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Shrinivas K. Kulkarni - One of the best experts on this subject based on the ideXlab platform.
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activation of striatal inflammatory mediators and caspase 3 is central to haloperidol induced Orofacial Dyskinesia
European Journal of Pharmacology, 2008Co-Authors: Mahendra Bishnoi, Kanwaljit Chopra, Shrinivas K. KulkarniAbstract:Abstract The undesired extrapyramidal movement disorders observed with long term treatment with haloperidol have been associated with striatal neurodegeneration. The present study was designed to investigate the effect of prolonged haloperidol treatment on striatal levels of inflammatory mediators and caspase-3 and to correlate it with Orofacial Dyskinesia, a movement disorder observed with long term haloperidol treatment. Prolonged administration of haloperidol (1, 2, 5 mg/kg) to rats produced dose-dependent increase in the Orofacial dyskinetic movements and induced a marked oxidative stress in the striatum. Lower dose of haloperidol (1 mg/kg) decreased NO levels but did not induce TNF-α or NF-κB expression. At higher doses (2 and 5 mg/kg), increased levels of total nitric oxide and TNF-α in cytoplasmic lysate and active p65 subunit of NF-κB in nuclear lysates of rat brain were observed. These doses (2 and 5 mg/kg) also induced an increased expression of caspase-3 protein in striatal cytoplasmic fraction as shown by western blot analysis. Collectively, we conclude that oxidative stress mediated increase in inflammatory mediators may initiate the apoptotic pathway (caspase-3) after chronic haloperidol treatment. All this is well correlated with behavioural development of Orofacial Dyskinesia.
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differential striatal levels of tnf α nfκb p65 subunit and dopamine with chronic typical and atypical neuroleptic treatment role in Orofacial Dyskinesia
Progress in Neuro-psychopharmacology & Biological Psychiatry, 2008Co-Authors: Mahendra Bishnoi, Kanwaljit Chopra, Shrinivas K. KulkarniAbstract:Abstract Long term use of typical neuroleptics such as haloperidol may be limited by unwanted motor side effects like tardive Dyskinesia characterized by repetitive involuntary movements, involving the mouth, face and trunk. Atypical neuroleptics, such as clozapine and risperidone are devoid of these side effects. However the precise mechanisms of the neuronal toxicity induced by haloperidol are poorly understood. It is possible that typical and atypical antipsychotic differently affects neuronal survival and death and that these effects considerably contribute to the differences in the development of TD. The aim of the present study is to investigate the role of TNF-α and NFκB on the toxicity induced by chronic haloperidol administration in an animal model of tardive Dyskinesia. Rats were treated for 21 days with: haloperidol (5 mg/kg), clozapine (5 and 10 mg/kg), risperidone (5 mg/kg) or saline. Orofacial dyskinetic movements and total locomotor activity was evaluated. Striatal levels of dopamine were measure by HPLC/ED whereas striatal levels of TNF-α and NFκB p65 subunit were measured by ELISA technique. Haloperidol increased Orofacial dyskinetic movements and total locomotor activity (on day 22) ( P ≤ 0.05). Clozapine and risperidone also increased the Orofacial dyskinetic movements but that significantly less than haloperidol ( P ≤ 0.05). Differential effect of haloperidol and atypical neuroleptics on striatal dopamine levels and striatal levels of TNF-α and NFκB p65 subunit was found out. Haloperidol significantly decreased the striatal dopamine levels whereas clozapine and risperidone did not. Haloperidol but not clozapine and risperidone significantly increased the levels of TNF-α and NFκB p65 subunit ( P ≤ 0.05). The present study suggests the impossible involvement of striatal TNF-α and NFκB p65 subunit in haloperidol-induced Orofacial Dyskinesia in rats, an animal model for human tardive Dyskinesia.
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protective effect of l type calcium channel blockers against haloperidol induced Orofacial Dyskinesia a behavioural biochemical and neurochemical study
Neurochemical Research, 2008Co-Authors: Mahendra Bishnoi, Kanwaljit Chopra, Shrinivas K. KulkarniAbstract:Haloperidol is a classical neuroleptic drug that is still in use and can lead to abnormal motor activity such as tardive Dyskinesia (TD) following repeated administration. TD has no effective therapy yet. There is involvement of calcium in triggering the oxidative damage and excitotoxicity, both of which play central role in haloperidol-induced Orofacial Dyskinesia and associated alterations. The present study was carried out to investigate the protective effect of calcium channel blockers [verapamil (10 and 20 mg/kg), diltiazem (10 and 20 mg/kg), nifedipine (10 and 20 mg/kg) and nimodipine (10 and 20 mg/kg)] against haloperidol induced Orofacial Dyskinesia and associated behavioural, biochemical and neurochemical alterations in rats. Chronic administration of haloperidol (1 mg/kg i.p., 21 days) resulted in a significant increase in Orofacial dyskinetic movements and significant decrease in % retention, coupled with the marked increase in lipid peroxidation and superoxide anion generation where as significant decrease in non protein thiols and endogenous antioxidant enzyme (SOD and catalase) levels in rat brain striatum homogenates. All these deleterious effects of haloperidol were significantly attenuated by co-administration of different calcium channel blockers. Neurochemically, chronic administration of haloperidol resulted in significant decrease in levels of catecholamines (dopamine, serotonin) and their metabolites (HVA and HIAA) but increased turnover of dopamine and serotonin. Co-administration of most effective doses of verapamil, diltiazem, nifedipine and nimodipine significantly attenuated these neurochemical changes. Results of the present study indicate that haloperidol-induced calcium ion influx is involved in the pathogenesis of tardive Dyskinesia and calcium channel blockers should be tested in clinical trials with nifedipine as the most promising one.
