7-Nitroindazole

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Douglas E Mcbean - One of the best experts on this subject based on the ideXlab platform.

Yun Sil Chang - One of the best experts on this subject based on the ideXlab platform.

Tsutomu Araki - One of the best experts on this subject based on the ideXlab platform.

  • Role of reactive nitrogen and reactive oxygen species against MPTP neurotoxicity in mice
    Journal of Neural Transmission, 2008
    Co-Authors: Hironori Yokoyama, Yu Watanabe, Hiroyuki Kato, Sho Takagi, Tsutomu Araki
    Abstract:

    There is growing evidence indicating that reactive nitrogen species (RNS) and reactive oxygen species (ROS) are a major contributor to the pathogenesis and progression of Parkinson’s disease. Here we investigated whether edaravone (free radical scavenger), minocycline (inducible nitric oxide synthase, iNOS inhibitor), 7-Nitroindazole (neuronal NOS, nNOS inhibitor), fluvastatin (endothelial NOS, eNOS activator) and pitavastatin (eNOS activator) can protect against MPTP neurotoxicity in mice under the same condition. The present study showed that 7-Nitroindazole could protect dose-dependently against the striatal dopamine depletions in mice 5 days after MPTP treatment. In contrast, edaravone, minocycline, fluvastatin and pitavastatin did not show the neuroprotective effect on MPTP-induced striatal dopamine depletion. Our immunohistochemical study showed that TH (tyrosine hydroxylase) and DAT (dopamine transporter) immunoreactivity was decreased significantly in the striatum and substantia nigra 5 days after MPTP treatment. The administration of 7-Nitroindazole showed a protective effect against the severe reductions in levels of TH and DAT immunoreactivity in the striatum and substantia nigra 5 days after MPTP treatment. Furthermore, our Western blot analyses study showed the remarkable loss of TH protein levels in the striatum 5 days after MPTP treatment. In contrast, 7-Nitroindazole prevented a significant loss in TH protein levels in the striatum 5 days after MPTP treatment. On the other hand, GFAP (glial fibrillary acidic protein) immunoreactivity increased significantly in the striatum and substantia nigra, 5 days after MPTP treatment. 7-Nitroindazole ameliorated severe increases in number of GFAP immunoreactive astrocytes in the striatum and substantia nigra 5 days after MPTP treatment. Furthermore, our Western blot analyses study showed the increase of GFAP protein levels in the striatum 5 days after MPTP treatment. 7-Nitroindazole prevented a significant increase in the GFAP protein levels in the striatum 5 days after MPTP treatment. The present results indicate that 7-Nitroindazole can protect dose-dependently against the striatal dopamine depletions in mice 5 days after MPTP treatment. In contrast, edaravone, minocycline, fluvastatin and pitavastatin did not show the neuroprotective effect on MPTP-induced striatal dopamine depletions. These findings demonstrate that the overexpression of nNOS may play a major role in the neurotoxic processes of MPTP, as compared to the production of ROS, the overexpression of iNOS and the modulation of eNOS. Thus, our findings provide strong evidence for neuroprotective properties of nNOS inhibitor in this animal model of Parkinson’s disease.

  • Protective action of neuronal nitric oxide synthase inhibitor in the MPTP mouse model of Parkinson’s disease
    Metabolic Brain Disease, 2008
    Co-Authors: Yu Watanabe, Hiroyuki Kato, Tsutomu Araki
    Abstract:

    We examined the effects of 7-Nitroindazole on the dopaminergic system in mice after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. The mice received four intraperitoneal injections of MPTP (20 mg/kg) at 2 h-intervals. Administration of 7-Nitroindazole showed dose-dependent neuroprotective effects against striatal dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) depletion 7 days after MPTP treatment. Behavioral testing showed that MPTP-treated mice exhibited motor deficits in the catalepsy test after 7 days, but 7-Nitroindazole prevented the appearance of motor abnormalities in this test. The MPTP-treated mice exhibited the loss of tyrosine hydroxylase-containing dopaminergic neurons in mice after 1, 3 and 7 days, but 7-Nitroindazole-treated mice showed a protective effect. GFAP (glial fibrillary acidic protein)-positive astrocytes were accumulated in the striatum 3 and 7 days and in the substantia nigra 1, 3 and 7 days after MPTP treatment. In contrast, 7-Nitroindazole prevented a significant increase in the number of GFAP-positive astrocytes in the striatum and substantia nigra after MPTP treatment. The reactive astrocytes in the striatum and substantia nigra after MPTP treatment increased the production of S100β protein, which is thought to promote neuronal damage, but 7-nitoindazole suppressed the expression of S100 β protein. Activation of microglia, with an increase in staining intensity and morphological changes, was observed in the striatum and substantia nigra 1 and 3 days after MPTP treatment, but 7-Nitroindazole prevented a significant increase in the number of isolectin B_4 positive microglia in the striatum and substantia nigra. On the other hand, nestin- immunoreactive cells were increased significantly in the striatum 3 and 7 days after MPTP treatment. 7-Nitroindazole treatment facilitated nestin expression in the striatum 7 days after MPTP treatment. Thus, nNOS inhibitor 7-Nitroindazole protected dopaminergic neurons against MPTP neurotoxicity in mice and ameliorated neurological deficits. The results suggest that the neuroprotection is mediated though the modulation of glial activation, including the inhibition of S100β synthesis and the prevention of microglial activation. These results suggest the therapeutic strategy targeted to glial modulation with 7-nitoindazole offers a great potential for the development of new neuroprotective therapies for Parkinson’s disease.

