TY  - JOUR
AU  - Depboylu, Candan
AU  - Rösler, Thomas W
AU  - de Andrade, Anderson
AU  - Oertel, Wolfgang H
AU  - Höglinger, Günter U
TI  - Systemically administered neuregulin-1β1 rescues nigral dopaminergic neurons via the ErbB4 receptor tyrosine kinase in MPTP mouse models of Parkinson's disease.
JO  - Journal of neurochemistry
VL  - 133
IS  - 4
SN  - 0022-3042
CY  - Oxford
PB  - Wiley-Blackwell
M1  - DZNE-2020-04230
SP  - 590-597
PY  - 2015
AB  - Previously, we demonstrated that systemically injected extracellular domain of neuregulin-1β1 (Nrg1β1), 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 Nrg1β1 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) Nrg1β1 or saline (control) were administered 1 h before each MPTP injection. We found that Nrg1β1 significantly reduced the loss of nigral dopaminergic neurons in both intoxication paradigms (7 days post-injection). However, Nrg1β1 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 Nrg1β1. Finally, neuroprotective properties of Nrg1β1 on nigral dopaminergic neurons are specifically mediated by ErbB4 as revealed through the study of ErbB4 knockout mice. In conclusion, systemically administered Nrg1β1 protects midbrain dopaminergic neurons against this PD-related toxic insult. Thus, Nrg1β1 may have a benefit in the treatment of PD patients. Previously, we demonstrated that systemically administered neuregulin-1β1 (Nrg1β1) passes the blood-brain barrier, phosphorylates ErbB4 receptors and elevates dopamine (DA) levels in the nigrostriatal system of healthy mice. Nrg1β1 protects nigral DAergic neurons in the 6-hydroxydopamine (6-OHDA) mouse model of Parkinson's disease (PD). Here, we show that Nrg1β1 rescues nigral DAergic neurons also against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced cell death. ErbB4 expression is essential for the neuroprotective effect of Nrg1β1 on midbrain DAergic neurons. Nrg1β1 might be beneficial in PD treatment.
KW  - 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine: pharmacology
KW  - Animals
KW  - Animals, Genetically Modified
KW  - Disease Models, Animal
KW  - Dopamine Agents: pharmacology
KW  - Dopamine Plasma Membrane Transport Proteins: metabolism
KW  - Dopaminergic Neurons: drug effects
KW  - MPTP Poisoning: chemically induced
KW  - MPTP Poisoning: pathology
KW  - Male
KW  - Mice
KW  - Mice, Inbred C57BL
KW  - Neuregulin-1: pharmacology
KW  - Neuregulin-1: therapeutic use
KW  - Neuroprotective Agents: pharmacology
KW  - Neuroprotective Agents: therapeutic use
KW  - Receptor, ErbB-4: deficiency
KW  - Receptor, ErbB-4: genetics
KW  - Substantia Nigra: pathology
KW  - Time Factors
KW  - Dopamine Agents (NLM Chemicals)
KW  - Dopamine Plasma Membrane Transport Proteins (NLM Chemicals)
KW  - Neuregulin-1 (NLM Chemicals)
KW  - Neuroprotective Agents (NLM Chemicals)
KW  - neuregulin beta (NLM Chemicals)
KW  - 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (NLM Chemicals)
KW  - Erbb4 protein, mouse (NLM Chemicals)
KW  - Receptor, ErbB-4 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:25581060
DO  - DOI:10.1111/jnc.13026
UR  - https://pub.dzne.de/record/137908
ER  -