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progesterone attenuates neuroleptic induced Orofacial Dyskinesia via the activity of its metabolite allopregnanolone a positive gabaa modulating neurosteroid
Progress in Neuro-psychopharmacology & Biological Psychiatry, 2008Co-Authors: Mahendra Bishnoi, Kanwaljit Chopra, Shrinivas K. KulkarniAbstract:Abstract GABAergic hypofunction in the basal ganglia is stated as an important mechanism underlying the pathophysiology of tardive Dyskinesia. In the present study we sought to establish the protective effect of progesterone in haloperidol-induced Orofacial Dyskinesia. Besides this we also tried to find out whether the GABA A facilitatory action of progesterone metabolites is responsible for the action of progesterone in attenuating the haloperidol-induced Orofacial Dyskinesia, an animal model of tardive Dyskinesia. Chronic administration of haloperidol (1 mg/kg, i.p. 21 days) induced significant increase in hyperkinetic Orofacial dyskinetic movements and oxidative damage in the brain as compared to control group. Coadministration of progesterone (5–20 mg/kg, i.p. 21 days) dose dependently prevented the hyperkinetic Orofacial movements as well as oxidative damage parameters. The protective activity of progesterone was reversed by pre treatment with finasteride (50 mg/kg i.p.), a 5α-reductase inhibitor that blocks the metabolism of progesterone to allopregnanolone and other metabolites. Further, chronic administration of haloperidol resulted in significant decrease in dopamine levels in rat striatum homogenates and increase in catecholamine metabolite levels. Coadministration of progesterone also reversed the decrease in dopamine levels induced by chronic haloperidol treatment, an effect which was again reversed by pre treatment with finasteride. Our study provides strong evidence that the protective effect of progesterone resides in the GABAergic as well as neuroprotective activity of its metabolite allopregnanolone. These findings lend support to recognized GABA hypofunction theory of tardive Dyskinesia and strongly suggest progesterone as a protective therapy in this debilitating movement disorder.
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Differential striatal levels of TNF-α, NFκB p65 subunit and dopamine with chronic typical and atypical neuroleptic treatment: Role in Orofacial Dyskinesia
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2008Co-Authors: Mahendra Bishnoi, Kanwaljit Chopra, Shrinivas K. KulkarniAbstract:Long term use of typical neuroleptics such as haloperidol may be limited by unwanted motor side effects like tardive Dyskinesia characterized by repetitive involuntary movements, involving the mouth, face and trunk. Atypical neuroleptics, such as clozapine and risperidone are devoid of these side effects. However the precise mechanisms of the neuronal toxicity induced by haloperidol are poorly understood. It is possible that typical and atypical antipsychotic differently affects neuronal survival and death and that these effects considerably contribute to the differences in the development of TD. The aim of the present study is to investigate the role of TNF-α and NFκB on the toxicity induced by chronic haloperidol administration in an animal model of tardive Dyskinesia. Rats were treated for 21 days with: haloperidol (5 mg/kg), clozapine (5 and 10 mg/kg), risperidone (5 mg/kg) or saline. Orofacial dyskinetic movements and total locomotor activity was evaluated. Striatal levels of dopamine were measure by HPLC/ED whereas striatal levels of TNF-α and NFκB p65 subunit were measured by ELISA technique. Haloperidol increased Orofacial dyskinetic movements and total locomotor activity (on day 22) (P ≤ 0.05). Clozapine and risperidone also increased the Orofacial dyskinetic movements but that significantly less than haloperidol (P ≤ 0.05). Differential effect of haloperidol and atypical neuroleptics on striatal dopamine levels and striatal levels of TNF-α and NFκB p65 subunit was found out. Haloperidol significantly decreased the striatal dopamine levels whereas clozapine and risperidone did not. Haloperidol but not clozapine and risperidone significantly increased the levels of TNF-α and NFκB p65 subunit (P ≤ 0.05). The present study suggests the impossible involvement of striatal TNF-α and NFκB p65 subunit in haloperidol-induced Orofacial Dyskinesia in rats, an animal model for human tardive Dyskinesia. © 2008 Elsevier Inc. All rights reserved.
Mahendra Bishnoi - One of the best experts on this subject based on the ideXlab platform.
