Like a prudent poker player, who buys in for only as many chips ashe's prepared to lose, the human brain starts life with all the neuronsit will ever have.

As advancing age takes a hand, the brain begins gradually to losemore and more of those irreplaceable nerve cells. Among them, thedopaminergic neurons are big-time players. Dopamine is a majorneurotransmitter, crucially involved in controlling bodily movementand emotion.

As the particular cells that secrete this key cerebral chemical growfewer and weaker in the aging brain, the amount of dopamine theysecrete diminishes. This is nature's way of telling an affectedindividual to slow down _ literally: A dearth of dopamine showsitself in bradykinesia, the slowing of movement.

With this early sign of Parkinson's disease (PD) come othersymptoms: rigidity, unstable posture, shuffling gait, shaky balance,tremor _ trembling of the extremities.

PD probably occurs worldwide, but it's most closely studied inEurope and North America. Among Caucasians, best guesses have itoccurring in 84 to 187 per 100,000. So a recent epidemiologicalguesstimate suggests that in the U.S., Canada and Mexico, at least amillion persons are afflicted with PD.

Unlike such chronic replacement therapies as insulin, dopamine doesnot cross the blood-brain barrier, so it can't be administeredtherapeutically. But a precursor of dopamine, levodopa, does pass thebarrier, and is the most popular treatment for PD.

`There Must Be a Better Way,' Scientists Say

Levodopa comes in tablet form, and patients swallow several a day.But this drug produces a wide spectrum of unpleasant to life-threatening side effects, from nausea to wild, uncontrollablemovements of the body.

Hence, the ongoing quest for better remedies. Fetal brain cellsinjected through the skull are one experimental method. (SeeBioWorld Today, Feb. 7, 1994, p. 1.)

A less draconian, and possibly more effective, variation on this themeis a subtle molecule called glial-cell-line-derived neurotrophic factor(GDNF).

"GDNF is present in embryonic development," said neuroscientistDon Gash. "It occurs in the brain's striatum, which is the target sitefor dopamine neurons. GDNF levels in adult life," he told BioWorldToday, "appear to go down to where they are barely detectable. So itis thought to be an important trophic factor in development of thedopaminergic system."

Amgen Inc., of Thousand Oaks, Calif., inherited a dominant patentposition covering recombinant GDNF when it acquired SynergenInc., of Boulder, Colo. (See BioWorld Today, Nov. 21, 1994, p. 1.)The company's vice president of neuroendocrinology, Frank Collins,discovered the factor.

Amgen will conduct Phase I human trials of GDNF this year fortreating PD patients, its spokesperson, David Kaye, told BioWorld."We will replicate in humans what Don Gash did in monkeys," hesaid.

Gash chairs the department of anatomy and neurobiology at theUniversity of Kentucky Medical Center in Lexington. He is firstauthor of a paper in today's Nature titled: "Functional recovery inparkinsonian monkeys treated with GDNF." Several Amgenscientists, including Collins, are among the co-authors.

From Rodents To Primates Is A Stretch

GDNF has been widely tried in PD-simulating mice and rats, Gashsaid, "but little is known of its effects in animal models closer to thehuman condition, namely, primates. We have a colony of over 50rhesus monkeys," he said, "which we are now using in preclinicaltrials."

The experiments reported in Nature injected recombinant GDNF intothe right lateral brain ventricles of half a dozen female rhesusmonkeys, and saline solution into an equal number of controls. Allthese animals had been turned into working models of PD by aneurotoxin that destroyed most of the dopaminergic neurons in one-half of their brains.

In reducing PD-like behavior, Gash said, "Our animals responded abit better to GDNF than we see with levodopa, which is the gold-standard treatment for PD in humans. The time course," hecontinued, "was truly dramatic. Patients take levodopa orally everythree or four hours. In contrast, one injection of GDNF was effectivefor at least four weeks. And the only side effect was some weightloss, regained by the end of the four-week test period."

Measuring dopaminergic recovery in the primates' brains, the teamfound that "In several of the key areas of the cerebral circuitry thatregulate motor movements, the dopamine level had doubled."

From this Gash concluded that "the neurochemistry is consistent withbehavioral improvements."

"Looking at anatomical changes," he went on, "we found that we hadrestored neuronal cell size. Moreover, the axonal and dendritic nerveprocesses by which the dopaminergic neurons communicate with thetarget areas, were far more abundant."

Now, Gash's group is "trying to determine what the GDNF doseresponse is in simians." Also, from ongoing rat studies, it is findingthat the factor has protective as well as restorative effects ondopamine neurons. "In the rat models we're using," Gash said,"we're able to prevent something like 50 percent of cell death inneurons that would normally die following exposure to theneurotoxin."

He added, "We don't have any evidence that we're stimulating newcells to develop."

Amgen's impending human trial will administer repetitive doses ofGDNF via a fixed device implanted through the skull, Kaye said,adding, "It is our plan to develop GDNF on a parallel track for bothParkinson's disease and amyotrophic lateral sclerosis." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.