Article

P2X7 receptor signaling pathway as a therapeutic target for neurodegenerative diseases.

Laboratory for Chemistry and Metabolism, Tokyo Metropolitan Institute for Neuroscience, Fuchu, Tokyo 183-8526, Japan.
Archivum Immunologiae et Therapiae Experimentalis (impact factor: 2.54). 02/2010; 58(2):91-6. DOI:10.1007/s00005-010-0069-y
Source: PubMed

ABSTRACT A recent study suggested that neuroinflammation plays a major role in the pathogenesis of a number of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Although the precise mechanism is obscure, dysregulation of the signaling transduction pathway in microglia may enhance inflammation, leading to synaptic dysfunction and ultimately to neuronal cell death. The expression and function of the P2X7 receptor (P2X7R), an ATP-gated ion channel abundantly expressed in microglia in the brain, is significantly up-regulated in the postmortem brain of Alzheimer's disease patients and various neurodegenerative disease animal models. This supports the role of the P2X7R pathway in the progression of neurodegeneration. Blocking P2X7R using brilliant blue G, a P2X7R antagonist that can cross the blood-brain barrier, has been shown to result in the amelioration of neuropathology in various animal models. Taken together, these results raise the possibility that the P2X7R signaling pathway could be a therapeutic target for treating various neurodegenerative diseases.

0 0
 · 
0 Bookmarks
 · 
64 Views
  • Source
    Dataset: Froestl 2012 Part1
    Wolfgang Froestl, Andreas Muhs, Andrea Pfeifer
  • Article: The NADPH Oxidase Pathway Is Dysregulated by the P2X7 Receptor in the SOD1-G93A Microglia Model of Amyotrophic Lateral Sclerosis.
    Savina Apolloni, Chiara Parisi, Maria Grazia Pesaresi, Simona Rossi, Maria Teresa Carrì, Mauro Cozzolino, Cinzia Volonté, Nadia D'Ambrosi
    [show abstract] [hide abstract]
    ABSTRACT: Inflammation and oxidative stress are thought to play determinant roles in the pathogenesis of amyotrophic lateral sclerosis (ALS). Degenerating motor neurons produce signals that activate microglia to release reactive oxygen species (ROS) and proinflammatory cytokines, resulting in a vicious cycle of neurodegeneration. The ALS-causing mutant protein Cu(+)/Zn(+) superoxide dismutase SOD1-G93A directly enhances the activity of the main ROS-producing enzyme in microglia, NADPH oxidase 2 (NOX2), a well-known player in the pathogenesis of ALS. Considering that extracellular ATP through P2X7 receptor constitutes a neuron-to-microglia alarm signal implicated in ALS pathology, we used primary microglial cells derived from transgenic SOD1-G93A mice and SOD1-G93A mice lacking the P2X7 receptor to investigate the effects of both pharmacological induction and genetic ablation of receptor activity on the NOX2 pathway. We observed that, in SOD1-G93A microglia, the stimulation of P2X7 receptor by 2'-3'-O-(benzoyl-benzoyl) ATP enhanced NOX2 activity in terms of translocation of p67(phox) to the membrane and ROS production; this effect was totally dependent on Rac1. We also found that, following P2X7 receptor stimulation, the phosphorylation of ERK1/2 was augmented in ALS microglia, and there was a mutual dependency between the NOX2 and ERK1/2 pathways. All of these microglia-mediated damaging mechanisms were prevented by knocking out P2X7 receptor and by the use of specific antagonists. These findings suggest a noxious mechanism by which P2X7 receptor leads to enhanced oxidative stress in ALS microglia and identify the P2X7 receptor as a promising target for the development of therapeutic strategies to slow down the progression of ALS.
    The Journal of Immunology 04/2013; · 5.79 Impact Factor
  • Source
    Dataset: Froestl 2012 Part1
    Andrea Pfeifer, Andreas Muhs, Wolfgang Froestl

Show more

Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

Alzheimer's disease
 
Alzheimer's disease patients
 
ATP-gated ion channel abundantly
 
Blocking P2X7R
 
brilliant blue G
 
neurodegeneration
 
neurodegenerative diseases
 
neuronal cell death
 
P2X7R antagonist
 
P2X7R pathway
 
P2X7R signaling pathway
 
Parkinson's disease
 
postmortem brain
 
precise mechanism
 
recent study
 
signaling transduction pathway
 
up-regulated
 
various animal models
 
various neurodegenerative disease animal models
 
various neurodegenerative diseases