  • therapeutic effect of neuronal nitric oxide synthase inhibitor 7 nitroindazole against mptp neurotoxicity in mice
    Metabolic Brain Disease, 2002
    Co-Authors: Y Muramatsu, R Kurosaki, T Mikami, Mari Michimata, Mitsunobu Matsubara, Yasuto Itoyama, Hiroyuki Kato, Yutaka Imai, Tsutomu Araki
    Abstract:

    Effects of neuronal nitric oxide synthase (nNOS) inhibitor (7-Nitroindazole), nonselective NOS inhibitor (NG-nitro-L-arginine methyl ester; L-NAME), and monoamine oxidase inhibitor (pargyline) were studied on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. The mice received four intraperitoneal injections of MPTP at 1-h intervals. A significant depletion in dopamine and DOPAC concentration was observed in the striatum from 1 day after MPTP treatment. The pretreatment of 7-Nitroindazole and pargyline, but not L-NAME, dose-dependently protected against MPTP-induced depletion in dopamine content 3 days after MPTP treatment. Our histochemical study also showed that 7-Nitroindazole and pargyline can prevent a marked decrease in the nigral cells and a marked increase in astrocytes in striatum 7 days after MPTP treatment. The protective effect of 7-Nitroindazole against MPTP-induced dopamine and DOPAC depletion in the striatum was not attenuated by intraperitoneal pretreatment with L-arginine. Furthermore, the posttreatment of 7-Nitroindazole or pargyline protected against MPTP-induced depletion of dopamine content. These results demonstrate that the protective mechanism by which 7-Nitroindazole counteracts MPTP neurotoxicity in mice may be due not only to inhibition of nNOS, but also to MAO-B inhibition. Furthermore, our study suggests that the posttreatment of 7-Nitroindazole and pargyline can prevent a significant decrease in dopamine levels in the striatum of MPTP-treated mice. These findings have important implications for the therapeutic time window and choice of nNOS or MAO inhibitors in patients with Parkinson's disease.

Stanislaw J Czuczwar - One of the best experts on this subject based on the ideXlab platform.

  • 7 nitroindazole potentiates the anticonvulsant action of some second generation antiepileptic drugs in the mouse maximal electroshock induced seizure model
    Journal of Neural Transmission, 2006
    Co-Authors: Jarogniew J Luszczki, Miroslaw Czuczwar, P Gawlik, G Sawiniecpozniak, Katarzyna Czuczwar, Stanislaw J Czuczwar
    Abstract:

    The effects of 7-Nitroindazole (7NI, a preferential neuronal nitric oxide synthase inhibitor) on the anticonvulsant activity of four second-generation antiepileptic drugs (AEDs: felbamate [FBM], lamotrigine [LTG], oxcarbazepine [OXC] and topiramate [TPM]) were studied in the mouse maximal electroshock-induced seizure (MES) model. Moreover, the influence of 7NI on the acute neurotoxic (adverse-effect) profiles of the studied AEDs, with regard to motor coordination, was determined in the chimney test in mice.

