Rotenone reproduces Parkinson's features in rats

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Ranjita Betarbet, Todd Sherer, Gillian MacKenzie, Monica Garcia-Osuna, Alexander Panov and J. Timothy Greenamyre, Emory University.

What happened

Rats given the pesticide rotenone chronically and systemically showed highly selective degeneration of nigrostriatal dopamine neurons, with hypokinesia and rigidity, and fibrillar cytoplasmic inclusions in nigral neurons containing ubiquitin and alpha-synuclein. Nat Neurosci 3:1301–1306, December 2000. A 2009 paper from the same group says this intravenous or subcutaneous pump regimen typically produced nigrostriatal lesions in only about one-third of animals, with variable lesion size. Their improved intraperitoneal version (rotenone 2.75–3.0 mg/kg a day in Lewis rats) gave bradykinesia, postural instability or rigidity in all treated animals, a 45% loss of dopamine neurons in the substantia nigra and alpha-synuclein-positive aggregates.

Why it moved us toward a cure

It linked an environmental mitochondrial toxin (landmark 11) to alpha-synuclein pathology in one animal model, supporting the idea that Parkinson's can arise from toxic exposure plus alpha-synuclein misfolding. It gave a model for testing neuroprotective drugs, and unlike MPTP it produces inclusions.

Outcome

Advanced, with caveats. The model is variable, and the human relevance of pesticide exposure rests mainly on epidemiology (covered in a later batch).

Sources

• Betarbet et al., Nat Neurosci 2000, DOI 10.1038/81834, PMID 11100151 (abstract read via Europe PMC)
• Cannon et al., Neurobiol Dis 2009, DOI 10.1016/j.nbd.2009.01.016 (one-third lesion rate read in PMC2757935)
• Not yet verified: funders; sample sizes in the 2000 paper; how well the model reproduces human Parkinson's in other labs.