Protective effect of curcumin, the active principle of turmeric (Curcuma longa) in Haloperidol-induced orofacial dyskinesia and associated behavioral, biochemical and neurochemical changes in rat brain
Tardive dyskinesia (TD) is a motor disorder of the orofacial region resulting from chronic neuroleptic treatment. A high incidence and irreversibility of this hyperkinetic disorder has been considered a major clinical issue in the treatment of schizophrenia. The molecular mechanism related to the pathophysiology of tardive dyskinesia is not completely known. Various animal studies have demonstrated an enhanced oxidative stress and increased glutamatergic transmission as well as inhibition in the glutamate uptake after the chronic administration of haloperidol. The present study investigated the effect of curcumin, an antioxidant, in haloperidol-induced tardive dyskinesia by using different behavioural (orofacial dyskinetic movements, stereotypy, locomotor activity, % retention), biochemical (lipid peroxidation, reduced glutathione levels, antioxidant enzyme levels (SOD and catalase) and neurochemical (neurotransmitter levels) parameters. Chronic administration of haloperidol (1 mg/kg i.p. for 21 days) significantly increased vacuous chewing movements (VCM's), tongue protrusions, facial jerking in rats which was dose-dependently inhibited by curcumin. Chronic administration of haloperidol also resulted in increased dopamine receptor sensitivity as evident by increased locomotor activity and stereotypy and also decreased % retention time on elevated plus maze paradigm. Pretreatment with curcumin reversed these behavioral changes. Besides, haloperidol also induced oxidative damage in all major regions of brain which was attenuated by curcumin, especially in the subcortical region containing striatum. On chronic administration of haloperidol, there was a decrease in turnover of dopamine, serotonin and norepinephrine in both cortical and subcortical regions which was again dose-dependently reversed by treatment with curcumin. The findings of the present study suggested for the involvement of free radicals in the development of neuroleptic-induced tardive dyskinesia and point to curcumin as a possible therapeutic option to treat this hyperkinetic movement disorder.
[Show abstract][Hide abstract] ABSTRACT: Objective
To evaluate the neuroprotective activity of Gentisic acid in PD. The study was conducted on swiss albinFo mice (20-25 g) & wistar rats (200-250 g).
Three behavioural models namely, Haloperidol induced catalepsy, Reserpine antagonism and Haloperidol induce orofacial dyskinesia were employed in this study, Swiss Albino mice (20-25 g) were used in first two models while Wistar rats (200-250 g) used in last one model. There are five group (n=6) in each animal model. Various behavior activity/parameter (cataleptic behavior, horizontal movements, rearing & grooming frequencies and Dyskinesia activity like vacuous chewing & tongue protrusion) in different animal models were used to evaluate the anti-Parkinson's activity of Gentisic acid.
Gentisic acid showed a significant (P<0.01) reduction in the duration of cataleptic behavior dose dependently when compared to haloperidol control group. Gentisic acid shows dose dependant increase in the frequency of horizontal movement and rearing behavior when compared to the Reserpine control group. But, the effect of Gentisic acid on the frequency of grooming behavior was found to be insignificant. Gentisic acid (80 mg/kg) showed a significant (P<0.05) decrease in the frequency of vacuous chewing & tongue protrusion but the other dose tested were found to be insignificant in this respect.
Results shows that the Gentisic acid produced dose dependent neuroprotective activity in different animal models of PD.
"1, 7-bis (4-hydroxy-3-methoxyphenyl)-1, 6-heptadiene-3, 5-dione (curcumin) is the main ingredient of curcuma longa, and has a variety of effects, such as anti-oxidative, anti-inflammatory, immunomodulatory, and neuro-protective , . Curcumin has neuroprotective effects in various neurological disorders, such as Alzheimer’s disease , tardive dyskinesia , major depression , and diabetic neuropathy , . Recently, several studies have demonstrated an anti-nociceptive effect of curcumin in neuropathic pain , . "
[Show abstract][Hide abstract] ABSTRACT: The management of neuropathic pain is still a major challenge because of its unresponsiveness to most common treatments. Curcumin has been reported to play an active role in the treatment of various neurological disorders, such as neuropathic pain. Curcumin has long been recognized as a p300/CREB-binding protein (CBP) inhibitor of histone acetyltransferase (HAT) activity. However, this mechanism has never been investigated for the treatment of neuropathic pain with curcumin. The aim of the present study was to investigate the anti-nociceptive role of curcumin in the chronic constriction injury (CCI) rat model of neuropathic pain. Furthermore, with this model we investigated the effect of curcumin on P300/CBP HAT activity-regulated release of the pro-nociceptive molecules, brain-derived neurotrophic factor (BDNF) and cyclooxygenase-2 (Cox-2). Treatment with 40 and 60 mg/kg body weight curcumin for 7 consecutive days significantly attenuated CCI-induced thermal hyperalgesia and mechanical allodynia, whereas 20 mg/kg curcumin showed no significant analgesic effect. Chromatin immunoprecipitation analysis revealed that curcumin dose-dependently reduced the recruitment of p300/CBP and acetyl-Histone H3/acetyl-Histone H4 to the promoter of BDNF and Cox-2 genes. A similar dose-dependent decrease of BDNF and Cox-2 in the spinal cord was also observed after curcumin treatment. These results indicated that curcumin exerted a therapeutic role in neuropathic pain by down-regulating p300/CBP HAT activity-mediated gene expression of BDNF and Cox-2.
PLoS ONE 03/2014; 9(3):e91303. DOI:10.1371/journal.pone.0091303 · 3.23 Impact Factor
"Long-term (21 days) administration of haloperidol increased vacuous chewing movements and facial jerkings and decreased turnover of dopamine in cortical and subcortical regions of the brain. Chronic pretreatment with curcumin reversed all changes induced by haloperidol (Bishoni et al., 2008 ▶). In addition, chronic oral administration of curcuminoids including curcumin, demethoxycurcumin, and bisdemethoxycurcumin prevented striatal dopaminergic neurodegeneration induced by 6-hydroxydopamine model of Parkinsonism in rats (Agrawal et al., 2012 ▶). "
[Show abstract][Hide abstract] ABSTRACT: Objective: Curcumin is a major constituent of turmeric and influences many functions of the brain. In the present study, we investigated the effect of curcumin on yawning induced by apomorphine in rats.
Materials and Methods: Curcumin administered orally for 10 consecutive days. Yawning was induced by subcutaneous (s.c.) injection of apomorphine (a dopamine receptor agonist) and the number of yawns was recorded for a period of 30 min.
Results: Apomorphine (0.05 and 0.1 mg/kg) produced yawning. Haloperidol (a dopamine receptors antagonist) at a dose of 0.05 mg/kg partially and at a dose of 0.2 mg/kg completely inhibited apomorphine-induced yawning. Curcumin alone produced no yawning, whereas at doses of 30 and 60 mg/kg, it increased yawning induced by 0.1 mg/kg of apomorphine. Curcumin at the high doses (30 and 60 mg/kg) produced yawning when apomorphine (0.1 mg/kg) action was partially blocked with 0.5 mg/kg of haloperidol. In the presence of complete blockade of apomorphine (0.1 mg/kg) action with 0.2 mg/kg of haloperidol, curcumin did not produce yawning.
Conclusion: The results showed that curcumin at high doses increased apomorphine-induced yawning. In the presence of partial, but not complete blockade of apomorphine action, curcumin produced yawning. Curcumin produced a dopamine-like effect on yawning.
Avicenna Journal of Phytomedicine 02/2013; 3(3):231-7.
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