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activation of striatal inflammatory mediators and caspase 3 is central to haloperidol induced Orofacial Dyskinesia
European Journal of Pharmacology, 2008Co-Authors: Mahendra Bishnoi, Kanwaljit Chopra, Shrinivas K. KulkarniAbstract:Abstract The undesired extrapyramidal movement disorders observed with long term treatment with haloperidol have been associated with striatal neurodegeneration. The present study was designed to investigate the effect of prolonged haloperidol treatment on striatal levels of inflammatory mediators and caspase-3 and to correlate it with Orofacial Dyskinesia, a movement disorder observed with long term haloperidol treatment. Prolonged administration of haloperidol (1, 2, 5 mg/kg) to rats produced dose-dependent increase in the Orofacial dyskinetic movements and induced a marked oxidative stress in the striatum. Lower dose of haloperidol (1 mg/kg) decreased NO levels but did not induce TNF-α or NF-κB expression. At higher doses (2 and 5 mg/kg), increased levels of total nitric oxide and TNF-α in cytoplasmic lysate and active p65 subunit of NF-κB in nuclear lysates of rat brain were observed. These doses (2 and 5 mg/kg) also induced an increased expression of caspase-3 protein in striatal cytoplasmic fraction as shown by western blot analysis. Collectively, we conclude that oxidative stress mediated increase in inflammatory mediators may initiate the apoptotic pathway (caspase-3) after chronic haloperidol treatment. All this is well correlated with behavioural development of Orofacial Dyskinesia.
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differential striatal levels of tnf α nfκb p65 subunit and dopamine with chronic typical and atypical neuroleptic treatment role in Orofacial Dyskinesia
Progress in Neuro-psychopharmacology & Biological Psychiatry, 2008Co-Authors: Mahendra Bishnoi, Kanwaljit Chopra, Shrinivas K. KulkarniAbstract:Abstract Long term use of typical neuroleptics such as haloperidol may be limited by unwanted motor side effects like tardive Dyskinesia characterized by repetitive involuntary movements, involving the mouth, face and trunk. Atypical neuroleptics, such as clozapine and risperidone are devoid of these side effects. However the precise mechanisms of the neuronal toxicity induced by haloperidol are poorly understood. It is possible that typical and atypical antipsychotic differently affects neuronal survival and death and that these effects considerably contribute to the differences in the development of TD. The aim of the present study is to investigate the role of TNF-α and NFκB on the toxicity induced by chronic haloperidol administration in an animal model of tardive Dyskinesia. Rats were treated for 21 days with: haloperidol (5 mg/kg), clozapine (5 and 10 mg/kg), risperidone (5 mg/kg) or saline. Orofacial dyskinetic movements and total locomotor activity was evaluated. Striatal levels of dopamine were measure by HPLC/ED whereas striatal levels of TNF-α and NFκB p65 subunit were measured by ELISA technique. Haloperidol increased Orofacial dyskinetic movements and total locomotor activity (on day 22) ( P ≤ 0.05). Clozapine and risperidone also increased the Orofacial dyskinetic movements but that significantly less than haloperidol ( P ≤ 0.05). Differential effect of haloperidol and atypical neuroleptics on striatal dopamine levels and striatal levels of TNF-α and NFκB p65 subunit was found out. Haloperidol significantly decreased the striatal dopamine levels whereas clozapine and risperidone did not. Haloperidol but not clozapine and risperidone significantly increased the levels of TNF-α and NFκB p65 subunit ( P ≤ 0.05). The present study suggests the impossible involvement of striatal TNF-α and NFκB p65 subunit in haloperidol-induced Orofacial Dyskinesia in rats, an animal model for human tardive Dyskinesia.
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protective effect of l type calcium channel blockers against haloperidol induced Orofacial Dyskinesia a behavioural biochemical and neurochemical study
Neurochemical Research, 2008Co-Authors: Mahendra Bishnoi, Kanwaljit Chopra, Shrinivas K. KulkarniAbstract:Haloperidol is a classical neuroleptic drug that is still in use and can lead to abnormal motor activity such as tardive Dyskinesia (TD) following repeated administration. TD has no effective therapy yet. There is involvement of calcium in triggering the oxidative damage and excitotoxicity, both of which play central role in haloperidol-induced Orofacial Dyskinesia and associated alterations. The present study was carried out to investigate the protective effect of calcium channel blockers [verapamil (10 and 20 mg/kg), diltiazem (10 and 20 mg/kg), nifedipine (10 and 20 mg/kg) and nimodipine (10 and 20 mg/kg)] against haloperidol induced Orofacial Dyskinesia and associated behavioural, biochemical and neurochemical alterations in rats. Chronic administration of haloperidol (1 mg/kg i.p., 21 days) resulted in a significant increase in Orofacial dyskinetic movements and significant decrease in % retention, coupled with the marked increase in lipid peroxidation and superoxide anion generation where as significant decrease in non protein thiols and endogenous antioxidant enzyme (SOD and catalase) levels in rat brain striatum homogenates. All these deleterious effects of haloperidol were significantly attenuated by co-administration of different calcium channel blockers. Neurochemically, chronic administration of haloperidol resulted in significant decrease in levels of catecholamines (dopamine, serotonin) and their metabolites (HVA and HIAA) but increased turnover of dopamine and serotonin. Co-administration of most effective doses of verapamil, diltiazem, nifedipine and nimodipine significantly attenuated these neurochemical changes. Results of the present study indicate that haloperidol-induced calcium ion influx is involved in the pathogenesis of tardive Dyskinesia and calcium channel blockers should be tested in clinical trials with nifedipine as the most promising one.
