By David N. Leff

Anyone in search of a warm, cuddly pet for the kids might do well to check out the Mongolian gerbil (Meriones unguiculatus). This hamster-size black or brown rodent has large eyes, big ears and a long hairy tail, tufted at the tip - the better for balance when it jumps.

Gerbils have long been a favorite in pet stores, and even longer in research laboratories. French neuropharmacologist Pierre-Etienne Chabrier, who studies stroke, observed of the gerbil: "In a global cerebral ischemia, it's a preferred animal model. These are particular rodents, which possess a unique cerebral circulation. If you occlude a gerbil's two carotid arteries, you completely block its brain's blood supply.

"In contrast," he added, "take rats for example. When you occlude both of their carotids you have what we call collateral blood vessels, which can allow some blood to come into the brain." In the brain's elaborate network of vessels nourishing it with blood, the vessels most often involved in ischemia are those paired carotids and the middle cerebral artery.

Cerebral ischemia is the third most common cause of death in Western countries. Of victims hospitalized with stroke, 20 percent do not leave alive.

When neurons in the brain suddenly find their blood supply cut off, the event triggers a cascade of dire molecules, of which the most prominent are nitric oxide synthase (NOS) and reactive oxygen species (ROS). Neurologists have long sought to scavenge these oxygen-free-radical marauders with inhibitors aimed at NOS (the NO-generating enzyme) and ROS. Both are heavily implicated in neuronal death from glutamate-provoked cellular cytotoxicity.

However, shooting their antioxidants at those two targets of opportunity have netted the therapists disappointing results. For example, most such anti-ischemic drugs that scored poorly in clinical studies failed to protect against middle cerebral occlusion, when treatment started after the stroke episode occurred.

To Strike Stroke, Make Two Ends Meet

Chabrier, who is head of biology at the Paris-based Beaufour-Ipsen Research Laboratories, recalled how he tackled this therapeutic dead end: "The experiments we conducted used the classical model of transient focal ischemia in rodents. What we observed at that time," he recounted, "was that if we administered an antioxidant alone, we could see some neuroprotection. And then when we gave NOS alone, it too achieved a degree of neuroprotection."

Our basic idea was to combine in the same molecule those two activities, each of which is neuroprotective by itself. This led to the discovery we made about three years ago showing that antioxidant agents and inhibitors of NOS were working synergistically to protect the brain against neuronal death.

"From these observations," Chabrier went on, we decided to synthesize new molecules - new chemical entities - by linking the two activities, antioxidant and NOS, in the same compound. In fact, we screened quite a number of these molecules and the first lead drug from our screening model we named BN 80933."

Chabrier is lead author of a report in today's Proceedings of the National Academy of Sciences (PNAS), dated Sept. 14, 1999. Its title is, "BN 80933, a dual inhibitor of neuronal nitric oxide synthase and lipid peroxidation: A promising neuroprotective strategy."

Drug Worked In Rodents On All Three Ischemias

He explained to BioWorld Today that the patent-pending, proprietary compound's "BN" acronym combines the first and last letters of his company's name - Beaufour-Ipsen. As reported in PNAS, Chabrier and his co-authors tested their candidate drug in three experimental types of stroke - transient, global and traumatic.

First, in anesthetized rats, they occluded the left middle cerebral artery for two hours, an ischemic treatment that produces infarction - brain necrosis - in the area starved of blood. Then, to assess the time-interval therapeutic window, the team administered five doses of BN 80933 over the 24 hours following the arterial blockage. As assessed seven days later, their PNAS paper reported, "[The drug] afforded a significant (62 percent protection) and long-lasting reduction of the infarct volume."

In anesthetized gerbils, they pinched shut both carotid arteries for five minutes. Then, after blood flow resumed, the co-authors injected the rodents intravenously with four staggered doses of BN 80933 over 48 hours. A week later, the animals were sacrificed and hippocampal sections of their brains analyzed. "In this model of global ischemia," the team noted, "BN 80933 offered histological improvement as seen by decreasing hippocampal damage."

To simulate a traumatic brain injury, they dealt the mice a blow on the head from a falling 50-gram weight, then injected them with the drug. "In this contusion brain trauma model," the paper reported, "[BN 80933] elicited behavioral improvement."

"In these different in vivo models of ischemia," Chabrier pointed out, "we found some neuroprotective activity when the compound is administered after the beginning of the ischemia. The overall results suggest that this kind of strategy to protect neurons could be useful in humans also, because instead of blocking only one event during stroke we block two events, which appear simultaneously.

"We may expect to start initial Phase I administration of BN 80933 in human patients," he said, "probably at the beginning of next year." As for the drug's possible application to neurodegenerative diseases, such as Alzheimer's or Parkinson's, for example, Chabrier pointed out "the pharmacological mechanism would be similar. There are some data in the literature showing that neuronal death may occur in the same way in these diseases. But that is speculative." He and his associates are planning to do preclinical testing of animal models for such disorders "probably with some different groups, maybe outside the company."

Neurologist Valina Dawson, of Johns Hopkins School of Medicine in Baltimore, wrote a commentary on Chabrier's paper in PNAS, which concluded: "[His] strategy could be exploited to the advantage of pharmaceutical companies and most importantly to the benefit of patients."