SEA0400, a specific Na+/Ca2+ exchange inhibitor, prevents dopaminergic neurotoxicity in an MPTP mouse model of Parkinson’s disease

• Published in: Neuropharmacology 2011-12, Vol.61 (8), p.1441-1451
• Main Authors: Ago, Yukio, Kawasaki, Toshiyuki, Nashida, Tetsuaki, Ota, Yuki, Cong, Yana, Kitamoto, Mari, Takahashi, Teisuke, Takuma, Kazuhiro, Matsuda, Toshio
• Format: Article
• Language: English
• Subjects: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine - adverse effects; Analysis of Variance; Aniline Compounds - therapeutic use; Animals; Brain - drug effects; Brain - pathology; Calcium-Binding Proteins - metabolism; Disease Models, Animal; Dopamine; Dopamine - metabolism; Dopaminergic Neurons - drug effects; Dose-Response Relationship, Drug; Drug Administration Schedule; Extracellular Signal-Regulated MAP Kinases - metabolism; Free Radical Scavengers - metabolism; Gene Expression Regulation - drug effects; Lipid Peroxidation - drug effects; Male; Mice; Mice, Inbred C57BL; Microfilament Proteins - metabolism; Motor Activity - drug effects; MPTP; MPTP Poisoning - pathology; MPTP Poisoning - prevention & control; Na+/Ca2+ exchanger (NCX); Neuroprotective Agents - therapeutic use; Nitric oxide (NO); Parkinson’s disease; Phenyl Ethers - therapeutic use; Phosphorylation - drug effects; Rotarod Performance Test; SEA0400; Sodium-Calcium Exchanger - antagonists & inhibitors; Time Factors; Tyrosine - analogs & derivatives; Tyrosine - metabolism; Tyrosine 3-Monooxygenase - metabolism
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2011.08.041

We have recently shown that the Na+/Ca2+ exchanger (NCX) is involved in nitric oxide (NO)-induced cytotoxicity in cultured astrocytes and neurons. However, there is no in vivo evidence suggesting the role of NCX in neurodegenerative disorders associated with NO. NO is implicated in the pathogenesis of neurodegenerative disorders such as Parkinson’s disease. This study examined the effect of SEA0400, the specific NCX inhibitor, on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity, a model of Parkinson’s disease, in C57BL/6J mice. MPTP treatment (10 mg/kg, four times at 2-h intervals) decreased dopamine levels in the midbrain and impaired motor coordination, and these effects were counteracted by S-methylthiocitrulline, a selective neuronal NO synthase inhibitor. SEA0400 protected against the dopaminergic neurotoxicity (determined by dopamine levels in the midbrain and striatum, tyrosine hydroxylase immunoreactivity in the substantia nigra and striatum, striatal dopamine release, and motor deficits) in MPTP-treated mice. SEA0400 had no radical-scavenging activity. SEA0400 did not affect MPTP metabolism and MPTP-induced NO production and microglial activation, while it attenuated MPTP-induced increases in extracellular signal-regulated kinase (ERK) phosphorylation and lipid peroxidation product, thiobarbituric acid reactive substance. These findings suggest that SEA0400 protects against MPTP-induced neurotoxicity probably by blocking ERK phosphorylation and lipid peroxidation which are downstream of NCX-mediated Ca2+ influx. ► The effect of the NCX inhibitor SEA0400 on dopaminergic neurotoxicity was examined. ► MPTP-induced dopaminergic neurotoxicity depends on NO production. ► SEA0400 protected against the dopaminergic neurotoxicity in MPTP-treated mice. ► SEA0400 attenuated MPTP-induced changes in ERK signal and lipid peroxidation. ► SEA0400 protects against the neurotoxicity by blocking NCX-mediated Ca2+ influx.