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progesterone attenuates neuroleptic induced Orofacial Dyskinesia via the activity of its metabolite allopregnanolone a positive gabaa modulating neurosteroid
Progress in Neuro-psychopharmacology & Biological Psychiatry, 2008Co-Authors: Mahendra Bishnoi, Kanwaljit Chopra, Shrinivas K. KulkarniAbstract:Abstract GABAergic hypofunction in the basal ganglia is stated as an important mechanism underlying the pathophysiology of tardive Dyskinesia. In the present study we sought to establish the protective effect of progesterone in haloperidol-induced Orofacial Dyskinesia. Besides this we also tried to find out whether the GABA A facilitatory action of progesterone metabolites is responsible for the action of progesterone in attenuating the haloperidol-induced Orofacial Dyskinesia, an animal model of tardive Dyskinesia. Chronic administration of haloperidol (1 mg/kg, i.p. 21 days) induced significant increase in hyperkinetic Orofacial dyskinetic movements and oxidative damage in the brain as compared to control group. Coadministration of progesterone (5–20 mg/kg, i.p. 21 days) dose dependently prevented the hyperkinetic Orofacial movements as well as oxidative damage parameters. The protective activity of progesterone was reversed by pre treatment with finasteride (50 mg/kg i.p.), a 5α-reductase inhibitor that blocks the metabolism of progesterone to allopregnanolone and other metabolites. Further, chronic administration of haloperidol resulted in significant decrease in dopamine levels in rat striatum homogenates and increase in catecholamine metabolite levels. Coadministration of progesterone also reversed the decrease in dopamine levels induced by chronic haloperidol treatment, an effect which was again reversed by pre treatment with finasteride. Our study provides strong evidence that the protective effect of progesterone resides in the GABAergic as well as neuroprotective activity of its metabolite allopregnanolone. These findings lend support to recognized GABA hypofunction theory of tardive Dyskinesia and strongly suggest progesterone as a protective therapy in this debilitating movement disorder.
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Differential striatal levels of TNF-α, NFκB p65 subunit and dopamine with chronic typical and atypical neuroleptic treatment: Role in Orofacial Dyskinesia
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2008Co-Authors: Mahendra Bishnoi, Kanwaljit Chopra, Shrinivas K. KulkarniAbstract:Long term use of typical neuroleptics such as haloperidol may be limited by unwanted motor side effects like tardive Dyskinesia characterized by repetitive involuntary movements, involving the mouth, face and trunk. Atypical neuroleptics, such as clozapine and risperidone are devoid of these side effects. However the precise mechanisms of the neuronal toxicity induced by haloperidol are poorly understood. It is possible that typical and atypical antipsychotic differently affects neuronal survival and death and that these effects considerably contribute to the differences in the development of TD. The aim of the present study is to investigate the role of TNF-α and NFκB on the toxicity induced by chronic haloperidol administration in an animal model of tardive Dyskinesia. Rats were treated for 21 days with: haloperidol (5 mg/kg), clozapine (5 and 10 mg/kg), risperidone (5 mg/kg) or saline. Orofacial dyskinetic movements and total locomotor activity was evaluated. Striatal levels of dopamine were measure by HPLC/ED whereas striatal levels of TNF-α and NFκB p65 subunit were measured by ELISA technique. Haloperidol increased Orofacial dyskinetic movements and total locomotor activity (on day 22) (P ≤ 0.05). Clozapine and risperidone also increased the Orofacial dyskinetic movements but that significantly less than haloperidol (P ≤ 0.05). Differential effect of haloperidol and atypical neuroleptics on striatal dopamine levels and striatal levels of TNF-α and NFκB p65 subunit was found out. Haloperidol significantly decreased the striatal dopamine levels whereas clozapine and risperidone did not. Haloperidol but not clozapine and risperidone significantly increased the levels of TNF-α and NFκB p65 subunit (P ≤ 0.05). The present study suggests the impossible involvement of striatal TNF-α and NFκB p65 subunit in haloperidol-induced Orofacial Dyskinesia in rats, an animal model for human tardive Dyskinesia. © 2008 Elsevier Inc. All rights reserved.
Kanwaljit Chopra - One of the best experts on this subject based on the ideXlab platform.
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activation of striatal inflammatory mediators and caspase 3 is central to haloperidol induced Orofacial Dyskinesia
European Journal of Pharmacology, 2008Co-Authors: Mahendra Bishnoi, Kanwaljit Chopra, Shrinivas K. KulkarniAbstract:Abstract The undesired extrapyramidal movement disorders observed with long term treatment with haloperidol have been associated with striatal neurodegeneration. The present study was designed to investigate the effect of prolonged haloperidol treatment on striatal levels of inflammatory mediators and caspase-3 and to correlate it with Orofacial Dyskinesia, a movement disorder observed with long term haloperidol treatment. Prolonged administration of haloperidol (1, 2, 5 mg/kg) to rats produced dose-dependent increase in the Orofacial dyskinetic movements and induced a marked oxidative stress in the striatum. Lower dose of haloperidol (1 mg/kg) decreased NO levels but did not induce TNF-α or NF-κB expression. At higher doses (2 and 5 mg/kg), increased levels of total nitric oxide and TNF-α in cytoplasmic lysate and active p65 subunit of NF-κB in nuclear lysates of rat brain were observed. These doses (2 and 5 mg/kg) also induced an increased expression of caspase-3 protein in striatal cytoplasmic fraction as shown by western blot analysis. Collectively, we conclude that oxidative stress mediated increase in inflammatory mediators may initiate the apoptotic pathway (caspase-3) after chronic haloperidol treatment. All this is well correlated with behavioural development of Orofacial Dyskinesia.