  • 7 nitroindazole a nitric oxide synthase inhibitor enhances the anticonvulsive action of ethosuximide and clonazepam against pentylenetetrazol induced convulsions
    Journal of Neural Transmission, 2000
    Co-Authors: Kinga K. Borowicz, Zdzisław Kleinrok, Jarogniew J. Łuszczki, Stanislaw J Czuczwar
    Abstract:

    The interaction of 7-Nitroindazole (7-NI), a nitric oxide synthase (NOS) inhibitor, with the protective activity of conventional antiepileptics against pentylenetetrazol (PTZ)-induced seizures was tested in mice. Alone, 7-Nitroindazole (up to 50 mg/kg) was ineffective in this model of experimental epilepsy. However, it potentiated the anticonvulsive activity of ethosuximide and clonazepam, significantly reducing their ED50s against PTZ-induced convulsions (from 144 to 76 mg/kg, and from 0.05 to 0.016 mg/kg, respectively). Conversely, the protective actions of valproate and phenobarbital were not affected by the NOS inhibitor. Since the nitric oxide precursor, L-arginine, did not reverse the action of 7-NI on ethosuximide or clonazepam, an involvement of central NO does not seem probable. Neither ethosuximide nor clonazepam, administered at their ED50s (144 and 0.05 mg/kg, respectively), produced significant adverse effects as regards motor coordination (chimney test) and long-term memory (passive avoidance task). Also 7-NI (50 mg/kg) and its combinations with ethosuximide and clonazepam (providing a 50% protection against PTZ-evoked seizures) did not disturb motor and mnemonic performance in mice. The interaction at the pharmacokinetic level does not seem probable, at least in the case of ethosuximide, because the NOS inhibitor did not interfere with its plasma or brain concentrations.

  • 7 nitroindazole a nitric oxide synthase inhibitor enhances the anticonvulsive action of ethosuximide and clonazepam against pentylenetetrazol induced convulsions
    Journal of Neural Transmission, 2000
    Co-Authors: Kinga K. Borowicz, Zdzisław Kleinrok, Jarogniew J łuszczki, Stanislaw J Czuczwar
    Abstract:

    The interaction of 7-Nitroindazole (7-NI), a nitric oxide synthase (NOS) inhibitor, with the protective activity of conventional antiepileptics against pentylenetetrazol (PTZ)-induced seizures was tested in mice. Alone, 7-Nitroindazole (up to 50 mg/kg) was ineffective in this model of experimental epilepsy. However, it potentiated the anticonvulsive activity of ethosuximide and clonazepam, significantly reducing their ED50s against PTZ-induced convulsions (from 144 to 76 mg/kg, and from 0.05 to 0.016 mg/kg, respectively). Conversely, the protective actions of valproate and phenobarbital were not affected by the NOS inhibitor. Since the nitric oxide precursor, L-arginine, did not reverse the action of 7-NI on ethosuximide or clonazepam, an involvement of central NO does not seem probable. Neither ethosuximide nor clonazepam, administered at their ED50s (144 and 0.05 mg/kg, respectively), produced significant adverse effects as regards motor coordination (chimney test) and long-term memory (passive avoidance task). Also 7-NI (50 mg/kg) and its combinations with ethosuximide and clonazepam (providing a 50% protection against PTZ-evoked seizures) did not disturb motor and mnemonic performance in mice. The interaction at the pharmacokinetic level does not seem probable, at least in the case of ethosuximide, because the NOS inhibitor did not interfere with its plasma or brain concentrations.

  • influence of 7 nitroindazole on the anticonvulsive action of conventional antiepileptic drugs
    European Journal of Pharmacology, 1997
    Co-Authors: Kinga K. Borowicz, Zdzisław Kleinrok, Stanislaw J Czuczwar
    Abstract:

    7-Nitroindazole (a selective neuronal nitric oxide (NO) synthase inhibitor) at 25 and 50 mg/kg, 30 min before the test, did not influence the electroconvulsive threshold. However, at 50 mg/kg, it enhanced the anticonvulsive activity of phenobarbital against maximal electroshock and did not affect that of carbamazepine, diphenylhydantoin and valproate. L-Arginine (500 mg/kg) did not modify the protective activity of phenobarbital alone or the 7-Nitroindazole-induced enhancement of its anticonvulsive potency against maximal electroshock. 7-Nitroindazole did not alter the plasma levels of antiepileptic drugs, so a pharmacokinetic interaction, in terms of total and free plasma levels, is not probable. 7-Nitroindazole combined with the antiepileptics resulted in motor disturbances, except for the combination with phenobarbital. On the other hand, the combined treatment of 7-Nitroindazole with carbamazepine or phenobarbital produced effects superior to those produced by single drugs, as regards long-term memory. Our results indicate that the protective activity of carbamazepine, diphenylhydantoin, or valproate against maximal electroshock may be not dependent upon the central NO level. The enhancement of the anticonvulsive action of phenobarbital by 7-Nitroindazole is probably not related to the decrease of NO in the central nervous system.

Jiwang Zheng - One of the best experts on this subject based on the ideXlab platform.