Systemically administered neuregulin-1β1 rescues nigral dopaminergic neurons via the ErbB4 receptor tyrosine kinase in MPTP mouse models of Parkinson's disease

Autor: Thomas W. Rösler, Wolfgang H. Oertel, Candan Depboylu, Günter U. Höglinger, Anderson de Andrade
Rok vydání: 2015
Předmět:
Male
therapeutic use [Neuregulin-1]
Time Factors
Receptor
ErbB-4
Dopamine Agents
Nigrostriatal pathway
drug effects [Dopaminergic Neurons]
genetics [Receptor
ErbB-4]
Striatum
Pharmacology
Biochemistry
Animals
Genetically Modified
Mice
chemistry.chemical_compound
pharmacology [1-Methyl-4-phenyl-1
2
3
6-tetrahydropyridine]
chemically induced [MPTP Poisoning]
neuregulin beta
biology
MPTP
Dopaminergic
therapeutic use [Neuroprotective Agents]
Substantia Nigra
Neuroprotective Agents
medicine.anatomical_structure
1-Methyl-4-phenyl-1
2
3
6-tetrahydropyridine
medicine.drug
pharmacology [Neuregulin-1]
Neuregulin-1
Substantia nigra
Neuroprotection
pathology [MPTP Poisoning]
Cellular and Molecular Neuroscience
Dopamine
medicine
Animals
ddc:610
pathology [Substantia Nigra]
Dopamine transporter
Dopamine Plasma Membrane Transport Proteins
pharmacology [Neuroprotective Agents]
business.industry
Dopaminergic Neurons
deficiency [Receptor
ErbB-4]
MPTP Poisoning
Erbb4 protein
mouse
Mice
Inbred C57BL
Disease Models
Animal
pharmacology [Dopamine Agents]
nervous system
chemistry
biology.protein
metabolism [Dopamine Plasma Membrane Transport Proteins]
business
Neuroscience
Zdroj: Journal of neurochemistry 133(4), 590-597 (2015). doi:10.1111/jnc.13026
ISSN: 0022-3042
DOI: 10.1111/jnc.13026
Popis: 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.
Databáze: OpenAIRE
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