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differential striatal levels of tnf α nfκb p65 subunit and dopamine with chronic typical and atypical neuroleptic treatment role in Orofacial Dyskinesia
Progress in Neuro-psychopharmacology & Biological Psychiatry, 2008Co-Authors: Mahendra Bishnoi, Kanwaljit Chopra, Shrinivas K. KulkarniAbstract:Abstract Long term use of typical neuroleptics such as haloperidol may be limited by unwanted motor side effects like tardive Dyskinesia characterized by repetitive involuntary movements, involving the mouth, face and trunk. Atypical neuroleptics, such as clozapine and risperidone are devoid of these side effects. However the precise mechanisms of the neuronal toxicity induced by haloperidol are poorly understood. It is possible that typical and atypical antipsychotic differently affects neuronal survival and death and that these effects considerably contribute to the differences in the development of TD. The aim of the present study is to investigate the role of TNF-α and NFκB on the toxicity induced by chronic haloperidol administration in an animal model of tardive Dyskinesia. Rats were treated for 21 days with: haloperidol (5 mg/kg), clozapine (5 and 10 mg/kg), risperidone (5 mg/kg) or saline. Orofacial dyskinetic movements and total locomotor activity was evaluated. Striatal levels of dopamine were measure by HPLC/ED whereas striatal levels of TNF-α and NFκB p65 subunit were measured by ELISA technique. Haloperidol increased Orofacial dyskinetic movements and total locomotor activity (on day 22) ( P ≤ 0.05). Clozapine and risperidone also increased the Orofacial dyskinetic movements but that significantly less than haloperidol ( P ≤ 0.05). Differential effect of haloperidol and atypical neuroleptics on striatal dopamine levels and striatal levels of TNF-α and NFκB p65 subunit was found out. Haloperidol significantly decreased the striatal dopamine levels whereas clozapine and risperidone did not. Haloperidol but not clozapine and risperidone significantly increased the levels of TNF-α and NFκB p65 subunit ( P ≤ 0.05). The present study suggests the impossible involvement of striatal TNF-α and NFκB p65 subunit in haloperidol-induced Orofacial Dyskinesia in rats, an animal model for human tardive Dyskinesia.
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protective effect of l type calcium channel blockers against haloperidol induced Orofacial Dyskinesia a behavioural biochemical and neurochemical study
Neurochemical Research, 2008Co-Authors: Mahendra Bishnoi, Kanwaljit Chopra, Shrinivas K. KulkarniAbstract:Haloperidol is a classical neuroleptic drug that is still in use and can lead to abnormal motor activity such as tardive Dyskinesia (TD) following repeated administration. TD has no effective therapy yet. There is involvement of calcium in triggering the oxidative damage and excitotoxicity, both of which play central role in haloperidol-induced Orofacial Dyskinesia and associated alterations. The present study was carried out to investigate the protective effect of calcium channel blockers [verapamil (10 and 20 mg/kg), diltiazem (10 and 20 mg/kg), nifedipine (10 and 20 mg/kg) and nimodipine (10 and 20 mg/kg)] against haloperidol induced Orofacial Dyskinesia and associated behavioural, biochemical and neurochemical alterations in rats. Chronic administration of haloperidol (1 mg/kg i.p., 21 days) resulted in a significant increase in Orofacial dyskinetic movements and significant decrease in % retention, coupled with the marked increase in lipid peroxidation and superoxide anion generation where as significant decrease in non protein thiols and endogenous antioxidant enzyme (SOD and catalase) levels in rat brain striatum homogenates. All these deleterious effects of haloperidol were significantly attenuated by co-administration of different calcium channel blockers. Neurochemically, chronic administration of haloperidol resulted in significant decrease in levels of catecholamines (dopamine, serotonin) and their metabolites (HVA and HIAA) but increased turnover of dopamine and serotonin. Co-administration of most effective doses of verapamil, diltiazem, nifedipine and nimodipine significantly attenuated these neurochemical changes. Results of the present study indicate that haloperidol-induced calcium ion influx is involved in the pathogenesis of tardive Dyskinesia and calcium channel blockers should be tested in clinical trials with nifedipine as the most promising one.
