Ampakines and HD

HD Lighthouse Contributing Editor's Comment:

A recent press release announced a discovery about a class of drugs known as ampakines that could be important to HD. The discovery pertains to the reversal of age related memory decline, which is of importance to HD. However, ampakines have additional properties that, along with the recent discovery, may make them well suited to treating HD. Ampakines are not yet available on the market, but one company, Cortex Pharmaeuticals, whose scientists were co-authors on the paper referred to in the press release, are shepherding the drugs through the stringent FDA drug-approval process. Hence, ampakines may become a treatment for HD in the next few years.

The details of the discovery are contained in Rex, et al., 2006, whose abstract is reprinted below along with the press release.

Amapkines have been pioneered by Dr. Gary Lynch, the principal investigator of the lab in which I work, at the University of California, Irvine (UCI), and by his colleagues, in particular Dr. Christine Gall, and by scientists at Cortex Phamaceuticals. It is now well-established that ampakines enhance attention span and alertness. They are therefore being studied for their potential benefit in a variety of neurodegenerative and psychiatric disorders.

Ampakines obtain their properties from their propensity to bind to a particular type of receptor in the brain known as AMPA receptors - hence the name ampakines. Receptors are proteins on the surface of neurons that control the inner workings of these cells. Receptors are activated by other proteins known as neurotransmitters. In the case of AMPA receptors the activating neurotransmitter is glutamate, and ampakines facilitate this activation, making it more powerful.

Ampakines have been shown to enhance a property of neurons called Long Term Potentiation (LTP). LTP occurs when electrical stimulation is applied in just the right way to neurons, causing them to change their electrical properties for minutes, hours or longer. Many believe that LTP is a major component in memory itself.

By enhacing LTP, it is therefore not too surprising that ampakines improve memory. What came as a surprise was the modest side-effect profile of these drugs. Furthermore, and of particular interest to us, is that some ampakines increase levels of the important trophic factor Brain Derived Neurotrophic Factor (BDNF). Trophic factors are molecules that provide support or nutrition for neurons, and BDNF is among the more important of these.

It has been known for some years (Zuccato, et al., 2001) that huntingtin, the protein whose mutation is responsible for HD, controls the production of BDNF, and that when huntingtin is abnormal, this production is reduced. Consequently, by improving memory through the modulation of glutamatergic transmission and up-regulating BDNF, ampakines may have a double impact in HD, causing improved cognition and reducing neurodegeneration. The HDlighthouse will therefore keep an eye on development of ampakines as they pertain to HD and post news as soon as it is available.

More information on Cortex pharmaceuticals can be obtained at:
http://www.cortexpharm.com/main.html

The web-site contains the full text of the paper by Rex, et al., 2006, that resulted in the above-mentioned press release.

Excellent introductions to ampakines and LTP can be found on Wikipedia at:
http://en.wikipedia.org/wiki/Ampakine
http://en.wikipedia.org/wiki/Long-term_potentiation

-- Malcolm Casale, Ph.D.

REFERENCES:

Lynch G, Gall CM. Ampakines and the threefold path to cognitive enhancement. Trends Neurosci. 2006 Aug 4;

Zuccato C, Ciammola A, Rigamonti D, Leavitt BR, Goffredo D, Conti L, MacDonald ME, Friedlander RM, Silani V, Hayden MR, Timmusk T, Sipione S, Cattaneo E. Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease. Science. 2001 Jul 20;293(5529):493-8. Epub 2001 Jun 14.
Posted to the HDL: 09 Sep 2006

Irvine, CA (August 2, 2006) - In the August 2006 issue of Journal of Neurophysiology, Drs. Christine Gall and Gary Lynch and their research staff reported that it was possible to use AMPAKINE compounds to reverse age-related declines in cognitive functions in old rats, returning their cognitive ability to that seen in young rats. The authors attributed this effect to the ability of AMPAKINE drugs to increase endogenous BDNF (brain-derived neurotrophic factor) in the neurons in the brains of older rats. The study used two of Cortex's high impact AMPAKINE drugs that are in preclinical development testing at the company. When an antagonist to BDNF was co-administered with the AMPAKINE compounds, the older rats returned to age-related cognitive impairment level.

Dr. Gall said, “This is a significant discovery because these results indicate the exciting possibility that AMPAKINE compounds could be used to treat learning and memory loss associated with normal aging.”

Cortex is developing both high and low impact AMPAKINE drugs that bind at different sites on the AMPA-receptor of neurons. The high impact compounds under development are orally active and therefore the up-regulation of BDNF with these drugs is a significant finding not only for restoring memory declines as a result of aging, but also for other neurodegenerative diseases such as Huntington's Disease, Fragile X, Parkinson's and Alzheimer's disease, where elevation of BDNF may produce disease modifying effects in the patient populations.

The Abstract

Restoration of neuronal viability and synaptic plasticity through increased trophic support is widely regarded as a potential therapy for the cognitive declines that characterize aging. Previous studies have shown that in the hippocampal CA1 basal dendritic field deficits in the stabilization of long-term potentiation (LTP) are evident by middle age. The present study tested whether increasing endogenous brain-derived neurotrophic factor (BDNF) could reverse this age-related change. We report here that in middle-aged (8- to 10-mo-old) rats, in vivo treatments with a positive AMPA-type glutamate receptor modulator both increase BDNF protein levels in the cortical telencephalon and restore stabilization of basal dendritic LTP as assessed in acute hippocampal slices 18 h after the last drug treatment. These effects were not attributed to enhanced synaptic transmission or to facilitation of burst responses used to induce LTP. Increasing extracellular levels of BDNF by exogenous application to slices of middle-aged rats was also sufficient to rescue the stabilization of basal dendritic LTP. Finally, otherwise stable LTP in ampakine-treated middle-aged rats can be eliminated by infusion of the extracellular BDNF scavenger TrkB-Fc. Together these results indicate that increases in endogenous BDNF signaling can offset deficits in the postinduction processes that stabilize LTP.

Source: J Neurophysiol. 2006 Aug;96(2):677-85.

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