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3 Nitropropionic Acid

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Anil Kumar – 1st expert on this subject based on the ideXlab platform

  • possible gabaergic mechanism in the neuroprotective effect of gabapentin and lamotrigine against 3 Nitropropionic Acid induced neurotoxicity
    European Journal of Pharmacology, 2012
    Co-Authors: Puneet Kumar, Harikesh Kalonia, Anil Kumar


    Abstract Huntington’s disease is a progressive neurodegenerative disorder that gradually reduces memory, cognitive skills and normal movements of affected individuals. Systemic administration of 3Nitropropionic Acid induces selective striatal lesions in rodents and non-human primates. Therefore, the present study has been designed to elucidate the comparative mechanistic profile of gabapentin, lamotrigine and their interactions with GABAergic modulators against 3Nitropropionic Acid induced neurotoxicity. Systemic 3Nitropropionic Acid (10 mg/kg) administration for 14 days significantly reduced body weight, locomotor activity, grip strength, oxidative defense (LPO, nitrite, SOD and catalase) and impaired mitochondrial complex enzyme (I, II, IV and MTT assay) activities in the striatum. 3Nitropropionic Acid treatment also increased TNF-α level in the striatum. Gabapentin (50 and 100 mg/kg) and lamotrigine (10, 20 and 40 mg/kg) treatments significantly restored behavioural, oxidative defense and mitochondrial complex enzyme activities and proinflammatory markers (TNF-α) as compared to 3Nitropropionic Acid treated group. Systemic picrotoxin (1 mg/kg) pretreatment with sub effective dose of gabapentin (50 mg/kg) or lamotrigine (20 mg/kg) significantly attenuated their protective effect. Further, GABA (50 mg/kg) and/or muscimol (0.05 mg/kg) pretreatment with sub effective dose gabapentin (50 mg/kg) and lamotrigine (20 mg/kg) significantly potentiated their protective effects which were significant as compared to their effect alone. The results of the present study suggest that a GABAergic mechanism is involved in the protective effect of gabapentin and lamotrigine against 3Nitropropionic Acid induced neurotoxicity.

  • protective effect of hesperidin and naringin against 3 Nitropropionic Acid induced huntington s like symptoms in rats possible role of nitric oxide
    Behavioural Brain Research, 2010
    Co-Authors: Puneet Kumar, Anil Kumar


    Abstract 3Nitropropionic Acid (3-NP) is a well known experimental model to study Huntington’s disease (HD) and associated neuropsychiatric problems. Present study has been designed to explore the protective effects of hesperidin, naringin, and their nitric oxide mechanism (if any) against 3Nitropropionic Acid induced neurotoxicity in rats. Systemic 3Nitropropionic Acid (10 mg/kg) treatment for 14 days in rats significantly induced HD like symptoms in rats as indicated by reduced locomotor activity, body weight, grip strength, oxidative defense and mitochondrial complex enzymes (complex-I, -II, and -IV) activities in striatum. Naringin and hesperidin pretreatment significantly attenuated behavioral alterations, oxidative stress and mitochondrial enzymes complex dysfunction in 3-NP treated group. l -Arginine (50 mg/kg) pretreatment with lower dose of hesperidin (50 mg/kg) and naringin (50 mg/kg) significantly attenuated the protective effect of hesperidin and naringin respectively. Whereas l -NAME (10 mg/kg), a non-selective NOS inhibitor pretreatment with hesperidin (50 mg/kg) and naringin (50 mg/kg) significantly potentiated their protective effect which was significant as compared to their effect per se. Study highlights the therapeutic potential of hesperidin and naringin against Huntington’s like conditions and further indicates that these drugs might act through nitric oxide mechanism.

  • lycopene modulates nitric oxide pathways against 3 Nitropropionic Acid induced neurotoxicity
    Life Sciences, 2009
    Co-Authors: Puneet Kumar, Harikesh Kalonia, Anil Kumar


    Abstract Aim The present study has been designed to investigate the involvement of the nitric oxide mechanism in the protective effect of lycopene against 3Nitropropionic Acid-induced Huntington’s disease-like symptoms in rats. Main methods The present experimental protocol design includes systemic 3Nitropropionic Acid (10 mg/kg i.p) treatment for 14 days. Lycopene (2.5, 5 and 10 mg/kg) was given orally, once a day, 1 h before 3Nitropropionic Acid treatment for 14 days. Body weight and behavioral parameters (locomotor and rotarod activity) were assessed on 1st, 5th, 10th and 15th day post-3Nitropropionic Acid administration. Malondialdehyde, nitrite concentration, superoxide dismutase and catalase levels were measured on the 15th day in the striatum, cortex and hippocampus. Mitochondrial enzyme complexes were also assessed in these brain areas. Systemic 3Nitropropionic Acid treatment significantly reduced body weight, locomotor activity and oxidative defense. The mitochondrial enzyme activities were also significantly impaired in the examined brain regions in 3Nitropropionic Acid-treated animals. Key findings Lycopene (2.5, 5 and 10 mg/kg) treatment significantly attenuated the impairment in behavioral, biochemical and mitochondrial enzyme activities as compared to the 3Nitropropionic Acid-treated group. l -arginine (50 mg/kg) pretreatment with a sub-effective dose of lycopene (5 mg/kg) significantly attenuated the protective effect of lycopene. Furthermore, L-NAME (10 mg/kg) pretreatment with a sub-effective dose of lycopene (5 mg/kg) for 14 days significantly potentiated the protective effect. Significance The results of the present study suggest that the nitric oxide modulation is involved in the protective effect of lycopene against 3-NP-induced behavioral, biochemical and cellular alterations in rats.

