The rat rotenone model reproduces the abnormal pattern of central catecholamine metabolism found in Parkinson's disease

Regev Landau, Reut Halperin, Patti Sullivan, Zion Zibly, Avshalom Leibowitz, David S. Goldstein, Yehonatan Sharabi

Research output: Contribution to journalArticlepeer-review

Abstract

Recent reports indicate that Parkinson's disease (PD) involves specific functional abnormalities in residual neurons - decreased vesicular sequestration of cytoplasmic catecholamines via the vesicular monoamine transporter (VMAT) and decreased aldehyde dehydrogenase (ALDH) activity. This double hit builds up the autotoxic metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), the focus of the catecholaldehyde hypothesis for the pathogenesis of PD. An animal model is needed that reproduces this abnormal catecholamine neurochemical pattern. Adult rats received subcutaneous vehicle or the mitochondrial complex 1 inhibitor rotenone (2 mg/kg/day via a minipump) for 10 days. Locomotor activity was recorded, and striatal tissue sampled for catechol contents and catechol ratios that indicate the above abnormalities. Compared to vehicle, rotenone reduced locomotor activity (P=0.002), decreased tissue dopamine concentrations (P=0.00001), reduced indices of vesicular sequestration (3,4-dihydroxyphenylacetic acid (DOPAC)/dopamine) and ALDH activity (DOPAC/DOPAL) (P=0.0025, P=0.036), and increased DOPAL levels (P=0.04). The rat rotenone model involves functional abnormalities in catecholaminergic neurons that replicate the pattern found in PD putamen. These include a vesicular storage defect, decreased ALDH activity and DOPAL build-up. The rat rotenone model provides a suitable in vivo platform for studying the catecholaldehyde hypothesis.

Original languageEnglish
Article numberdmm049082
JournalDMM Disease Models and Mechanisms
Volume15
Issue number1
DOIs
StatePublished - Jan 2022

Keywords

  • Aldehyde dehydrogenase
  • Catechol
  • Catecholamine
  • DOPAL
  • Dopamine
  • Lewy body diseases
  • Norepinephrine
  • Parkinson's disease
  • Rotenone
  • Vesicular uptake

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