What do the brain, the gut and the male sexual organ have incommon? The answer: VIP, or vasoactive peptide, which was firstfound in the intestines of mammals.
"There it causes gastric motility," said clinical biochemist IllanaGozes, "and too much VIP can bring on diarrhea."
It turned out that VIP's main function is to dilate blood vessels,everywhere in the body, not just in the gut. In the brain, Gozes toldBioWorld Today, "it's probably a neurotransmitter orneuromodulator, associated with energy formation." VIP messengerRNA decreases markedly in the cerebral cortex of aging mammals,including humans.
At present a Fogarty scholar-in-residence at the National Institute ofChild Health and Human Development (NICHD), Gozes is on thefaculty of Israel's Tel Aviv University. There at the Sackler School ofMedicine, she and organic chemist Mati Fridkin at the WeizmannInstitute of Science, in Rehovot, developed a lipophilic analogue ofVIP.
"We developed this molecule as a peptide that goes through skin,"Gozes said. Meanwhile, at the NICHD laboratory of developmentalneurobiology," she continued, "neuroscientist Douglas Brennemanhad discovered that VIP is a neuronal protective factor. That is, moreaccurately, it promotes neuronal survival via the brain's glial cells."
"It was natural for us to collaborate on that, and see if our lipophilicanalogue will also protect neurons from cell death _ which they do100-fold more potently than native VIP," Gozes said.
The Israeli analogue, she explained, "is stabler than VIP, because inplace of methionine we inserted a norleucine, so it's not prone tooxidation. And it has a lipophilic [fat-loving] moiety attached to themolecule's N-terminal, which makes it more lipophilic."
These enhancements, Gozes pointed out, "enable it to crossmembranes, maybe the membrane bilayers, and perhaps the blood-brain barrier also." She and her co-workers in Israel have developeda version of their molecule for intranasal administration. "A part ofour Alzheimer's disease study," Gozes added, "is licensed to acompany for use in the Far East only."
Gozes, Fridkin and Brenneman are the principal co-authors of apaper in the current Proceedings of the National Academy ofSciences (PNAS), dated Jan. 9, 1996. Its title: "Neuroprotectivestrategy for Alzheimer's disease: Intranasal administration of a fattyneuropeptide."
Cerebral amyloid plaque is a smoking molecular gun in theAlzheimer brain, and beta-amyloid peptide is a major neurotoxiccomponent of that plaque. In their PNAS-reported experiments, ratbrain tissues dosed with beta-amyloid peptide lost 70 percent of theirneurons. "This cell death," the paper stated, "was completelyprevented by co-treatment with the analogue of VIP."
Rats Model Neuronal Destruction, Survival
Acetylcholine is a neurotransmitter implicated in the loss of memoryand cognitive function in Alzheimer's patients. When this substanceis chemically blocked in rat brains, the animals become to someextent laboratory models of Alzheimer's disease cognition.
"In Israel," Gozes said, "we adapted our analogue to a version moreappropriate for studying Alzheimer's disease in vivo in a cholinergicdeficiency animal model."
When Gozes and her co-authors insufflated their VIP analogue intothe nostrils of such Alzheimer's disease-surrogate rats, "the treatmentprevented impairments in spatial learning and memory associatedwith cholinergic blockade."
Gozes surmises that her analogue works "by inhibiting the first steptoward the deterioration of the neuron. That's fantasy of course," sheadded, "but it is a beginning."
She perceives the improved peptide, "or a derivative of this moleculethat is even more stable, smaller and can certainly go into the brain,"as a potential therapeutic.
As for what causes the initial deterioration of neuronal cells inAlzheimer's, leading to cell death, Gozes observed that "We are juststarting to investigate this. I guess that originally there is a loss ofenzymatic activity in the cell, and then breakdown of DNA."
Impotence Trials Now, Alzheimer's Later
She and her group are also "trying to map the core side of themolecule that is responsible for VIP's protective activity." Sheadded, "We are not yet ready for human trials in Alzheimer'spatients."
Male impotence is another matter. "Our VIP analogue," she said,"causes penile erection in rats. Now we are going to go to clinicaltrials." This application, developed jointly by Gozes and Fridkin,depends on the molecule's two main properties: ability to permeatethe skin, and vasodilation to pump circulating blood to the scene.
Hence, treatment of impotent patients will be topical. "The basis ofthe technology," Gozes said, "is already licensed out to companies[which Gozes declined to name]." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.