We have recently shown that the Na(+)/Ca(2+) 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 Ca(2+) influx.