curcumin and Dyskinesia--Drug-Induced

Histone acetylation is a key regulatory factor for gene expression in cells. Modulation of histone acetylation by targeting of histone acetyltransferases (HATs) effectively alters many gene expression profiles and synaptic plasticity in the brain. However, the role of HATs on L-DOPA-induced dyskinesia of Parkinson's disease (PD) has not been reported. Our aim was to determine whether HAT inhibitors such as anacardic acid, garcinol, and curcumin from natural plants reduce severity of L-DOPA-induced dyskinesia using a unilaterally 6-hydroxydopamine (6-OHDA)-lesioned PD mouse model. Anacardic acid 2 mg/kg, garcinol 5 mg/kg, or curcumin 100 mg/kg co-treatment with L-DOPA significantly reduced the axial, limb, and orofacial (ALO) score indicating less dyskinesia with administration of HAT inhibitors in 6-OHDA-lesioned mice. Additionally, L-DOPA's efficacy was not altered by the compounds in the early stage of treatment. The expression levels of c-Fos, Fra-2, and Arc were effectively decreased by administration of HAT inhibitors in the ipsilateral striatum. Our findings indicate that HAT inhibitor co-treatment with L-DOPA may have therapeutic potential for management of L-DOPA-induced dyskinesia in patients with PD.

Topics: Anacardic Acids; Animals; Antiparkinson Agents; Curcumin; Cytoskeletal Proteins; Drug Evaluation, Preclinical; Dyskinesia, Drug-Induced; Enzyme Inhibitors; Fos-Related Antigen-2; Gene Expression Regulation; Histone Acetyltransferases; Histone Code; Levodopa; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Oxidopamine; Parkinsonian Disorders; Proto-Oncogene Proteins c-fos; Specific Pathogen-Free Organisms; Substantia Nigra; Terpenes

Curcumin (Curcuma Longa Linn), the active component of turmeric, has been shown to be effective in ameliorating several stress and drug-induced disorders in rats and humans. However, it is unclear whether short term curcumin administration can prevent the abnormal oro-facial movements (AOFM) which develop following blockade of dopamine D2 receptors by antagonist such as Haloperidol. The objective of this study is to determine whether short term treatment with curcumin along with Haloperidol can prevent the development of AOFM in rats. Male Sprague Dawley rats were administered curcumin at 200 mg/kg, and Haloperidol at 2 mg/kg daily for 2 weeks, and AOFMs and locomotor activity were assessed at baseline, day 7 and day 14. By day 14, rats receiving concurrent curcumin administration had a significant reduction in the incidence of Haloperidol-induced AOFMs, but no change on the Haloperidol-induced hypolocomotion. There was no spiked increase in locomotor activity in absence of challenge with dopamine D2 receptor agonist. The exact mechanism by which curcumin attenuates AOFMs remains unknown, therefore, we performed a proteomic analysis of the striatal samples obtained from control and curcumin treated groups. A number of proteins were altered by curcumin, among them an antiapoptotic protein, Bcl-XL, was significantly upregulated. These results suggest that curcumin may be a promising treatment to prevent the development of AOFMs and further suggest some therapeutic value in the treatment of movement disorders.

Topics: Animals; Antipsychotic Agents; bcl-X Protein; Curcumin; Dyskinesia, Drug-Induced; Enzyme Inhibitors; Face; Haloperidol; Male; Mouth; Rats; Rats, Sprague-Dawley

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.

Topics: Animals; Anti-Anxiety Agents; Anti-Dyskinesia Agents; Antipsychotic Agents; Behavior, Animal; Body Weight; Brain Chemistry; Catalase; Curcuma; Curcumin; Dyskinesia, Drug-Induced; Glutathione; Haloperidol; Lipid Peroxidation; Male; Motor Activity; Nerve Tissue Proteins; Neurotransmitter Agents; Rats; Rats, Wistar; Stereotyped Behavior; Sulfhydryl Compounds; Superoxide Dismutase