M F Beal – 2nd expert on this subject based on the ideXlab platform

  • 3 Nitropropionic Acid toxicity in the striatum
    Journal of Neurochemistry, 2002
    Co-Authors: Ullrich Wullner, Anne B Young, J B Penney, M F Beal


    : We examined the effects of chronic systemic administration of the mitochondrial toxin 3Nitropropionic Acid (3-NP) in doses ranging from 12 to 16 mg/kg/day for 30 days on striatal cytoarchitecture in rats. Administration of 3-NP at a dose of 16 mg/kg/day resulted in large lesions with a central necrotic core that was depleted of both neurons and glia. Glial fibrillary Acidic protein (GFAP) gene expression was decreased in the lesion core, whereas the tissue surrounding this area showed a massive increase in signal intensity. Enkephalin and substance P mRNA expression in the striatum showed dose-dependent decreases following administration of 3-NP. A substantial decrease occurred even in animals treated with 3-NP at a dose of 12 mg/kg/day, in which there was little discernible neuronal loss and no increase in GFAP gene expression. In contrast to the decrease in enkephalin and substance P mRNA expression, somatostatin mRNA-expressing neurons were largely preserved. There was no preferential loss of [3H]naloxone patches in the rat striatum following chronic administration of 3-NP. In animals treated with 12–15 mg/kg/day neither the area nor binding density of the patches was changed. To study the effect of 3-NP on N-methyl-d-aspartate (NMDA)-gated Ca2+ channels we used in vivo administration of [3H]MK-801. Three hours after a single injection of 3-NP at a dose of 30 mg/kg there was a three- to fivefold increase in [3H]MK-801 binding in cortex and striatum as compared with saline-treated animals, consistent with an activation of NMDA receptors.

  • oral dyskinesias and striatal lesions in rats after long term co treatment with haloperidol and 3 Nitropropionic Acid
    Neuroscience, 1998
    Co-Authors: Ole A Andreassen, Robert J Ferrante, M F Beal, Hugo A Jorgensen


    Abstract The pathophysiologic basis of tardive dyskinesia remains unclear. It has been proposed that tardive dyskinesia may be a result of excitotoxic neurodegeneration in the striatum caused by a neuroleptic-induced increase in striatal glutamate release and impaired energy metabolism. To investigate this hypothesis, haloperidol decanoate (38 mg/kg/four weeks intramuscularly) and the succinate dehydrogenase inhibitor 3Nitropropionic Acid (8 mg/kg/day via subcutaneous osmotic mini-pumps), were administered alone or together for 16 weeks to four-months-old rats. Control rats received sesame oil intramuscularly and had empty plastic tubes subcutaneously. Vacuous chewing movements, a putative analogue to human tardive dyskinesia, were recorded during and after drug treatment. Haloperidol alone, 3Nitropropionic Acid alone, and 3Nitropropionic Acid+haloperidol treatments induced an increase in vacuous chewing movements. However, vacuous chewing movements were more pronounced and appeared earlier in rats treated with 3Nitropropionic Acid+haloperidol. After drug withdrawal, increases in vacuous chewing movements persisted for 16 weeks in the haloperidol alone and 3Nitropropionic Acid+haloperidol group and for four weeks in the 3Nitropropionic Acid alone group. Brains from each group were analysed for histopathological alterations. Bilateral striatal lesions were present only in rats with high levels of vacuous chewing movements in the 3Nitropropionic Acid+haloperidol-treated rats. Nerve cell depletion and astrogliosis were prominent histopathologic features. There was selective neuronal sparing of both large- and medium-sized aspiny striatal neurons. These results suggest that mild mitochondrial impairment in combination with neuroleptics results in striatal excitotoxic neurodegeneration which may underlie the development of persistent vacuous chewing movements in rats and possibly irreversible tardive dyskinesia in humans.

