Document Detail

Involvement of microglial RhoA/Rho-kinase pathway activation in the dopaminergic neuron death. Role of angiotensin via angiotensin type 1 receptors.
MedLine Citation:
PMID:  22542954     Owner:  NLM     Status:  MEDLINE    
It has recently been shown that the dopaminergic cell loss induced by neurotoxins is enhanced by brain angiotensin II (AII) via type 1 receptors (AT1). However, the mechanisms involved in the dopaminergic degeneration and the brain inflammatory effects of AII have not been clarified. The RhoA-Rho-Kinase (ROCK) pathway may play a critical role in the inflammatory and oxidative effects of AII. In the substantia nigra of mice, administration of the dopaminergic neurotoxin MPTP induced an increase in the expression of RhoA and ROCK II mRNA levels and ROCK activity, which were inhibited by AT1 receptor deletion (i.e., in AT1a null mice treated with MPTP). Administration of the ROCK inhibitor Y-27632 or AT1 deletion induced a significant decrease in MPTP-induced microglial activation and dopaminergic cell death. In rat primary mesencephalic cultures treated with MPP(+), the increase in dopaminergic cell loss induced by AII administration was also inhibited by treatment with Y27632. Intense expression of ROCK II was observed in the microglial cells in the substantia nigra of mice treated with MPTP, and the major role of the microglial ROCK was confirmed by comparing mesencephalic cultures with and without microglia. Activation of the RhoA/ROCK pathway is involved in the MPTP-induced dopaminergic degeneration, and in the enhancing effect of AII/AT1 activation on the microglial response and dopaminergic degeneration. ROCK inhibitors and AT1 receptor antagonists may provide new neuroprotective strategies against the progression of Parkinson's disease.
Begoña Villar-Cheda; Antonio Dominguez-Meijide; Belen Joglar; Ana I Rodriguez-Perez; Maria J Guerra; Jose L Labandeira-Garcia
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-04-19
Journal Detail:
Title:  Neurobiology of disease     Volume:  47     ISSN:  1095-953X     ISO Abbreviation:  Neurobiol. Dis.     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-06-04     Completed Date:  2013-04-03     Revised Date:  2013-04-24    
Medline Journal Info:
Nlm Unique ID:  9500169     Medline TA:  Neurobiol Dis     Country:  United States    
Other Details:
Languages:  eng     Pagination:  268-79     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier Inc. All rights reserved.
Department of Morphological Sciences, Faculty of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain.
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MeSH Terms
Amides / pharmacology,  therapeutic use
Angiotensins / physiology*
Cell Death / drug effects,  physiology
Cells, Cultured
Dopaminergic Neurons / enzymology,  metabolism*,  pathology
Enzyme Inhibitors / pharmacology,  therapeutic use
Mice, Inbred C57BL
Mice, Knockout
Microglia / enzymology,  metabolism*,  pathology
Parkinson Disease / physiopathology,  prevention & control
Pyridines / pharmacology,  therapeutic use
Receptor, Angiotensin, Type 1 / physiology*
Signal Transduction / physiology*
rho GTP-Binding Proteins / physiology*
rho-Associated Kinases / antagonists & inhibitors,  physiology
Reg. No./Substance:
0/Amides; 0/Angiotensins; 0/Enzyme Inhibitors; 0/Pyridines; 0/Receptor, Angiotensin, Type 1; 138381-45-0/Y 27632; EC Kinases; EC protein, mouse; EC GTP-Binding Proteins

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