Brain inflammation enhances 1-methyl-4-phenylpyridinium-evoked neurotoxicity in rats

Toxicol Appl Pharmacol. 2004 May 1;196(3):381-9. doi: 10.1016/j.taap.2003.12.022.


Experimental Parkinson's disease and Parkinson's disease in humans include a CNS inflammatory component that may contribute to the pathogenesis of the disease. CNS inflammation produces a loss in cytochrome P450 metabolism and may impair the brain's protection against neurotoxins. We have examined if preexisting inflammation in the brain could increase the toxicity of the dopaminergic toxin 1-methyl-4-phenylpyridinium (MPP(+)). Lipopolysaccharide (LPS, 25 microg) or saline (control) was injected into the left lateral cerebral ventricle. A single injection of MPP(+) into the median forebrain bundle followed 48 h later and produced a reduction in striatal dopamine content that was dose- and time-dependent. Two-days after 5 microg of MPP(+) was administered, a 90% decrease in striatal dopamine content was observed in saline- and LPS-pretreated rats. However, 4 and 7 days after 5 microg MPP(+) treatment, striatal dopamine recovered up to 70-80% of control values in saline-pretreated rats but remained depressed (80-90%) in rats treated with LPS. These results suggested that CNS inflammation might create an increased risk factor for drug-induced CNS toxicity or chemically mediated Parkinson's disease. The prolonged toxicity of MPP(+) may be due to a decrease in brain cytochrome P450 metabolism that occurs during inflammation. As a second objective for the study, we examined if the CNS lesion produced by MPP(+) altered cytochrome P450 metabolic activity in the liver, kidney, and lung. We have demonstrated a novel mechanism whereby the brain pathology produced by MPP(+) treatment contributes to a reduction in cytochrome P450 metabolism in the kidney but not the liver or lung. Therefore, a chemically evoked CNS disorder with a chronic inflammatory component might have major effects on the renal metabolism of drugs or endogenous substrates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / pharmacology*
  • 1-Methyl-4-phenylpyridinium / toxicity*
  • Animals
  • Brain / drug effects*
  • Brain / enzymology
  • Brain / metabolism
  • Cytochrome P-450 Enzyme System / metabolism*
  • Dopamine Agents / toxicity*
  • Inflammation / metabolism*
  • Kidney / enzymology
  • Lipopolysaccharides / toxicity
  • Liver / drug effects
  • Liver / enzymology
  • Lung / drug effects
  • Lung / enzymology
  • Male
  • Rats
  • Rats, Sprague-Dawley


  • Dopamine Agents
  • Lipopolysaccharides
  • Cytochrome P-450 Enzyme System
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • 1-Methyl-4-phenylpyridinium