3 Nitropropionic Acid

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Anil Kumar - One of the best experts 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:

    Abstract Huntington's disease is a progressive neurodegenerative disorder that gradually reduces memory, cognitive skills and normal movements of affected individuals. Systemic administration of 3-Nitropropionic 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 3-Nitropropionic Acid induced neurotoxicity. Systemic 3-Nitropropionic 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. 3-Nitropropionic 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 3-Nitropropionic 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 3-Nitropropionic 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:

    Abstract 3-Nitropropionic 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 3-Nitropropionic Acid induced neurotoxicity in rats. Systemic 3-Nitropropionic 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:

    Abstract Aim The present study has been designed to investigate the involvement of the nitric oxide mechanism in the protective effect of lycopene against 3-Nitropropionic Acid-induced Huntington's disease-like symptoms in rats. Main methods The present experimental protocol design includes systemic 3-Nitropropionic 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 3-Nitropropionic Acid treatment for 14 days. Body weight and behavioral parameters (locomotor and rotarod activity) were assessed on 1st, 5th, 10th and 15th day post-3-Nitropropionic 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 3-Nitropropionic 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 3-Nitropropionic 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 3-Nitropropionic 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.

  • Lycopene modulates nitric oxide pathways against 3-Nitropropionic Acid-induced neurotoxicity.
    Life sciences, 2009
    Co-Authors: Puneet Kumar, Harikesh Kalonia, Anil Kumar
    Abstract:

    The present study has been designed to investigate the involvement of the nitric oxide mechanism in the protective effect of lycopene against 3-Nitropropionic Acid-induced Huntington's disease-like symptoms in rats. The present experimental protocol design includes systemic 3-Nitropropionic Acid (10mg/kg i.p) treatment for 14 days. Lycopene (2.5, 5 and 10mg/kg) was given orally, once a day, 1h before 3-Nitropropionic Acid treatment for 14 days. Body weight and behavioral parameters (locomotor and rotarod activity) were assessed on 1st, 5th, 10th and 15th day post-3-Nitropropionic 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 3-Nitropropionic 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 3-Nitropropionic Acid-treated animals. Lycopene (2.5, 5 and 10mg/kg) treatment significantly attenuated the impairment in behavioral, biochemical and mitochondrial enzyme activities as compared to the 3-Nitropropionic Acid-treated group. l-arginine (50mg/kg) pretreatment with a sub-effective dose of lycopene (5mg/kg) significantly attenuated the protective effect of lycopene. Furthermore, L-NAME (10mg/kg) pretreatment with a sub-effective dose of lycopene (5mg/kg) for 14 days significantly potentiated the protective effect. 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.

  • protective effect of rivastigmine against 3 Nitropropionic Acid induced huntington s disease like symptoms possible behavioural biochemical and cellular alterations
    European Journal of Pharmacology, 2009
    Co-Authors: Puneet Kumar, Anil Kumar
    Abstract:

    3-Nitropropionic Acid inhibits succinate dehydrogenase, complex II enzyme in the mitochondrial respiratory chain that leads to cellular energy deficit and oxidative stress. Huntington's disease is characterized by abnormal body movements (chorea) and cognitive dysfunctions. Rivastigmine, a well known cholinesterase inhibitor used in the management of Alzheimer's disease in a clinical practice. Recent clinical studies suggest the potential role of rivastigmine in the management of Huntington's disease. The present study has been designed to explore the possible role of rivastigmine against 3-Nitropropionic Acid induced behavioral, biochemical and cellular alterations. Intraperitoneal administration of 3-Nitropropionic Acid (10 mg/kg for 14 days) caused significant loss in body weight, motor in coordination (locomotor activity and rota rod performance) and poor memory retention in Morris water maze and elevated plus maze performance tasks as compared to vehicle treated animals. Biochemical analysis revealed significant increase in lipid peroxidation, nitrite concentration and depleted superoxide dismutase, catalase levels and alterations in mitochondrial complex enzymes (I, II, IV and MTT assay) in the different regions (striatum, cortex and hippocampus) of rat brain. Rivastigmine (0.5, 1 and 2 mg/kg, orally) once daily treatment for a period of 14 days significantly improved motor performance and cognitive task in both Morris water maze and elevated plus maze tests. Further, rivastigmine treatment significantly attenuated oxidative damage and improved mitochondrial complexes enzyme activities in different regions (striatum, cortex and hippocampus) of rat brain. The results show that rivastigmine could be used as an effective therapeutic agent in the management of Huntington's disease and related conditions.

