Systemic Exposure to Rotenone Produces Selective Nigral Degeneration (AAN 2000)

Subject: Systemic Exposure to Rotenone Produces Selective Nigral Degeneration (AAN 2000)

Date: 5/4/2000

A new model for Parkinson's disease may help explain how chronic, systemic exposure to environmental toxins can cause selective degeneration in the substantia nigra, according to Tim Greenamyre of Emory University School of Medicine. Greenamyre described his new model in a Plenary Session at the 52nd Annual Meeting of the American Academy of Neurology, in San Diego, California, 4 May 2000.

The model uses rotenone, a pesticide often used as an "organic" alternative to synthetic insecticides. Rotenone is a potent and specific inhibitor of mitochondrial complex I, part of the energy-harnessing machinery found in all cells. Unlike MPTP, which is also a complex I inhibitor, rotenone is not selective for dopaminergic neurons, since it does not require the dopamine transporter to gain access to the neuronal interior. Therefore, said Greenamyre, rotenone may offer a more widely applicable model of environmental toxin exposure than MPTP.

Despite systemic exposure, widespread uptake and uniform inhibition of complex I, however, rotenone induces selective cell death in the dopaminergic neurons of the substantia nigra, with relative sparing of other dopamine pathways. Degeneration begins in the nerve terminals in the striatum, and progresses toward the cell body, with cell death at least partly by apoptosis. Neurons contain pale inclusions that stain for ubiquitin and alpha-synuclein, which are "reminiscent" of Lewy bodies in PD, noted Greenamyre. Treated animals develop a progressive akinetic rigidity.

Greenamyre presented evidence that rotenone exposure potentiates the effects of oxidative stress, suggesting that the combination of the two may be required for cell death. This effect also suggests a mechanism by which a variety of other environmental toxins that inhibit complex I may also cause PD. Why nigral cells are particularly susceptible to this combination of insults remains to be determined.

"These studies demonstrate clearly that chronic pesticide exposure, while causing a systemic mitochondrial defect, can produce a highly selective degeneration of the nigrostriatal dopamine system," said Greenamyre. "Together, our results suggest that a systemic complex I defect, whether genetic or pesticide-induced, is sufficient to cause the clinical and pathological features of PD."

E-MOVE Editor: Richard Robinson, NASW, WE MOVE

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