6-hydroxydopamine injections into the nigrostriatal pathway attenuate striatal malonate and 3-nitropropionic acid lesions

William F. Maragos, Rebekah J. Jakel, Zhen Pang, James W. Geddes

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

Abstract

The mitochondrial inhibitors malonate and 3-nitropropionic (3NP) acid are potent neurotoxins in vivo. Administration of these compounds results in neuronal loss similar to that seen in Huntington's disease. Although the mechanism of cell death produced by these compounds likely involves activation of N-methyl-D-aspartate receptors, it remains unclear why the striatum demonstrates regional susceptibility to the toxicity of these and other mitochondrial poisons. We hypothesized that dopamine, a weak neurotoxin that occurs in high concentrations in the striatum, may contribute to the neuronal damage caused by mitochondrial inhibition. We investigated whether depletion of striatal dopamine using the catecholaminergic toxin 6- hydroxydopamine would attenuate lesions induced by mitochondrial inhibition. We found that dopamine depletion reduced significantly the extent of histological damage in the striatum elicited by both intraparenchymal injections of 0.8 μmol malonate and 20 mg/kg systemic administration of 3NP. These data suggest that dopamine or one of its metabolites may contribute to mitochondrial toxin-induced cell death.

Original languageEnglish
Pages (from-to)637-644
Number of pages8
JournalExperimental Neurology
Volume154
Issue number2
DOIs
StatePublished - Dec 1998

Bibliographical note

Funding Information:
The authors wish to thank Drs. Celia M. Kearns and Don M. Gash for their assistance with 6OHDA lesions and Drs. Joe E. Springer and Wayne A. Cass for critically reviewing the manuscript. This work was supported by NIH Grant K08-NS01941-01 to W.F.M.

Keywords

  • 3NP
  • Dopamine
  • Excitotoxicity
  • Malonate
  • Mitochondria
  • Striatum

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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