M F Beal - One of the best experts 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
    Abstract:

    : We examined the effects of chronic systemic administration of the mitochondrial toxin 3-Nitropropionic 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:

    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 3-Nitropropionic 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, 3-Nitropropionic Acid alone, and 3-Nitropropionic Acid+haloperidol treatments induced an increase in vacuous chewing movements. However, vacuous chewing movements were more pronounced and appeared earlier in rats treated with 3-Nitropropionic Acid+haloperidol. After drug withdrawal, increases in vacuous chewing movements persisted for 16 weeks in the haloperidol alone and 3-Nitropropionic Acid+haloperidol group and for four weeks in the 3-Nitropropionic 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 3-Nitropropionic 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
    Abstract:

    : 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 3-Nitropropionic 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 3-Nitropropionic 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 - One of the best experts on this subject based on the ideXlab platform.

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

    The neurotoxin 3-Nitropropionic 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
    Abstract:

    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 3-Nitropropionic 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:

    Abstract Chronic systemic treatment with 3-Nitropropionic 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 3-Nitropropionic 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 3-Nitropropionic 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 3-Nitropropionic 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 3-Nitropropionic 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 3-Nitropropionic 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 3-Nitropropionic 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 3-Nitropropionic 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.

  • Riluzole protects from motor deficits and striatal degeneration produced by systemic 3-Nitropropionic Acid intoxication in rats
    Neuroscience, 1997
    Co-Authors: Marie-caroline Guyot, Stéphane Palfi, Jean-marie Stutzmann, Mariannick Mazière, Philippe Hantraye, Emmanuel Brouillet
    Abstract:

    Abstract The putative neuroprotective effect of riluzole was investigated in a rat model of progressive striatal neurodegeneration induced by prolonged treatment (three weeks, intraperitoneal) with 3-Nitropropionic Acid, an irreversible inhibitor of succinate dehydrogenase. Quantitative analysis of motor behaviour indicated a significant protective effect (60%) of riluzole (8 mg/kg/day) on 3-Nitropropionic Acid-induced motor deficits as assessed using two independent motor tests. Furthermore, quantitative analysis of 3-Nitropropionic Acid-induced lesions indicated a significant 84% decrease in the volume of striatal damage produced by 3-Nitropropionic Acid, the neuroprotective effect apparently being more pronounced in the posterior striatum and pallidum. In addition, it was checked that this neuroprotective effect of riluzole against systemic 3-Nitropropionic Acid did not result from a decreased bioavailability of the neurotoxin or a direct action of riluzole on 3-Nitropropionic Acid-induced inhibition of succinate dehydrogenase. We found that riluzole significantly decreased by 48% the size of striatal lesions produced by stereotaxic intrastriatal injection of malonate, a reversible succinate dehydrogenase inhibitor. Furthermore, the inhibition of cortical and striatal succinate dehydrogenase activity induced by systemic 3-Nitropropionic Acid was left unchanged by riluzole administration. The present results, consistent with a beneficial effect of riluzole in amyotrophic lateral sclerosis, suggest that this compound may be useful in the treatment of chronic neurodegenerative diseases.

  • quantifiable bradykinesia gait abnormalities and huntington s disease like striatal lesions in rats chronically treated with 3 Nitropropionic Acid
    Neuroscience, 1997
    Co-Authors: M C Guyot, P Hantraye, R Dolan, S Palfi, M Maziere, Emmanuel Brouillet
    Abstract:

