ABSTRACT
We investigated the therapeutic effect of zonisamide against 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in mice, using Western blot analysis, immunohistochemistry and behavioral test. Our Western blot analysis and immunohistochemical study showed that the post-treatment with zonisamide prevented significantly dopaminergic cell damage, the depletion of tyrosine-hydroxylase (TH) protein levels and the proliferation of microglia in the striatum and/or substantia nigra 8 days after MPTP treatment. Furthermore, our behavioral study showed that the post-treatment with zonisamide attenuated significantly the motor deficits 7 days after MPTP treatment. These results show that zonisamide has the therapeutic effect in the MPTP model of Parkinson's disease (PD) in mice. Our study also demonstrates the neuroprotective effect of zonisamide against dopaminergic cell damage after MPTP treatment in mice. Thus our present findings suggest that therapeutic strategies targeted to the activation of TH protein and/or the inhibition of microglial activation with zonisamide may offer a great potential for restoring the functional capacity of the surviving dopaminergic neurons in individuals affected with PD.
Subject(s)
Antiparkinson Agents/pharmacology , Isoxazoles/pharmacology , Nerve Degeneration/drug therapy , Neuroprotective Agents/pharmacology , Parkinsonian Disorders/drug therapy , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine , Animals , Antioxidants/pharmacology , Antioxidants/therapeutic use , Antiparkinson Agents/therapeutic use , Disease Models, Animal , Dopamine/biosynthesis , Isoxazoles/therapeutic use , Male , Mice , Mice, Inbred C57BL , Nerve Degeneration/metabolism , Neuroprotective Agents/therapeutic use , Parkinsonian Disorders/pathology , Parkinsonian Disorders/physiopathology , Substantia Nigra/drug effects , Substantia Nigra/metabolism , Substantia Nigra/physiopathology , Treatment Outcome , ZonisamideABSTRACT
We investigated the therapeutic effect of zonisamide against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in mice, using Western blot analysis, immunohistochemistry and behavioral test. Our Western blot analysis and immunohistochemical study showed that the post-treatment with zonisamide prevented significantly dopaminergic cell damage, the depletion of tyrosine-hydroxylase (TH) protein levels and the proliferation of microglia in the striatum and/or substantia nigra 8 days after MPTP treatment. Furthermore, our behavioral study showed that the post-treatment with zonisamide attenuated significantly the motor deficits 7 days after MPTP treatment. These results show that zonisamide has the therapeutic effect in the MPTP model of Parkinson's disease (PD) in mice. Our study also demonstrates the neuroprotective effect of zonisamide against dopaminergic cell damage after MPTP treatment in mice. Thus our present findings suggest that therapeutic strategies targeted to the activation of TH protein and/or the inhibition of microglial activation with zonisamide may offer a great potential for restoring the functional capacity of the surviving dopaminergic neurons in individuals affected with PD.
Subject(s)
Antiparkinson Agents/pharmacology , Isoxazoles/pharmacology , Nerve Degeneration/drug therapy , Neuroprotective Agents/pharmacology , Parkinsonian Disorders/drug therapy , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine , Animals , Antioxidants/pharmacology , Antioxidants/therapeutic use , Antiparkinson Agents/therapeutic use , Disease Models, Animal , Dopamine/biosynthesis , Isoxazoles/therapeutic use , Male , Mice , Mice, Inbred C57BL , Nerve Degeneration/metabolism , Neurons/drug effects , Neurons/metabolism , Neurons/pathology , Neuroprotective Agents/therapeutic use , Parkinsonian Disorders/pathology , Parkinsonian Disorders/physiopathology , Substantia Nigra/drug effects , Substantia Nigra/metabolism , Substantia Nigra/physiopathology , Treatment Outcome , ZonisamideABSTRACT
An excessive expression of poly(ADP-ribose)polymerase (PARP) has been demonstrated to play a key role in the pathogenesis of Parkinson's disease (PD). Here we investigated the therapeutic effect of the PARP inhibitor benzamide against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in mice. In our HPLC and Western blot analysis, pretreatment with benzamide showed a neuroprotective effect against MPTP neurotoxicity in mice. Posttreatment with benzamide also attenuated MPTP neurotoxicity in mice. Furthermore, our immunohistochemical study showed that posttreatment with benzamide significantly prevented neuronal damage by suppressing overexpression of neuronal, microglial, and astroglial PARP after MPTP treatment. These findings have important implications for the therapeutic time window and choice of PARP inhibitors in PD patients. Our present findings provide further evidence that PARP inhibitor may offer a novel therapeutic strategy for PD.