Role of nitric oxide in inflammation-mediated neurodegeneration.
Increasing evidence has suggested that inflammation in the brain is closely associated with the pathogenesis of several degenerative neurologic disorders, including Parkinson's disease, Alzheimer's diseases, multiple sclerosis, amyotrophic lateral sclerosis, and AIDS dementia. The hallmark of brain inflammation is the activation of glial cells, especially that of microglia that produce a variety of proinflammatory and neurotoxic factors, including cytokines, fatty acid metabolites, free radicals--such as nitric oxide (NO) and superoxide. Excessive production of NO, as a consequence of nitric oxide synthase induction in activated glia, has been attributed to participate in neurodegeneration. Using primary mixed neuron-glia cultures and glia-enriched cultures prepared from embryonic rodent brain tissues, we have systemically studied the relationship between the production of NO and neurodegeneration in response to stimulation by the inflammagen lipopolysaccharide. This review summarizes our recent findings on the kinetics of NO generation, the relative contribution of microglia and astrocytes to NO accumulation, the relationship between NO production and neurodegeneration, and points of intervention along the pathways associated with NO generation to achieve neuroprotection. We also describe our results relating to the effect of several opioid-related agents on microglial activation and neuroprotection. Among these agents, the opioid receptor antagonist naloxone, especially its non-opioid enantiomer (+)-naloxone, promises to be of potential therapeutic value for the treatment of inflammation-related diseases.
Liu
Bin
B
Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, North Carolina 27710, USA. liu3@niehs.nih.gov
Gao
Hui-Ming
HM
Wang
Jiz-Yuh
JY
Jeohn
Gwang-Ho
GH
Cooper
Cynthia L
CL
Hong
Jau-Shyong
JS
D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D008070:Lipopolysaccharides / Q000378:metabolism; D009294:Narcotics / Q000378:metabolism; D009410:Nerve Degeneration; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*
D016207:Cytokines; D008070:Lipopolysaccharides; D009294:Narcotics; D009569:Nitric Oxide