    Abstract Impairment in energy metabolism is thought to be involved in the aetiology of Huntington's disease. In line with this hypothesis, chronic systemic administration of the mitochondrial toxin 3-Nitropropionic Acid to rats and monkeys produces selective striatal lesions similar to Huntington's disease. The present study examined whether rats treated with varying regimen of 3-Nitropropionic Acid could present motor abnormalities reminiscent of Huntington's disease symptomatology, correlated with Huntington's disease specific striatal symptomatology. Subacute 3-Nitropropionic Acid treatment (15 mg/kg per day intraperitoneally for 10 days) produced dramatic motor symptoms associated with extensive neuronal loss and gliosis in the lateral striatum as well as severe hippocampal degeneration in 50% of the cases. In contrast, chronic 3-Nitropropionic Acid treatment (10 mg/kg per day subcutaneously for one month) led to more subtle excitotoxic-like lesions, selective for the dorsolateral striatum and more closely resembling Huntington's disease striatal pathology. Animals with these Huntington's disease-like lesions showed spontaneous motor symptoms including mild dystonia, bradykinesia and gait abnormalities, which were barely detectable on visual inspection but could be readily identified and quantified by computerized video analysis. In these chronic animals, the degree of striatal neuronal loss was significantly correlated with the severity of spontaneous motor abnormalities, as is the case in Huntington's disease. The present study demonstrates that chronic low-dose 3-Nitropropionic Acid treatment in rats results in a valuable model of both the histological features and motor deficits which occur in Huntington's disease. Despite the interanimal variability in terms of response to 3-Nitropropionic Acid treatment, this rat model may be particularly useful for evaluating the functional benefits of new therapeutic strategies for Huntington's disease, particularly those aiming to reduce the severity of motor symptoms.

Puneet Kumar - One of the best experts on this subject based on the ideXlab platform.

  • Beneficial effect of rice bran extract against 3-Nitropropionic Acid induced experimental Huntington's disease in rats
    Toxicology reports, 2015
    Co-Authors: Navneet Kaur, Rahul Deshmukh, Sumit Jamwal, Vinod Gauttam, Puneet Kumar
    Abstract:

    Abstract Huntington's disease (HD) is a neurodegenerative disorder, characterized by progressive motor and non-motor dysfunction due to degeneration of medium spiny neurons in striatum. 3-Nitropropionic Acid is commonly used to induce the animal model of HD. Rice bran is supposed to have beneficial effects on mitochondrial function. The present study has been designed to explore the effect of rice bran extract against 3-Nitropropionic Acid induced neurotoxicity in rats. 3-Nitropropionic Acid (10 mg/kg, i.p) was administered systemically for 21 days. Hexane and ethanol extract of rice bran were prepared using Soxhlation. Hexane (250 mg/kg) and ethanol extract (250 mg/kg) were administered per os for 21 days in 3-NP treated groups. Behavioral parameters (body weight, grip strength, motor coordination, locomotion) were conducted on 7th, 14th and 21st day. Animals were sacrificed on 22nd day for biochemical, mitochondrial dysfunction (Complex II), neuroinflammatory and neurochemical estimation in striatum. This study demonstrates significant alteration in behavioral parameters, oxidative burden (increased lipid peroxidation, nitrite concentration and decreased glutathione), mitochondrial function (decreased Complex II enzyme activity), pro-inflammatory mediators and neurochemical levels in 3-Nitropropionic Acid treated animals. Administration of hexane and ethanol extract prevented the behavioral, biochemical, neuroinflammatory (increased TNF-α, IL-1β and IL-6) and neurochemical alterations (decreased dopamine, norepinephrine, serotonin, 5-hydroxy indole acetic Acid, GABA and increased 3,4-dihydro phenyl acetaldehyde, homovanillic Acid and glutamate levels) induced by 3-Nitropropionic Acid. The outcomes of present study suggest that rice bran extract is beneficial and might emerge as an adjuvant or prophylactic therapy for treatment of HD like symptoms.

