Reversal of Haloperidol-Induced Orofacial Dyskinesia and Neuroinflammation by Isoflavones

Schizophrenia is a serious mental illness, and its pharmacological treatment consists in the administration of antipsychotics, such as haloperidol. However, treatment with haloperidol often causes extrapyramidal motor disorders such as tardive dyskinesia (TD). TD is a movement disorder characterized by involuntary movements, which can be studied in animals. So far, there is no effective treatment for TD and alternatives have been sought. Thus, the objective was to evaluate the possible protective effect of isoflavones against the induction of involuntary movements induced by haloperidol in an animal model. Male Wistars rats were treated with haloperidol (1 mg/ kg/day) and/or isoflavones (80 mg/kg) for 28 days. Rats were submitted to behavioral evaluation to quantify vacuous chewing movements (VCM) and the locomotor activity. In addition, the levels of pro-inflammatory cytokines were measured in the striatum. Haloperidol treatment reduced the locomotor activity and increased the number of VCM in rats. Co-treatment with isoflavones was able to reverse hypolocomotion and reduce the number of VCM to the levels of the control group. Besides, haloperidol caused significant increase in the proinflammatory cytokines (interleukin-1β:IL-1β, tumor necrosis factor-α:TNF-a and IL-6 and the co-treatment with isoflavones was able to reduce the levels of IL-1β and TNF-α, but not IL-6. It is believed that the beneficial effect found with this treatment is related to their anti-inflammatory potential and also to the action on estrogen receptors (based on findings in the scientific literature). Finally, further studies are needed to elucidate the mechanisms of isoflavones in reducing motor disorders induced by antipsychotic.

Antipsychotic Behavioral Phenotypes in the Mouse Collaborative Cross Recombinant Inbred Inter-Crosses (RIX)

Schizophrenia is an idiopathic disorder that affects approximately 1% of the human population, and presents with persistent delusions, hallucinations, and disorganized behaviors. Antipsychotics are the standard pharmacological treatment for schizophrenia, but are frequently discontinued by patients due to inefficacy and/or side effects. Chronic treatment with the typical antipsychotic haloperidol causes tardive dyskinesia (TD), which manifests as involuntary and often irreversible orofacial movements in around 30% of patients. Mice treated with haloperidol develop many of the features of TD, including jaw tremors, tongue protrusions, and vacuous chewing movements (VCMs). In this study, we used genetically diverse Collaborative Cross (CC) recombinant inbred inter-cross (RIX) mice to elucidate the genetic basis of antipsychotic-induced adverse drug reactions (ADRs). We performed a battery of behavioral tests in 840 mice from 73 RIX lines (derived from 62 CC strains) treated with haloperidol or placebo in order to monitor the development of ADRs. We used linear mixed models to test for strain and treatment effects. We observed highly significant strain effects for almost all behavioral measurements investigated (P < 0.001). Further, we observed strong strain-by-treatment interactions for most phenotypes, particularly for changes in distance traveled, vertical activity, and extrapyramidal symptoms (EPS). Estimates of overall heritability ranged from 0.21 (change in body weight) to 0.4 (VCMs and change in distance traveled) while the portion attributable to the interactions of treatment and strain ranged from 0.01 (for change in body weight) to 0.15 (for change in EPS). Interestingly, close to 30% of RIX mice exhibited VCMs, a sensitivity to haloperidol exposure, approximately similar to the rate of TD in humans chronically exposed to haloperidol. Understanding the genetic basis for the susceptibility to antipsychotic ADRs may be possible in mouse, and extrapolation to humans could lead to safer therapeutic approaches for schizophrenia.

Evaluation of Antioxidant and Anti-Parkinson Activity of Portulaca oleracea Seed Methanolic Extract

