Sigma-1 receptor deficiency reduces MPTP-induced parkinsonism and death of dopaminergic neurons

Sigma-1 receptor (sigma R-1) has been reported to be decreased in nigrostriatal motor system of Parkinson's disease patients. Using heterozygous and homozygous sigma R-1 knockout (sigma R-1(+/-) and sigma R-1(-/-)) mice, we investigated the influence of sigma R-1 deficiency on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-impaired nigrostriatal motor system. The injection of MPTP for 5 weeks in wild-type mice (MPTP-WT mice), but not in sigma R-1(+/-) or sigma R-1(-/-) mice (MPTP-sigma R-1(+/-) or MPTP-sigma R-1(-/-) mice), caused motor deficits and similar to 40% death of dopaminergic neurons in substantia nigra pars compacta with an elevation of N-methyl-D-aspartate receptor (NMDAr) NR2B phosphorylation. The s1R antagonist NE100 or the NR2B inhibitor Ro25-6981 could alleviate the motor deficits and the death of dopaminergic neurons in MPTP-WT mice. By contrast, MPTP-sigma R-1(+/-) mice treated with the sigma R-1 agonist PRE084 or MPTP-sigma R-1(-/-) mice treated with the NMDAr agonist NMDA appeared to have similar motor deficits and loss of dopaminergic neurons as MPTP-WT mice. The pharmacological or genetic inactivation of sigma R-1 suppressed the expression of dopamine transporter (DAT) in substantia nigra, which was corrected by NMDA. The activation of sigma R-1 by PRE084 enhanced the DAT expression in WT mice or sigma R-1(+/-) mice. By contrast, the level of vesicular monoamine transporter 2 (VMAT2) in sigma R-1(+/)- mice or sigma R-1(-/-) mice had no difference from WT mice. Interestingly, MPTP-WT mice showed the reduction in the levels of DAT and VMAT2, but MPTP-sigma R-1(-/-) mice did not. The inactivation of sigma R-1 by NE100 could prevent the reduction of VMAT2 in MPTP-WT mice. In addition, the activation of microglia cells in substantia nigra was equally enhanced in MPTP-WT mice and MPTP-sigma R-1(-/-) mice. The number of activated astrocytes in MPTP-sigma R-1(-/-) mice was less than that in MPTP-WT mice. The findings indicate that the sigma R-1 deficiency through suppressing NMDAr function and DAT expression can reduce MPTP-induced death of dopaminergic neurons and parkinsonism.