  • Role of neurosteroids in experimental 3-Nitropropionic Acid induced neurotoxicity in rats
    European Journal of Pharmacology, 2013
    Co-Authors: P. A. Kumar, Puneet Kumar, A. Khan, Rahul Deshmukh, Pyare Lal Sharma
    Abstract:

    Abstract Huntington's disease is an autosomal dominant, progressive, and fatal neurodegenerative disease characterized by motor and non-motor symptoms. Systemic administration of 3-Nitropropionic Acid, a complex II inhibitor of the electron transport chain induces selective striatal lesions in rodents. Neurosteroids are synthesized in central nervous system, able to modulate GABA A receptor function and has been reported to have neuroprotective action. The present study has been designed to investigate the role of neurosteroids such as progesterone and pregnenolone which are positive and negative modulators of GABA respectively against 3-Nitropropionic Acid induced experimental Huntington's disease. Systemic administration of 3-Nitropropionic Acid (10 mg/kg i.p.) for 14 days significantly reduced body weight, locomotor activity, motor coordination, balance beam walk performance, antioxidant defense enzymes (reduced glutathione and catalase) and significantly increase oxidative stress markers (lipid peroxidation and nitrite level) in striatum and cortex. 3-Nitropropionic Acid treatment also increases pro-inflammatory cytokines (TNF-α and IL-1β) level in striatum. Progesterone (10, 20 mg/kg/day i.p.) treatments for 14 days significantly reversed the behavioral, antioxidant defense enzymes, oxidative stress marker and pro-inflammatory cytokines as compared to the 3-Nitropropionic Acid treated group. Pregnenolone (1 and 2 mg/kg i.p.), a negative modulator of GABA A pretreatment significantly reversed the protective effect of progesterone on behavioral and biochemical parameters. The results of the present study suggest that the positive GABAergic modulation may be beneficial for the treatment of motor disorder.

  • 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:

    Abstract Huntington's disease is a progressive neurodegenerative disorder that gradually reduces memory, cognitive skills and normal movements of affected individuals. Systemic administration of 3-Nitropropionic 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 3-Nitropropionic Acid induced neurotoxicity. Systemic 3-Nitropropionic 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. 3-Nitropropionic 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 3-Nitropropionic 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 3-Nitropropionic 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:

    Abstract 3-Nitropropionic 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 3-Nitropropionic Acid induced neurotoxicity in rats. Systemic 3-Nitropropionic 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:

    Abstract Aim The present study has been designed to investigate the involvement of the nitric oxide mechanism in the protective effect of lycopene against 3-Nitropropionic Acid-induced Huntington's disease-like symptoms in rats. Main methods The present experimental protocol design includes systemic 3-Nitropropionic 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 3-Nitropropionic Acid treatment for 14 days. Body weight and behavioral parameters (locomotor and rotarod activity) were assessed on 1st, 5th, 10th and 15th day post-3-Nitropropionic 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 3-Nitropropionic 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 3-Nitropropionic 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 3-Nitropropionic 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.

Isaac Túnez - One of the best experts on this subject based on the ideXlab platform.

  • Model of Huntington's disease induced with 3-Nitropropionic Acid
    Revista De Neurologia, 2009
    Co-Authors: Isaac Túnez, Santamaría A
    Abstract:

    INTRODUCTION: Huntington's disease is an autosomal dominant hereditary disorder. This neurodegenerative illness is characterized by mutation of the huntingtin protein gene, causing the formation of intracellular protein aggregates. DEVELOPMENT: Intensive research efforts have been made to investigate the molecular mechanism involved. For this reason, the development of animal and cellular models of Huntington's disease has offered alternative approaches to study of this disease. The alteration of succinate dehydrogenase activity has been linked to Huntington's disease. 3-Nitropropionic Acid is an inhibitor of this enzyme, prompting oxidative stress and death neuronal, mimic some aspects of Huntington's disease as anatomical, physiological and chemical changes. CONCLUSION: This model is a useful tool to study the mechanisms involved in this disease and to evaluate new therapeutic strategies.

  • Effect of testosterone on oxidative stress and cell damage induced by 3-Nitropropionic Acid in striatum of ovariectomized rats.
    Life Sciences, 2007
    Co-Authors: Isaac Túnez, Maria C. Muñoz, Ignacio Jimena, Ignacio Rueda, José Peña, Montserrat Feijóo, Francisco J. Medina, Juan A. Collado, Francisco Franco, Jordi Muntané
    Abstract:

