Development of a model for Parkinson's disease in sheep using unilateral intracarotid injection of MPTP via slow continuous infusion

David S. Baskin, Jeffrey L. Browning, Marsha A. Widmayer, Zhen Qing Zhu, Robert G. Grossman

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

The effects of unilateral intracarotid administration of MPTP (1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine) in sheep were studied with the goal of producing a non-primate, large animal model of Parkinson's Disease. Adult female sheep were given an acute (over 30 min) of chronic (over 1 week) injection of MPTP (0.4-5.0 mg/kg) via the common carotid artery. Both methods produced parkinsonian-like behavior. Turning contralateral to the side of injection was induced by apomorphine (APO) in both groups. However, amphetamine (AMP) induced ipsilateral turning only in the chronic treatment group. Acute and chronic MPTP treatment resulted in a loss of substantia nigra tyrosine hydroxylase immunoreactive (THIR) neurons with a significantly greater loss ipsilateral to the injection in each treatment group (acute p<0.05; chronic p<0.01)). Caudate dopamine (DA) was depleted in both treatment groups, although the difference between ipsilateral and contralateral DA content was significant only in the chronic treatment group (p<0.05). The best results were seen in those animals with chronic infusion with the occipital artery occipital artery occluded to prevent entry of drug into the posterior circulation with subsequent bilateral distribution. Use of slow and continuous intracarotid administration of MPTP with the ipsilateral occipital artery occluded can prevent some of the bilateral effects of accute treatment, and results in statistically significant ipsilateral reduction of THIR neurons in the substantia nigra and reduction of tissue levels of DA in the caudate nucleus. Such treatment produces appropriate turning responses to both AMP and APO challenge not seen in the accute treatment group, and appears to be an effective method of producing parkinsonian-like behavior in a large animal.

Original languageEnglish (US)
Pages (from-to)471-479
Number of pages9
JournalLife sciences
Volume54
Issue number7
DOIs
StatePublished - Jan 1 1994

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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