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Vol. 293, Issue 2, 607-617, May 2000
Neuropharmacology Section, Laboratory of Pharmacology and
Chemistry, National Institute of Environmental Health Sciences,
Research Triangle Park, North Carolina
Degeneration of dopaminergicrgic neurons in the substantia nigra of the
brain is a hallmark of Parkinson's disease and inflammation and
oxidative stress are closely associated with the pathogenesis of
degenerative neurological disorders. Treatment of rat mesencephalic mixed neuron-glia cultures with lipopolysaccharide (LPS)-activated microglia, resident immune cells of the brain, to release
proinflammatory and neurotoxic factors tumor necrosis factor-
,
interleukin-1
, nitric oxide, and superoxide and subsequently caused
damage to midbrain neurons, including dopaminergic neurons. The
LPS-induced degeneration of the midbrain neurons was significantly
reduced by cotreatment with naloxone, an opioid receptor antagonist.
This study focused on understanding the mechanism of action for the protective effect of naloxone on dopaminergic neurons because of
relevance to Parkinson's disease. Both naloxone and its opioid receptor inactive stereoisomer (+)-naloxone protected the dopaminergic neurons with equal potency. Naloxone inhibited LPS-induced activation of microglia and release of proinflammatory factors, and inhibition of
microglia generation of superoxide free radical best correlated with
the neuroprotective effect of naloxone isomers. To further delineate
the site of action, naloxone was found to partially inhibit the binding
of [3H]LPS to cell membranes, whereas it failed to
prevent damage to dopaminergic neurons by peroxynitrite, a product of
nitric oxide and superoxide. These results suggest that naloxone at
least in part interferes with the binding of LPS to cell membranes to
inhibit microglia activation and protect dopaminergic neurons as well as other neurons in the midbrain cultures from inflammatory damage.
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