By David N. Leff

It all began in Northern California nearly 20 years ago, when various heroin addicts tried shooting up a new, synthetic, illicit "designer heroin" to pamper their habit. Four of them promptly ended up hospitalized in San Jose's Santa Clara Valley Medical Center.

A paper in Science dated Feb. 25, 1983, told their story. Its title: "Chronic parkinsonism in humans due to a product of meperidine-analog synthesis." Its authors are neurologists at Stanford University. "All patients became symptomatic within a week after starting to use the new drug," they reported. These manifestations ranged from visual hallucinations to jerking limbs, near immobility, a fixed stare, constant drooling and cogwheel rigidity of the upper extremities - all characteristic of Parkinson's disease (PD).

Treatment with L-dopa, the drug of choice for PD therapy, abated their symptoms temporarily -which in itself confirmed a diagnosis of classical PD. And like this neurodegenerative ailment of the aged, it proved irreversible in these prime-of-life heroin addicts. "Five months after onset," the paper noted, "none of these patients have shown signs of remission."

Some chemical detective work by the Stanford neurologists revealed that the clandestine laboratory that formulated and supplied this heroin-simulating "designer drug" had goofed - contaminating their concoction with "virtually pure MPTP." That acronym stands for "1-methyl-4-phenyl-1,2,5,6-tetrahydro-pyridine," a commercially available chemical intermediate. The two-decades-old Science article concluded presciently, "Given . . . the relative purity of the clinical syndrome seen in our patients, and its remarkable clinical resemblance to Parkinson's disease, the drug may be of value in producing an animal model of PD." It did.

A New Model For The New Millennium

Now a swift segue to an article in the December 2000 issue of Nature Neuroscience, bearing the title: "Chronic systemic pesticide exposure reproduces features of Parkinson's disease." Its first author is neuroscientist Todd Sherer, a postdoctoral fellow in the neurology department at Emory University in Atlanta.

Sherer and his co-authors created an animal model that more faithfully mirrors the neurochemical and behavioral aspects of PD than the still-current surrogate mammals - mice or monkeys injected with MPTP. Instead they injected rats with rotenone, a natural plant substance, which reproduced PD in their motor neurons and physical symptoms.

Rotenone, extracted from a South American plant, Derris elliptica, is an insecticide - a key ingredient of flea powders, fly sprays and antibug dusting on vegetables. Veterinarians use it against mange; dermatologists to treat scabies and chiggers, agonizingly itchy mite-borne skin infestations.

Like many other pesticides, Rotenone inhibits the same mitochondrial enzyme - complex I - as does MPP⁺, the metabolite of MPTP. In the Emory team's rat model, that chronic, systemic exposure to low doses of rotenone resulted in Parkinson-like symptoms. "We gave the rote none intravenously to laboratory rats over one to four weeks," Sherer told BioWorld Today. "A percentage of those animals started to show features of PD that included degeneration of the dopaminergic pathway in the brain - the nigrostriatal pathway - and Lewy bodies, which are the pathological hallmarks of PD. They also showed some motor deficits and reduced bodily movements that resembled the disease. "In the brains of PD patients," he explained, "there are dopamine-secreting neurons from the substantia nigra that project to the striatum. And that is the pathway that is damaged, or degenerates, in the disease - in which dopamine steadily diminishes."

At another level, it's the mitochondrial organelles - the cell's energy source - in those neurons that control that disease process. "Mitochondria are in charge of making ATP - adenosine triphosphate," Sherer said. "It accomplishes that power transfer through a process known as oxidative phosphorylation, in which electrons are used to generate ATP. In the mitochondrial membrane, there are four complexes, which make up the electron transport chain. They pass electrons from complex I to complex II to III to IV. In that way, they create an electrical charge differential across the membrane that the enzyme ATP synthase uses to make ATP.

"The initial evidence for that," Sherer continued, "came from the original MPTP study. Researchers then investigated by what mechanism MPTP was having this effect. They found that MPTP is converted to a metabolite known as MPP⁺, an inhibitor of complex I - the electron transport gene that's first in line. This led to the hypothesis that perhaps an inhibition or dysfunction in complex I of the electron transport gene may result in a Parkinson-like syndrome. "So the searchers then went and actually looked in tissues from sporadic PD patients," he said, "and found that a majority of these people had decreased activity of complex I genes. So, using the results of their MPTP study, they were able to develop a link between complex I function, and PD in sporadic PD patients.

"The way mitochondria makes ATP," Sherer noted, "is through the electron transport genes. Complexes are passing electrons along from one complex to the next. As a natural byproduct of that process, when the electrons exit the mitochondria, they release free electrons - such as hydrogen peroxide, which is very reactive - looking to bind to other proteins. And when they do that, it damages them."

If It Works In Rats - Humans Next

Sherer and his co-authors note that "chronic, systemic inhibition of complex 1 by rotenone "causes nigrostriatal dopaminergic degeneration that is associated behaviorally with hypkinesis and rigidity. These results," it concludes, "indicate that chronic exposure to a common pesticide can reproduce the anatomical, neurochemical, behavioral and neuropathological features of PD."

The Emory team, Sherer said, "hopes to treat our animal models with various agents to see if we can block these effects. We're looking now at antioxidants, such as vitamin E. Another compound, which can enhance mitochondrial electron transport function, is coenzyme Q₁₀ to protect against the free radical production that would result from rotenone.

"Potentially if they work out in our rats, these remedies could be extrapolated to human patients," Sherer said. But he added a caveat: "We administered the rotenone to the rats intravenously, which is not how individuals would be exposed to this compound. So not everyone who has come in contact with rotenone should be panicking."