"Free CRF" may sound like the shouted mantra of someangry street demonstration. In fact, it describes a trendyneuropeptide, corticotrophin releasing factor (CRF), in itsunbound state _ free of its binding protein and receptor.
What makes the 41-amino-acid CRF so topical is itsrecently revealed connection to Alzheimer's disease.Thus, at the ongoing 25th annual meeting of the Societyfor Neuroscience, in San Diego, fully 46 paper and posterentries dealt with CRF. At last year's 24th annualmeeting, the CRF score was only 30.
Neuropharmacologist Errol DeSouza co-authored six ofthose 46 abstracts. DeSouza is founder and executive vicepresident for research and development of NeurocrineBioSciences Inc., of San Diego. He told BioWorld Today:"If you look at a normal CRF neuron, it has a beadedappearance with extensions, very typical of a neuronalstructure. If you look at the same kind of staining in apatient who died of Alzheimer's disease, it appears as aglob."
He continued: "Does this CRF glob have any associationwith any of Alzheimer's disease's landmarks? Whatwe've shown is that indeed the abnormal CRF fibersappear to be co-localized with Alzheimer's disease'samyloid plaques."
But the connection runs deeper than just microscopicpropinquity to Alzheimer's disease's telltale neuriticplaques. CRF apparently mediates the dementia's loss ofmemory. Besides those abnormal globs in affected brainareas, CRF content decreases dramatically in Alzheimer'sdisease patients, while CRF receptors increaseconcomitantly.
In their cerebrospinal fluid, CRF concentration varies indirect proportion to cognitive impairment.
DeSouza is senior author of a paper in today's Nature,which describes Neurocrine's recent findings in thisarena. Its title: "Displacement of corticotrophin releasingfactor from its binding protein as a possible treatment forAlzheimer's disease."
"In this paper," DeSouza said, "we were the first ones toshow that CRF exists in two different forms. People haveonly thought," he explained, "about one form of CRF,which has all been in the free state. They've never lookedat a form that's bound to CRF binding protein and a formthat's free. This concept is totally new."
He explained: "We've been able to modulate thatneurotransmitter in brain-specific areas that are involvedin cognitive processes, but not change them in other areasthat are involved in emotional or stress responses."
Neurocrine has developed, and is now testing in animals,a series of small-molecule ligands that can compete withCRF binding protein, which inactivates it, and thusmaintain the neuron's bioactivity, notably in preventingmemory-loss.
"The Nature paper," DeSouza said, "shows primarilywhat we can do with these compounds in normal rats thatare being asked to learn different tasks _ do they learnbetter? remember better? _ those kinds of components.
"What's not in the Nature article," he added, "is thatwe've subsequently repeated these trials with agedanimals, which just in their natural state show memorydeficits in these tasks. We show that we can reverse thesedeficits with these compounds, to the point where theyperform like young animals."
To be sure, native free CRF, infused into the brains ofrats, can improve their learning and memory scores. But,as the paper describes, its receptor agonist also increasestheir stress anxiety _ as evinced by the dose-dependentsuppression of their urge to explore a maze. That's onereason the peptide isn't under consideration as a potentialtherapeutic agent. "Clearly," DeSouza observed, "thosearen't going to be drug targets, because they don't crossthe blood-brain barrier, and they're not orally bioactive."
Neurocrine's chemically synthesized analogs, in the 500-molecular-weight range, are both.
"What we have done," he said, "is screen our library of40,000-plus chemical compounds, and optimized themost promising leads to a point where we have very high-affinity small molecules in our animal models."
He added, "Now we have to aggressively make sure thatwe find the right compound in this series, which has theright duration of action and optimal bioavailability. Ipredict that's going to take another six months. Then wewill do some of the preliminary toxicology studies thatwill make us comfortable in terms of nominating acandidate for human development in the foreseeablefuture, meaning 1996.
"And that," he predicted, "means Phase I clinical trials in1997."
That's not all. Neurocrine's prospective drug treatmentfor symptomatically treating memory deficits inAlzheimer's patients is only the half of it.
"The other aspect," DeSouza pointed out, "is that obesityis also associated with low levels of CRF. Others haveshown," he continued, "that if you give CRF to obeseanimals, you can attenuate their weight gain prettydrastically. The problem again is that you can't use a CRFagonist peptide as a human therapy. Our binding-proteinblockers will achieve essentially the same thing." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.