Aim: Evaluation of Antioxidant and Anti-Parkinson activity of Portulaca oleracea seed methanolic extract. Place: C. U. Shah College of Pharmacy and Research, Wadhwan, Surendranagar, Gujarat, India. Methodology: Collect plant materials were extracted with methanol. Extract was subjected to qualitative and quantitative investigation and antioxidant properties of extract was determine by Nitric oxide free radical scavenging activity and Reducing power by FeCl3 method. Anti-Parkinson activity evaluated by two behavioral models namely, haloperidol induced catalepsy, and orofacial dyskinesia both models various behavioral activity/ parameter (catalepsy, vacuous chewing movement and tongue protrusion) were evaluated. Results: Preliminary qualitative phytochemical screening was to reveal presence of polyphenols, flavanoids, glycoside, alkaloids, carbohydrates and reducing sugar etc. Based preliminary qualitative phytochemical screening; quantitative estimation of methanolic extract showed significant amount of polyphenols. In-vitro antioxidants was performed by two method reducing power by FeCl3 and nitric oxide free radical scavenging, the methanolic extract shows significant antioxidant properties, based on polyphenols and antioxidant properties extracts was used for the Anti-Parkinson activity Haloperidol induced catalepsy in mice Treatment with Portulaca oleracea seed showed a significant (P<0.01) reduction in the duration of cataleptic behavior dose dependently when compared to haloperidol treated group. Haloperidol induced orofacial dyskinesia in rat recovery of orofacial dyskinesia as evidenced by decrease in the frequency of vacuous chewing movement and tongue significant (P<0.05) decrease in the frequency of vacuous chewing & tongue protrusion while Portulaca oleracea seed (200 mg/kg) was found to be insignificant in this respect. Conclusion: After Portulaca oleracea seed (MLPO) treatment, the significant alterations produced in Parkinson’s affected rodents in respect to lipid peroxidation and antioxidant concentration significantly contributing its antioxidant potential. This antiperoxide action observed in Portulaca oleracea seed (MLPO) treated animals might be due to the suppression of the production of reactive oxygen species. This compound may be found to scavenge free radicals, including hydroxyl anions and reduce the level of lipid peroxidation in MLPO animals. Inhibition of oxidative stress may be one of the possible mechanisms for the anti-Parkinson effects of Portulaca oleracea seed (MLPO).

Antipsychotic behavioral phenotypes in the mouse Collaborative Cross recombinant inbred inter-crosses (RIX)

ABSTRACTSchizophrenia is an idiopathic disorder that affects approximately 1% of the human population, and presents with persistent delusions, hallucinations, and disorganized behaviors. Antipsychotics are the standard pharmacological treatment for schizophrenia, but are frequently discontinued by patients due to inefficacy and/or side effects. Chronic treatment with the typical antipsychotic haloperidol causes tardive dyskinesia (TD), which manifests as involuntary and often irreversible orofacial movements in around 30% of patients. Mice treated with haloperidol develop many of the features of TD, including jaw tremors, tongue protrusions, and vacuous chewing movements (VCMs). In this study, we used genetically diverse Collaborative Cross (CC) recombinant inbred inter-cross (RIX) mice to elucidate the genetic basis of antipsychotic-induced adverse drug reactions (ADRs). We performed a battery of behavioral tests in 840 mice from 73 RIX lines (derived from 62 CC strains) treated with haloperidol or placebo in order to monitor the development of ADRs. We used linear mixed models to test for strain and treatment effects. We observed highly significant strain effects for almost all behavioral measurements investigated (p<0.001). Further, we observed strong strain-by-treatment interactions for most phenotypes, particularly for changes in distance traveled, vertical activity, and extrapyramidal symptoms (EPS). Estimates of overall heritability ranged from 0.21 (change in body weight) to 0.4 (VCMs and change in distance traveled) while the portion attributable to the interactions of treatment and strain ranged from 0.01 (for change in body weight) to 0.15 (for change in EPS). Interestingly, close to 30% of RIX mice exhibited VCMs, a sensitivity to haloperidol exposure, approximately similar to the rate of TD in humans chronically exposed to haloperidol. Understanding the genetic basis for the susceptibility to antipsychotic ADRs may be possible in mouse, and extrapolation to humans could lead to safer therapeutic approaches for schizophrenia.

PHYTOCHEMICAL ANALYSIS AND COMPARATIVE ANTIPARKINSON ACTIVITY OF FOUR SPECIES OF MUCUNA

Objective: The aim was to study the antiparkinson activity in the seed extracts of four species of Mucuna.Methods: The hydroalcoholic extracts of seeds of four species of Mucuna were evaluated for antiparkinson activity of after a preliminary phytochemical study. The activity was measured in rats by indirectly measuring the decrease in malondialdehyde level, decrease in tongue protrusion frequency, and reduction in vacuous chewing movement after administering reserpine at the dose of 1 mg/kg. The dose levels of four species of Mucuna seed extract were kept at 100, 200, and 300 mg/Kg.Results: Extracts exhibited potent antiparkinson activity and achieved statistically significant p values compared with control group. The study corroborates and compares all four species of Mucuna. Conclusion: Among the extracts, the highest percentage of antiparkinson activity was recorded for Mucuna pruriens.