Targeting microglia-mediated neurotoxicity: the potential of NOX2 inhibitors - PubMed (original) (raw)

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Targeting microglia-mediated neurotoxicity: the potential of NOX2 inhibitors

Michael J Surace et al. Cell Mol Life Sci. 2012 Jul.

Abstract

Microglia are key sentinels of central nervous system health, and their dysfunction has been widely implicated in the progressive nature of neurodegenerative diseases. While microglia can produce a host of factors that are toxic to neighboring neurons, NOX2 has been implicated as a common and essential mechanism of microglia-mediated neurotoxicity. Accumulating evidence indicates that activation of the NOX2 enzyme complex in microglia is neurotoxic, both through the production of extracellular reactive oxygen species that damage neighboring neurons as well as the initiation of redox signaling in microglia that amplifies the pro-inflammatory response. More specifically, evidence supports that NOX2 redox signaling enhances microglial sensitivity to pro-inflammatory stimuli, and amplifies the production of neurotoxic cytokines, to promote chronic and neurotoxic microglial activation. Here, we describe the evidence denoting the role of NOX2 in microglia-mediated neurotoxicity with an emphasis on Alzheimer's and Parkinson's disease, describe available inhibitors that have been tested, and detail evidence of the neuroprotective and therapeutic potential of targeting this enzyme complex to regulate microglia.

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Fig. 1

Fig. 1

NOX2 is key for neurotoxic microglial activation. Microglial NOX2 is activated by cytokines, endogenous disease proteins, inflammogens, and soluble neuron injury signals from neuron death/damage (reactive microglisosis), which is implicated in self-propagating neurotoxicity. Thus, specific inhibition of NOX2 is a promising target with the potential to break the cycle of chronic and neurotoxic microglial activation that is implicated in the progressive nature of neurodegenerative diseases

Fig. 2

Fig. 2

Inhibitors target microglial NOX2 activation through two mechanisms. Activation of the NOX2 complex occurs in microglia in response to several stimuli and multiple signaling pathways, where activation is due to the assembly of the enzyme complex, as depicted here. Several putative NOX2 inhibitors have been identified that attenuate microglial activation to confer neuroprotection. Here, we classify compounds that have been shown to inhibit microglial NOX2 activity into one of two categories based on whether the molecules were: (1) proposed to directly inhibit the catalytic subunit or (2) indirectly modulate NOX2 through inhibition of phosporylation and translocation of cytosolic subunits or other pathways. Notably, most of these molecules are not specific for NOX2 and the mechanism of NOX2 inhibition are either poorly understood or unknown at this time

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