Systemically administered neuregulin-1 beta 1 rescues nigral dopaminergic neurons via the ErbB4 receptor tyrosine kinase in MPTP mouse models of Parkinson's disease

摘要

Previously, we demonstrated that systemically injected extracellular domain of neuregulin-1 beta 1 (Nrg1 beta 1), a nerve growth and differentiation factor, passes the blood-brain barrier and rescues dopaminergic neurons of substantia nigra in the 6-hydroxydopamine- mouse model of Parkinson's disease (PD). Here, we studied the effects of peripherally administered Nrg1 beta 1 in another toxin-based mouse model of PD. For this purpose, (i) nigrostriatal pathway injury was induced by treatment of adult wild-type mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in acute and subchronic paradigms; and (ii) Nrg1 beta 1 or saline (control) were administered 1 h before each MPTP injection. We found that Nrg1 beta 1 significantly reduced the loss of nigral dopaminergic neurons in both intoxication paradigms (7 days post-injection). However, Nrg1 beta 1 did not reverse MPTP-induced decrease in dopamine levels and dopaminergic fibers in the striatum. We also show that MPTP conversion to its toxic metabolite 1-methyl-4-phenylpyridinium as well as levels of dopamine transporter, mediating intracellular uptake of 1-methyl-4-phenylpyridinium, are unaffected by Nrg1 beta 1. Finally, neuroprotective properties of Nrg1 beta 1 on nigral dopaminergic neurons are specifically mediated by ErbB4 as revealed through the study of ErbB4 knockout mice. In conclusion, systemically administered Nrg1 beta 1 protects midbrain dopaminergic neurons against this PD-related toxic insult. Thus, Nrg1 beta 1 may have a benefit in the treatment of PD patients.