NADPH oxidases: novel therapeutic targets for neurodegenerative diseases

Trends Pharmacol Sci. 2012 Jun;33(6):295-303. doi: 10.1016/j.tips.2012.03.008. Epub 2012 Apr 11.

Abstract

Oxidative stress is a key pathologic factor in neurodegenerative diseases such as Alzheimer and Parkinson diseases (AD, PD). The failure of free-radical-scavenging antioxidants in clinical trials pinpoints an urgent need to identify and to block major sources of oxidative stress in neurodegenerative diseases. As a major superoxide-producing enzyme complex in activated phagocytes, phagocyte NADPH oxidase (PHOX) is essential for host defense. However, recent preclinical evidence has underscored a pivotal role of overactivated PHOX in chronic neuroinflammation and progressive neurodegeneration. Deficiency in PHOX subunits mitigates neuronal damage induced by diverse insults/stresses relevant to neurodegenerative diseases. More importantly, suppression of PHOX activity correlates with reduced neuronal impairment in models of neurodegenerative diseases. The discovery of PHOX and non-phagocyte NADPH oxidases in astroglia and neurons further reinforces the crucial role of NADPH oxidases in oxidative stress-mediated chronic neurodegeneration. Thus, proper modulation of NADPH oxidase activity might hold therapeutic potential for currently incurable neurodegenerative diseases.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Animals
  • Antioxidants / pharmacology
  • Antioxidants / therapeutic use
  • Astrocytes / enzymology
  • Drug Discovery / trends
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • Humans
  • Membrane Glycoproteins / antagonists & inhibitors*
  • Membrane Glycoproteins / metabolism
  • Mice
  • NADPH Oxidase 2
  • NADPH Oxidases / antagonists & inhibitors*
  • NADPH Oxidases / metabolism
  • Neurons / enzymology
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use
  • Oxidative Stress / drug effects*
  • Parkinson Disease / drug therapy*
  • Parkinson Disease / enzymology
  • Phagocytes / enzymology
  • Reactive Oxygen Species / antagonists & inhibitors
  • Reactive Oxygen Species / metabolism
  • Superoxides / metabolism

Substances

  • Antioxidants
  • Enzyme Inhibitors
  • Membrane Glycoproteins
  • Neuroprotective Agents
  • Reactive Oxygen Species
  • Superoxides
  • CYBB protein, human
  • NADPH Oxidase 2
  • NADPH Oxidases