12 October 2012

Going On the Offensive Against Dementia

This article is re-posted from the Al Fin Longevity blog

Rather than fighting a rear-guard action against advancing dementia, some researchers are taking an offensive approach -- a "procognitive" approach. This means that instead of trying to slow down the inevitable decline of dementia, these researchers aim to rebuild brain tissues and brain function. They aim to push back against the decline and reverse it.
Scientists have developed a small peptide that they say can reverse some of the cognitive repercussions of neurodegenerative and potentially trauma-related brain disorders such as Alzheimer’s disease, by increasing synaptogenesis. The peptide, called dihexa, is a stabilized derivative of angiotensin IV (AngIV)...

...Washington State University’s Joseph W. Harding, Ph.D., Alene T. McCoy, Ph.D., and colleagues based their development on prior work demonstrating that the three terminal amino acids of AngIV and its analog Norleucine1-angiotensin IV (Nle1-AngIV) are central to the precognitive activities of the peptides. The team thus set out to develop much smaller, more stable derivatives of Nle1-AngIV that retained the active structure but could be administered orally and cross the blood-brain barrier.

The resulting lead compound, dihexia (N-hexanoic-Tyr-Ile-(6) aminohexanoic amide) not only fulfilled these requirements, but proved to be active at picomolar concentrations, and led to dramatic improvements in the cognitive abilities of a scopolamine-treated rat model of learning deficits, and also aged Sprague-Dawley rats.

Importantly, the treatment was effective whether the animals received it directly into the brain, via injection, or orally. Further analyses indicated that dihexia’s precognitive activity was associated with a drug-induced stimulation of dendritic spinogenesis in the hippocampal brain region, and that the newly formed dendritic spins were creating functional synapses. Encouragingly, dihexia was even more potent than brain-derived neurotrophic factor (BDNF), a growth-promoting protein that is used to create neuronal connections, but which hasn’t yet been developed for therapeutic use.

“At its core dementia results from a combination of diminished synaptic connectivity among neurons and neuronal death in the entorhinal cortex, hippocampus, and neocortex,” the researchers note in their published paper in the Journal of Pharmacology and Experimental Therapeutics. However, previous attempts to develop protein neurotrophic factors as therapeutics has been limited by their inability to cross the blood-brain barrier, and the need to manufacture such agents by recombinant methods, which is costly. “The development of dihexa has seemingly overcome these impediments by virtue of its oral activity, demonstrated pro-cognitive/anti-dementia activity, and anticipated low manufacturing costs.” _Gen Engineering News

Another interesting candidate for procognitive therapy is ABT-288, an H3 receptor antagonist.

Another very interesting class of procognitive drugs is the Ampakines. Ampakine CX546 is a recent drug candidate undergoing study.

Here are two different approaches to procognition in the context of developing novel anti-psychotic drugs:

Egis 11150 which has broad spectrum adrenergic, serotenergic, and dopaminergic antagonist activity
New anti-psychotics with 5HT2C receptor agonist and 5HT6 receptor antagonist activity

It is important for neuropharmacologists to take this fateful step, of taking the offensive in the fight against dementia. Repairing and rebuilding the damaged tissues in the brain will likely get better results than a piecemeal promotion of this neurotransmitter, or combating this protein or another. A procognitive approach holds out the possibility of a return to normal function, rather than a mere slowing of inevitable decline.

The technology of the early diagnosis of future dementia is advancing on multiple fronts, from better brain scanners to genetic testing to two recent interesting developments:

Virtual Reality Functional Capacity Assessment Tool (VRFCAT). Not only does VRFCAT promise to provide early diagnosis of cognitive problems, but it should also prove useful for monitoring of different therapeutic regimens.

New mathematical approaches to model the brain as a complex network of interconnected processing nodes Such mathematical modeling approaches should provide new ways of diagnosing normal vs. impaired brain network activity, as well as new ways to monitor effects of therapies on brain network function.

Eventually, what we will want from procognitive treatments, is for all of us to be able to become capable of clearer and deeper thought. For now, we will be happy to watch dementia sufferers coming back into themselves.

But once we see that beginning to happen, we are likely to want to "spread the wealth around" to include more and more people, maybe even ourselves.

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