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progesterone attenuates neuroleptic induced Orofacial Dyskinesia via the activity of its metabolite allopregnanolone a positive gabaa modulating neurosteroid
Progress in Neuro-psychopharmacology & Biological Psychiatry, 2008Co-Authors: Mahendra Bishnoi, Kanwaljit Chopra, Shrinivas K. KulkarniAbstract:Abstract GABAergic hypofunction in the basal ganglia is stated as an important mechanism underlying the pathophysiology of tardive Dyskinesia. In the present study we sought to establish the protective effect of progesterone in haloperidol-induced Orofacial Dyskinesia. Besides this we also tried to find out whether the GABA A facilitatory action of progesterone metabolites is responsible for the action of progesterone in attenuating the haloperidol-induced Orofacial Dyskinesia, an animal model of tardive Dyskinesia. Chronic administration of haloperidol (1 mg/kg, i.p. 21 days) induced significant increase in hyperkinetic Orofacial dyskinetic movements and oxidative damage in the brain as compared to control group. Coadministration of progesterone (5–20 mg/kg, i.p. 21 days) dose dependently prevented the hyperkinetic Orofacial movements as well as oxidative damage parameters. The protective activity of progesterone was reversed by pre treatment with finasteride (50 mg/kg i.p.), a 5α-reductase inhibitor that blocks the metabolism of progesterone to allopregnanolone and other metabolites. Further, chronic administration of haloperidol resulted in significant decrease in dopamine levels in rat striatum homogenates and increase in catecholamine metabolite levels. Coadministration of progesterone also reversed the decrease in dopamine levels induced by chronic haloperidol treatment, an effect which was again reversed by pre treatment with finasteride. Our study provides strong evidence that the protective effect of progesterone resides in the GABAergic as well as neuroprotective activity of its metabolite allopregnanolone. These findings lend support to recognized GABA hypofunction theory of tardive Dyskinesia and strongly suggest progesterone as a protective therapy in this debilitating movement disorder.
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Differential striatal levels of TNF-α, NFκB p65 subunit and dopamine with chronic typical and atypical neuroleptic treatment: Role in Orofacial Dyskinesia
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2008Co-Authors: Mahendra Bishnoi, Kanwaljit Chopra, Shrinivas K. KulkarniAbstract:Long term use of typical neuroleptics such as haloperidol may be limited by unwanted motor side effects like tardive Dyskinesia characterized by repetitive involuntary movements, involving the mouth, face and trunk. Atypical neuroleptics, such as clozapine and risperidone are devoid of these side effects. However the precise mechanisms of the neuronal toxicity induced by haloperidol are poorly understood. It is possible that typical and atypical antipsychotic differently affects neuronal survival and death and that these effects considerably contribute to the differences in the development of TD. The aim of the present study is to investigate the role of TNF-α and NFκB on the toxicity induced by chronic haloperidol administration in an animal model of tardive Dyskinesia. Rats were treated for 21 days with: haloperidol (5 mg/kg), clozapine (5 and 10 mg/kg), risperidone (5 mg/kg) or saline. Orofacial dyskinetic movements and total locomotor activity was evaluated. Striatal levels of dopamine were measure by HPLC/ED whereas striatal levels of TNF-α and NFκB p65 subunit were measured by ELISA technique. Haloperidol increased Orofacial dyskinetic movements and total locomotor activity (on day 22) (P ≤ 0.05). Clozapine and risperidone also increased the Orofacial dyskinetic movements but that significantly less than haloperidol (P ≤ 0.05). Differential effect of haloperidol and atypical neuroleptics on striatal dopamine levels and striatal levels of TNF-α and NFκB p65 subunit was found out. Haloperidol significantly decreased the striatal dopamine levels whereas clozapine and risperidone did not. Haloperidol but not clozapine and risperidone significantly increased the levels of TNF-α and NFκB p65 subunit (P ≤ 0.05). The present study suggests the impossible involvement of striatal TNF-α and NFκB p65 subunit in haloperidol-induced Orofacial Dyskinesia in rats, an animal model for human tardive Dyskinesia. © 2008 Elsevier Inc. All rights reserved.
Pattipati S Naidu - One of the best experts on this subject based on the ideXlab platform.
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reversal of reserpine induced Orofacial Dyskinesia and cognitive dysfunction by quercetin
Pharmacology, 2004Co-Authors: Pattipati S Naidu, Amanpreet Singh, Shrinivas K. KulkarniAbstract:Tardive Dyskinesia (TD) is a serious neurological syndrome associated with long-term administration of neuroleptics to humans and experimental animals. The pathophysiology of this disabling and common
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possible antioxidant and neuroprotective mechanisms of fk506 in attenuating haloperidol induced Orofacial Dyskinesia
European Journal of Pharmacology, 2003Co-Authors: Amanpreet Singh, Pattipati S Naidu, Shrinivas K. KulkarniAbstract:Tardive Dyskinesia is a serious motor side effect of chronic neuroleptic therapy. The pathophysiology of this disabling and commonly irreversible movement disorder is still obscure. It may be caused by a loss of dopaminergic cells, due to free radicals as a product of high synaptic dopamine levels. Chronic treatment with neuroleptics leads to the development of abnormal oral movements in rats called vacuous chewing movements. Vacuous chewing movements in rats are widely accepted as an animal model of tardive Dyskinesia. Chronic haloperidol (1 mg/kg for 21 days) treatment significantly induced vacuous chewing movements and tongue protrusions in rats, and FK506 (Tacrolimus) {[3S-[3R*[E(1S*,3S*,4S*)],4S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*,19S*,26aR*]]-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5, 19-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylethenyl]-14, 16-dimethoxy-4,10,12, 18-tetramethyl-8-(2-propenyl)-15, 19-epoxy-3H-pyrido[2,1-c][1,4] oxaazacyclotricosine-1,7,20, 21(4H,23H)-tetrone, monohydrate} dose dependently (0.5 and 1 mg/kg) reduced these haloperidol-induced movements. Biochemical analysis revealed that chronic haloperidol treatment significantly induced lipid peroxidation and decreased the levels of glutathione and of the antioxidant defense enzymes, superoxide dismutase and catalase, in the brains of rats. Co-administration of FK506 dose dependently (0.5 and 1 mg/kg) and significantly reduced the lipid peroxidation and restored the decreased glutathione levels induced by chronic haloperidol treatment. It also significantly reversed the haloperidol-induced decrease in brain superoxide dismutase and catalase levels. The major findings of the present study suggest that oxidative stress-induced neuronal death might play a significant role in neuroleptic-induced Orofacial Dyskinesia. In conclusion, FK506 could be a useful drug for the treatment of neuroleptic-induced Orofacial Dyskinesia.
