-kappaB p50 and p65 subunit expression in haloperidol-induced neurotoxicity and stereotyped behavior in rats. Eur Neuropsychopharmacol 16(7):491–497PubMedCrossRefGoogle Scholar
  55. Sandur SK, Ichikawa H, Pandey MK, Kunnumakkara AB, Sung B, Sethi G, Aggarwal BB (2007a) Role of pro-oxidants and antioxidants in the anti-inflammatory and apoptotic effects of curcumin (diferuloylmethane). Free Radic Biol Med 43(4):568–580PubMedCrossRefGoogle Scholar
  56. Sandur SK, Pandey MK, Sung B, Ahn KS, Murakami A, Sethi G, Limtrakul P, Badmaev V, Aggarwal BB (2007b) Curcumin, demethoxycurcumin, bisdemethoxycurcumin, tetrahydrocurcumin and turmerones differentially regulate anti-inflammatory and anti-proliferative responses through a ROS-independent mechanism. Carcinogenesis 28(8):1765–1773PubMedCrossRefGoogle Scholar
  57. Schaaf MJ, Willetts L, Hayes BP, Maschera B, Stylianou E, Farrow SN (2006) The relationship between intranuclear mobility of the NF-KB subunit p65 and its DNA-binding affinity. J Biol Chem 281(31):22409–22420PubMedCrossRefGoogle Scholar
  58. See RE, Lynch AM (1995) Chronic haloperidol potentiates stimulated glutamate release in caudate putamen, but not prefrontal cortex. Neuroreport 6(13):1795–1798PubMedCrossRefGoogle Scholar
  59. See RE, Lynch AM, Aravagiri M, Nemeroff CB, Owens MJ (1995) Chronic haloperidol-induced changes in regional dopamine release and metabolism and neurotensin content in rats. Brain Res 704(2):202–209PubMedCrossRefGoogle Scholar
  60. Selvendiran K, Singh JP, Krishnan KB, Sakthisekaran D (2003) Cytoprotective effect of piperine against benzo[a]pyrene induced lung cancer with reference to lipid peroxidation and antioxidant system in Swiss albino mice. Fitoterapia 74(1–2):109–115PubMedCrossRefGoogle Scholar
  61. Sethi G, Ahn KS, Sandur SK, Lin X, Chaturvedi MM, Aggarwal BB (2006) Indirubin enhances tumor necrosis factor-induced apoptosis through modulation of nuclear factor-kappa B signaling pathway. J Biol Chem 281(33):23425–23435PubMedCrossRefGoogle Scholar
  62. Sharma RA, Gescher AJ, Steward WP (2005) Curcumin: the story so far. Eur J Cancer (13):1955–1968Google Scholar
  63. Sharma RA, Steward WP, Gescher AJ (2007a) Pharmacokinetics and pharmacodynamics of curcumin. Adv Exp Med Biol 595:453–470PubMedCrossRefGoogle Scholar
  64. Sharma S, Chopra K, Kulkarni SK (2007b) Effect of insulin and its combination with resveratrol or curcumin in attenuation of diabetic neuropathic pain: participation of nitric oxide and TNF-alpha. Phytother Res 21(3):278–283PubMedCrossRefGoogle Scholar
  65. Shishodia S, Sethi G, Aggarwal BB (2005) Curcumin: getting back to the roots. Ann N Y Acad Sci 1056:206–217PubMedCrossRefGoogle Scholar
  66. Shishodia S, Chaturvedi MM, Aggarwal BB (2007) Role of curcumin in cancer therapy. Curr Probl Cancer 31(4):243–305PubMedCrossRefGoogle Scholar
  67. Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PS (1998) Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med 64(4):353–356PubMedCrossRefGoogle Scholar
  68. Singh S, Khanna M, Sarin JPS (1981) High pressure liquid chromatographic determination of Curcumin in biological fluids. Indian Drugs 18:207–209Google Scholar
  69. Tamminga CA, Thaker GK, Moran M, Kakigi T, Gao XM (1994) Clozapine in tardive dyskinesia: observations from human and animal model studies. J Clin Psychiatry 55(Suppl B):102–106PubMedGoogle Scholar
  70. Terland O, Almås B, Flatmark T, Andersson KK, Sørlie M (2006) One-electron oxidation of catecholamines generates free radicals with an in vitro toxicity correlating with their lifetime. Free Radic Biol Med 41(8):1266–1271Google Scholar
  71. Tsai G, Goff DC, Wang RW, Flood J, Baer L, Coyle JT (1998) Markers of glutamatergic neurotransmission and oxidative stress associated with tardive dyskinesia. Am J Psychiatry 155:1207–1213PubMedGoogle Scholar
  72. Vijayakumar RS, Surya D, Nalini N (2004) Antioxidant efficacy of black pepper (Piper nigrum L.) and piperine in rats with high fat diet induced oxidative stress. Redox Rep 9(2):105–110Google Scholar
  73. Vilner BJ, Costa BR, Bowen WD (1995) Cytotoxic effects of sigma ligands: sigma receptor-mediated alterations in cellular morphology and viability. J Neurosci 15:134–137Google Scholar
  74. Wills ED (1966) Mechanism of lipid peroxide formation in animal tissues. Biochem Jour 99:667–676Google Scholar
  75. Xu Y, Ku BS, Yao HY, Lin YH, Ma X, Zhang YH, Li XJ (2005a) The effects of curcumin on depressive-like behaviors in mice. Eur J Pharmacol 518(1):40–46PubMedCrossRefGoogle Scholar
  76. Xu Y, Ku BS, Yao HY, Lin YH, Ma X, Zhang YH, Li XJ (2005b) Antidepressant effects of curcumin in the forced swim test and olfactory bulbectomy models of depression in rats. Pharmacol Biochem Behav 82(1):200–206PubMedCrossRefGoogle Scholar
  77. Yuan J, Yankner BA (2000) Apoptosis in the nervous system. Nature 407:802–809PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Mahendra Bishnoi
    • 4
    • 1
  • Kanwaljit Chopra
    • 2
  • Lu Rongzhu
    • 3
  • Shrinivas K. Kulkarni
    • 1
    • 2
  1. 1.Centre with Potential for Excellence in Biomedical Sciences (CPEBS)Panjab UniversityChandigarhIndia
  2. 2.Pharmacology DivisionUniversity Institute of Pharmaceutical Sciences, Panjab UniversityChandigarhIndia
  3. 3.Department of Preventive MedicineSchool of Medical Sciences and Laboratory Medicine, Jiangsu UniversityZhenjiangChina
  4. 4.Department of PharmacologySouthern Illinois University-School of MedicineSpringfieldUSA

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