    Abstract This paper evaluates the effects of testosterone (0.5 mg/kg subcutaneously (s.c.) for 8 days) on oxidative stress and cell damage induced by 3-Nitropropionic Acid (20 mg/kg intraperitoneally (i.p.) for 4 days) in ovariectomized rats. Gonadectomy triggered oxidative damage and cell loss, evaluated by the detection of caspase-3, whereas 3-Nitropropionic Acid increased the levels of oxidative stress induced by ovariectomy and prompted cell damage characterized by enhanced levels of lactate dehydrogenase. These changes were blocked by testosterone administration. Our results support the following conclusions: i) ovariectomy triggers oxidative and cell damage via caspase-3 in the striatum; ii) 3-Nitropropionic Acid exacerbates oxidative stress induced by ovariectomy and leads to cell damage characterized by increased levels of lactate dehydrogenase; iii) testosterone administration decreases oxidative stress and cell damage. Additionally, these data support the hypothesis that testosterone might play an important role in the onset and development of neurodegenerative diseases.

  • 17 β-Estradiol may affect vulnerability of striatum in a 3-Nitropropionic Acid-induced experimental model of Huntington's disease in ovariectomized rats
    Neurochemistry International, 2006
    Co-Authors: Isaac Túnez, Maria C. Muñoz, Ignacio Jimena, Ignacio Rueda, José Peña, Montserrat Feijóo, Francisco J. Medina, Juan A. Collado, Francisco Franco, Jordi Muntané
    Abstract:

    Abstract The aim of present study was to clarify the role of female sex hormones in the development and course of neurodegenerative disease in an experimental model of Huntington's disease induced by 3-Nitropropionic Acid (NPA) (30 mg/kg intraperitoneally (i.p.)/day for 4 days) in ovariectomized rat. Gonadectomy prompted oxidative stress and cell death evaluated by the detection of caspase-3, whereas 3-Nitropropionic Acid enhanced the oxidative stress induced by ovariectomy and it triggered cell damage characterized by increases of LDH levels. These changes were prevented by administration of 17 β-estradiol. Our findings suggested that: (i) ovariectomy induced oxidative stress and apoptosis in the brain; (ii) 3-Nitropropionic Acid exacerbated oxidative stress induced by ovariectomy and shifting cell to cell death; and (iii) 17 β-estradiol administration decreased oxidative stress and cell death induced by ovariectomy and 3-Nitropropionic Acid. These results revealed that sex ovarian hormones play a important role in onset and development of neurodegenerative diseases, as well as neuroprotective effects of 17 β-estradiol against the changes induced ovariectomy and ovariectomy plus 3-Nitropropionic Acid.

  • Treatment with dehydroepiandrosterone prevents oxidative stress induced by 3-Nitropropionic Acid in synaptosomes.
    Pharmacology, 2005
    Co-Authors: Isaac Túnez, M. Carmen Muñoz, Pedro Montilla
    Abstract:

    This study evaluates the antioxidative effect of dehydroepiandrosterone (DHEA) treatment on 3-Nitropropionic Acid (3-NPA)-induced oxidative stress in striatal and brain cortex synaptosomes. The oxidative derangement was confirmed by a high level of lipid peroxidation products and protein carbonyls, as well as by an enhanced superoxide dismutase activity (p

  • Effect of nicotine on 3-Nitropropionic Acid-induced oxidative stress in synaptosomes.
    European Journal of Pharmacology, 2004
    Co-Authors: Isaac Túnez, Pedro Montilla, M. Carmen Muñoz, René Drucker-colín
    Abstract:

    In this paper, the effect of nicotine on the oxidative changes produced by 3-Nitropropionic Acid (20 mg/kg i.p./day for 4 days) in striatal and cortical synaptosomes of Wistar rats was studied. The effects of 3-Nitropropionic Acid were evaluated as changes in the quantity of protein carbonyl groups, lipid peroxidation products, superoxide distumase activity and reduced succinate dehydrogenase activity. All changes were prevented by the pre-injection of nicotine (1.5 mg/kg i.p./day), beginning 4 days before and continuing for 4 days after the first injection of 3-Nitropropionic Acid. These findings indicate that: (i) 3-Nitropropionic Acid induces a state of oxidative stress in cortical and striatal synaptosomes and (ii) nicotine prevents oxidative stress induced by 3-nitropropinonic Acid. In conclusion, the results show the ability of nicotine to modify neural response to 3-Nitropropionic Acid with the protective mechanism likely involving the antioxidative processes of nicotine.