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quercetin a bioflavonoid attenuates haloperidol induced Orofacial Dyskinesia
Neuropharmacology, 2003Co-Authors: Pattipati S Naidu, Amanpreet Singh, Shrinivas K. KulkarniAbstract:Abstract Chronic treatment with neuroleptics leads to the development of abnormal Orofacial movements described as vacuous chewing movements (VCMs) in rats. Vacuous chewing movements in rodents are widely accepted as one of the animal models of tardive Dyskinesia. Oxidative stress and the products of lipid peroxidation are implicated in the pathophysiology of various neurological disorders including tardive Dyskinesia. In the present study chronic haloperidol (1.0 mg kg −1 for 21 days) treatment induced vacuous chewing movements and tongue protrusions in rats. Co-administration of quercetin, a bioflavonoid, dose dependently (25–100 mg kg −1 ) reduced haloperidol-induced vacuous chewing movements and tongue protrusions. Biochemical analysis revealed that chronic haloperidol treatment induces lipid peroxidation and decreases the glutathione (GSH) levels in the forebrains of rats. The antioxidant defense enzymes, superoxide dismutase (SOD) and catalase were also decreased due to chronic haloperidol treatment. Co-administration of quercetin (25–100 mg kg −1 ) significantly reduced the lipid peroxidation and restored the decreased glutathione levels in these animals. Further quercetin (50–100 mg kg −1 ) also reversed the haloperidol-induced decrease in forebrain SOD and catalase levels in rats. The major findings of the present study suggested that oxidative stress plays a significant role in neuroleptic-induced Orofacial Dyskinesia and quercetin co-administration reverses these behavioral and biochemical changes. Quercetin, a naturally occurring bioflavonoid could prove to be a useful agent in neuroleptic-induced Orofacial Dyskinesia.
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reversal of haloperidol induced Orofacial Dyskinesia by quercetin a bioflavonoid
Psychopharmacology, 2003Co-Authors: Pattipati S Naidu, Amanpreet Singh, Shrinivas K. KulkarniAbstract:Rationale Tardive Dyskinesia is a serious neurological syndrome associate with long-term administration of neuroleptics to humans and experimental animals. It may be caused by loss of dopaminergic cells, due to free radicals as a product of high synaptic dopamine levels. Quercetin is a bioflavonoid with strong antioxidant properties.
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possible mechanism of action in melatonin attenuation of haloperidol induced Orofacial Dyskinesia
Pharmacology Biochemistry and Behavior, 2003Co-Authors: Pattipati S Naidu, Amanpreet Singh, Pushpinder Kaur, Rajat Sandhir, Shrinivas K. KulkarniAbstract:Abstract Tardive Dyskinesia (TD) is a late complication of prolonged neuroleptic treatment characterized by involuntary movements of the oral region. In spite of high incidence and much research, the pathophysiology of this devastating movement disorder remains elusive. Chronic treatment with neuroleptics leads to the development of abnormal oral movements in rats, referred to as vacuous chewing movements (VCMs). VCMs in rats are widely accepted as an animal model of TD. Rats chronically treated with haloperidol (1.5 mg/kg ip) significantly developed VCMs and tongue protrusions. Melatonin dose-dependently (1, 2, and 5 mg/kg) reversed the haloperidol-induced VCM and tongue protrusions frequencies. Biochemical analysis reveals that chronic haloperidol treatment significantly induced lipid peroxidation and decreased the forebrain glutathione (GSH) levels in the rats. Chronic haloperidol-treated rats also showed decreased levels of antioxidant defense enzymes, superoxide dismutase (SOD), and catalase. Coadministration of melatonin (1, 2, and 5 mg/kg) along with haloperidol significantly reduced the lipid peroxidation and restored the decreased GSH levels by chronic haloperidol treatment, and significantly reversed the haloperidol-induced decrease in forebrain SOD and catalase levels in rats. However, a lower dose of melatonin (1 mg/kg) failed to reverse chronic haloperidol-induced decreases in forebrain GSH, SOD, and catalase levels. In conclusion, melatonin could be screened as a potential drug candidate for the prevention or treatment of neuroleptic-induced Orofacial Dyskinesia.
