title: Zonisamide reduces nigrostriatal dopaminergic neurodegeneration in a mouse genetic model of Parkinson's disease.
abstract: Parkinson's disease (PD) is a chronic neurodegenerative disorder characterized by the loss of nigrostriatal dopaminergic neurons and consequent motor dysfunction. Zonisamide (1,2-benzisoxazole-3-methanesulfonamide), which was originally developed as an antiepileptic drug, has been found to have therapeutic benefits for PD. However, the pharmacological mechanisms behind the beneficial actions of zonisamide in PD are not fully understood. Here, we investigated the neuroprotective effects of zonisamide on nigrostriatal dopaminergic neurons of the Engrailed mutant mouse, a genetic model of PD. Chronic administration of zonisamide in Engrailed mutant mice was shown to improve the survival of nigrostriatal dopaminergic neurons compared with that under saline treatment. In addition, dopaminergic terminals in the striatum and the motor function were improved in zonisamide-treated Engrailed mutant mice to the levels of those in control mice. To clarify the mechanism behind the neuroprotective effects of zonisamide, the contents of neurotrophic factors were determined after chronic administration of zonisamide. Brain-derived neurotrophic factor content was increased in the striatum and ventral midbrain of the zonisamide-treated mice compared to saline-treated mice. These findings imply that zonisamide reduces nigrostriatal dopaminergic cell death through brain-derived neurotrophic factor signaling and may have similar beneficial effects in human parkinsonian patients as well.
authors: Division of System Neurophysiology, National Institute for Physiological Sciences, Okazaki, Aichi, Japan.|Department of Physiological Sciences, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Aichi, Japan.
authors: Hiromi
authors: H
authors: Sano
authors: Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
authors: Miho
authors: M
authors: Murata
authors: Division of System Neurophysiology, National Institute for Physiological Sciences, Okazaki, Aichi, Japan.|Department of Physiological Sciences, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Aichi, Japan.
authors: Atsushi
authors: A
authors: Nambu
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D000978:Antiparkinson Agents / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000473:pathology; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020734:Parkinsonian Disorders / Q000473:pathology*; D000078305:Zonisamide
chemical_list: D000975:Antioxidants; D000978:Antiparkinson Agents; D019208:Brain-Derived Neurotrophic Factor; D007555:Isoxazoles; D018696:Neuroprotective Agents; D000078305:Zonisamide
keywords: Parkinson's disease; dopaminergic neurons; neuroprotection; neurotrophic factor