  • age dependent vulnerability of the striatum to the mitochondrial toxin 3 Nitropropionic Acid
    Journal of Neurochemistry, 1993
    Co-Authors: Emmanuel Brouillet, Bruce G Jenkins, Bradley T Hyman, R J Ferrante, Neil W Kowall, Rachana Srivastava, Bruce R Rosen, M F Beal


    : The mechanisms of delayed onset and cell death in Huntington’s disease (HD) are unknown. One possibility is that a genetic defect in energy metabolism may result in slow excitotoxic neuronal death. Therefore, we examined the effects of age on striatal lesions produced by local administration of the mitochondrial toxin 3Nitropropionic Acid in rats. In vivo chemical shift magnetic resonance imaging showed marked increases in striatal lactate concentrations that significantly correlated with increasing age. Histologic and neurochemical studies showed a striking age dependence of the lesions, with 4- and 12-month-old animals being much more susceptible than 1-month-old animals. Continuous systemic administration of low doses of 3Nitropropionic Acid for 1 month resulted in striatal lesions showing growth-related changes in dendrites of striatal spiny neurons using the Golgi technique. These results show that a known mitochondrial toxin can produce selective axon-sparing striatal lesions showing both the age dependence and striatal spiny neuron dendritic changes that characterize HD.

Emmanuel Brouillet – 3rd expert on this subject based on the ideXlab platform

  • 3Nitropropionic Acid
    Encyclopedia of Movement Disorders, 2020
    Co-Authors: Emmanuel Brouillet


    The neurotoxin 3Nitropropionic Acid (3NP) is a mitochondrial toxin produced by plants and fungi. Since the 1970s, neurologists have reported nearly 1000 cases of 3NP poisoning that occurred in North China. Ingestion of sugar cane contaminated by the fungus Arthrinium that produces 3NP in high quantities rapidly leads to gastrointestinal signs and acute encephalopathy, followed in many cases by delayed dyskinesia with the degeneration of the putamen and the globus pallidus.

  • promethazine protects against 3 Nitropropionic Acid induced neurotoxicity
    Neurochemistry International, 2010
    Co-Authors: Carine Cleren, Emmanuel Brouillet, Noel Y Calingasan, Anatoly A Starkov, Carine Jacquard, Junya Chen, Flint M Beal


    Promethazine (PMZ), an FDA-approved antihistaminergic drug, was identified as a potentially neuroprotective compound in a NINDS screening program. It was shown to protect against ischemia in mice, to delay disease onset in a mouse model of amyotrophic lateral sclerosis and to inhibit Ca2+-induced mitochondrial permeability transition in rat liver mitochondria. We investigated whether PMZ could protect against the neurotoxic effects induced by 3Nitropropionic Acid (3-NP), an inhibitor of the succinate dehydrogenase, used to model Huntington’s disease (HD) in rats. Lewis rats receiving chronic subcutaneous infusion of 3-NP were treated with PMZ. The findings indicate that chronic PMZ treatment significantly reduced 3-NP-induced striatal lesion volume, loss of GABAergic neurons and number of apoptotic cells in the striatum. PMZ showed a strong neuroprotective effect against 3-NP toxicity in vivo.

  • major strain differences in response to chronic systemic administration of the mitochondrial toxin 3 Nitropropionic Acid in rats implications for neuroprotection studies
    Neuroscience, 2000
    Co-Authors: S Ouary, P Hantraye, Nicolas Bizat, S Altairac, H Menetrat, V Mittoux, F Conde, Emmanuel Brouillet


    Abstract Chronic systemic treatment with 3Nitropropionic Acid in rats produces persistent dystonia and bradykinesia, and striatal lesions reminiscent of Huntington’s disease. However, the interpretation of results obtained with this model are complicated by a heterogeneous distribution of the response to a given toxic dose of 3Nitropropionic Acid: approximately half of the animals develop selective striatal lesions, which in certain cases are associated with extrastriatal lesions, and the other half are apparently spared. Thus, the chronic 3Nitropropionic Acid lesion model can be difficult for neuroprotection studies in which a consistent response to neurotoxic treatment is prerequisite. We hypothesized that some of the variability in the model was related to the use of Sprague–Dawley rats, since inter-individual variability in response to various stressful conditions has been described previously in this rat strain. We therefore compared 3Nitropropionic Acid toxicity in rat strains known to be highly (Fisher 344) or poorly (Lewis) responsive to stress and compared the distribution of responses to that of Sprague–Dawley rats. In a protocol of intraperitoneal injection, toxicity of 3Nitropropionic Acid was highest in Fisher rats, intermediate in Sprague–Dawley rats and lowest in Lewis rats. In addition, survival curves showed a more heterogeneous response to 3Nitropropionic Acid toxicity in Sprague–Dawley rats than that observed in Lewis and Fisher rats. These differences between Sprague–Dawley and Lewis rats were confirmed in a protocol of subcutaneous 3Nitropropionic Acid intoxication using osmotic minipumps, where doses up to 36–45 mg/kg per day for five days were necessary to induce striatal lesions in Lewis rats as compared to 12–14 mg/kg per day for five days in Sprague–Dawley rats. The selectivity of the striatum to lesions, and homogeneous progression of symptoms and neurodegeneration, were more consistently observed in Lewis as compared to Sprague–Dawley rats. These results suggest that vulnerability to 3Nitropropionic Acid may depend on genetic factors, which could also influence the physiological response to stress. The present findings also establish an improved model of progressive striatal degeneration in the rat adapted for the testing of new neuroprotective strategies.