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role of the retrorubral nucleus in striatally elicited Orofacial Dyskinesia in cats effects of muscimol and bicuculline
Psychopharmacology, 1998Co-Authors: Monique P M Arts, Frank F J Bemelmans, A R CoolsAbstract:Orofacial Dyskinesia (OFD) is a disorder characterized by involuntary movements of the oral and facial muscles. OFD attacks can be elicited acutely in cats by local injections of dopaminergic agents into the anterodorsal part (r-CRM) of the caudate nucleus. Because the dopaminergic A8 cell group, being embedded in the retrorubral nucleus (RRN), gives rise to fibres which terminate in the r-CRM, two questions arose: (1) whether the A8 cell group forms part of the circuitry that directs and/or modulates OFD, and (2) whether GABA-ergic compounds in the RRN play a role in OFD, and if so, whether a pharmacological GABA-ergic intervention of the activity in the RRN modulates or mediates OFD. For this purpose, the activity of the RRN was manipulated with local injections of the GABAA agonist muscimol and antagonist bicuculline. These local injections into the RRN were subsequently combined with manipulations of dopamine transmission in the r-CRM with local injections of the selective DAi receptor agonist (3,4-dihydroxyphenylimino)-2-imidazoline. The present study shows that local injections of GABA-ergic compounds into the RRN do not elicit OFD attacks in cats, but can modulate oral behaviour elicited from the r-CRM. The latter effect is dose dependent and GABA-ergic specific.
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activation of n methyl d aspartate receptors in the feline retrorubral nucleus elicits Orofacial Dyskinesia
European Journal of Pharmacology, 1998Co-Authors: Monique P M Arts, Frank F J Bemelmans, A R CoolsAbstract:Abstract Stimulation of dopamine receptors within a circumscribed subregion of the feline caudate nucleus, that is the anterodorsal part of this nucleus, with dopamine or the dopamine receptor agonist (3,4-dihydroxyphenylimino)-2-imidazoline (DPI) elicits Orofacial Dyskinesia. Orofacial Dyskinesia is a syndrome of tic-like contractions of the facial muscles which ends with a tongue protrusion. Afferent fibres of the anterodorsal part of the caudate nucleus are known to emanate from the retrorubral nucleus, including the dopaminergic A8 cell group. The present study was undertaken to investigate whether excitation of A8 cells can mediate and/or modulate Orofacial Dyskinesia. For this purpose, the activity of the retrorubral nucleus was manipulated with local injections of N-methyl- d -aspartate (NMDA). These local injections into the retrorubral nucleus were subsequently combined with manipulations of the dopamine transmission in the anterodorsal part of the caudate nucleus with local injections of DPI. The present study shows that injections of NMDA into the retrorubral nucleus elicits Orofacial Dyskinesia. This effect is dose-dependent, NMDA-specific, and inhibited by intra-caudate injections of DPI.
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the substantia innominata complex and the peripeduncular nucleus in Orofacial Dyskinesia a pharmacological and anatomical study in cats
Neuroscience, 1993Co-Authors: Will P J M Spooren, W H A M Mulders, Jan G Veening, A R CoolsAbstract:Abstract It has been shown that Orofacial Dyskinesia, i.e. a syndrome of abnormal involuntary movements of the facial muscles, can be elicited from the sub-commissural part of the globus pallidus and the adjoining dorsal parts of the extended amygdala in cats. Until now it is unknown whether the peripeduncular nucleus, which receives input from these structures according to anterograde tracing studies, plays a role in the funneling of Orofacial Dyskinesia to lower output stations. In the present study the connection of the subcommissural part of the globus pallidus and dorsal parts of the extended amygdala with the peripeduncular nucleus was investigated anatomically, using cholera toxin subunit B as a retrograde tracer, and functionally, using intracerebral injections of GABAergic compounds. The anatomical data show that the sub-commissural part of the globus pallidus and dorsal parts of the extended amygdala were marked by cholera toxin sub-unit B-immunoreactive cells following injections of this retrograde tracer into the peripeduncular nucleus. Thus, it could be confirmed that the peripeduncular nucleus receives input from the sub-commissural part of the globus pallidus and dorsal parts of the extended amygdala. Still, the Orofacial Dyskinesia elicited by local injections of the GABA antagonist picrotoxin (500 ng/0.5 ml) into the sub-commissural part of the globus pallidus and dorsal extended amygdala was only in part attenuated by local injections of the GABA agonist muscimol (100 ng/l ml) into the peripeduncular nucleus. Only the number of tongue protrusions was significantly attenuated, but not that of the ear and cheek movements. Furthermore, tongue protrusions, but no additional oral movements, were elicited by picrotoxin injections (375–500 ng) into the peripeduncular nucleus. However, these effects were dose dependent and could only be elicited from the dorsal parts of the peripeduncular nucleus. Injections into the ventral parts of the extended amygdala were ineffective in every respect in the present investigation. The data show that the peripeduncular nucleus does not funnel the Orofacial Dyskinesia from the sub-commissural part of the globus pallidus and dorsal parts of the extended amygdala to lower brain structures despite the fact that it is innervated by the former regions. The finding that the peripeduncular nucleus itself is only involved in the modulation of the display of tongue protrusions may explain why manipulations with the peripeduncular nucleus only affected this aspect of the Orofacial Dyskinesia elicited from the sub-commissural part of the globus pallidus and dorsal parts of the extended amygdala.
