HD Lighthouse Contributing Editor's Comment: As the drug pipeline moves from assays to animal models to clinical trials, it narrows. A drug which works in a cell model may not work in an animal model and a drug which works in an animal model may not help people with Huntington's Disease.

One set of drugs at the beginning of the pipeline are adenosine receptor antagonists. Recent assays suggest that adenosine receptor antagonists warrant preclinical testing to see if they help the HD mice and if so, should be considered for clinical trials. One such antagonist, KW-6002, has completed Phase III clinical trials for Parkingon's Disease and nears possible FDA approval as a treatment. As Lighthouse contributor Jim Tretheway recently reported, CHDI will be conducting further testing on KW-6002 in HD models to see if this drug might be helpful for Huntington's patients. (see HDL: 2007 Therapeutic Conference)

The authors of the study below suggest caution, however. In a review of the research literature, they show that adenosine receptors play a complex role in Huntington's Disease.

Adenosine is one of the building blocks of nucleic acid. It has a role in energy transfer and signal transduction (See Wikipedia: Adenosine ).

Adenosine's activities are mediated through its receptors which are widely distributed throughout the body. There are four types of receptors. The A(2A) receptor is the one of interest in Huntington's Disease research. These receptors are highly concentrated in the striatum, nucleus acumbens, and olfactory tubercules, and are also found in the cortex, hippocampus, and amygdala. Research shows that there is an aberrant amplification of A(2A) signaling in striatal cells in people with Huntington's Disease.

Interest in the neuroprotective aspects of A(2A) receptor antagonists stems from solid evidence that they prevent the extracellular glutamate outflow which appears to be a pathology in Huntington's Disease. This would be a pre-synaptic function.

On the post synaptic side, NMDA receptors are known to be abnormally activated in Huntington's Disease. This is the well supported excitotoxicity theory of HD pathology. The authors cite evidence to show that in this case, it is A(2A) receptor agonists, rather than antagonists which are neuroprotective.

Another major pathology in HD is mitochondrial dysfunction. These are the cells' energy factories. Toxin models are often used to mimic the effect of the HD protein on the mitochondria. A number of studies have found that A(2A) receptor antagonists appear to be neuroprotective in rats given these toxins. The authors, however, suggest that a closer look at a variety of studies reveals a more complicated picture. With one dose of a mitochondrial toxin, the antagonist appears to be neuroprotective, but with a heavier dose lesions are produced in a different part of the brain than usual with the toxin.

Another area of concern is BDNF which we know is reduced in HD affected brains. The authors provide evidence that A(2A) receptors likely have an important role in regulating BDNF.

Finally, the authors raise the possibility that either receptor agonists or antagonists may be neuroprotective, depending on how far the individual has progressed in the disease.

The authors call for more basic research into A(2A) receptors as well as the development of drugs that act differentially on pre and post synaptic functions.

This article is very technical but it illustrates some important points. First, drugs that show some promise in a cell model are not necessarily going to work in a living HD model organism. There is no substitute for careful preclinical testing with HD mouse and other models. Second, the parallel approach of CHDI to drug development is critical. Multiple drugs are currently under investigation. If A(2A) receptor antagonists (or any other drug in the pipeline) are shown to be ineffective or harmful, resources will be redirected to those with more promise.

The Lighthouse will continue to follow this line of research to see if KW-6002 or other A(2A)R antagonists will move all the way through the pipeline to treatment. The preclinical research in HD as well as the Parkinson's experience will advance our knowledge.

-- Marsha L. Miller, Ph.D.
Posted to the HDL: 20 Mar 2007

Functions, dysfunctions and possible therapeutic relevance of adenosine A(2A) receptors in Huntington's disease

Patrizia Popili, David Blum, Alberto Martire, Catherine Ledent, Stefania Ceruti, and Maria Abbrachio

The aim of this review is to summarize and critically discuss the complex role played by adenosine A(2A) receptors (A(2A)Rs) in Huntington's disease (HD). Since A(2A)Rs are mainly localized on the neurons, which degenerate early in HD, and given their ability to stimulate glutamate outflow and inflammatory gliosis, it was hypothesized that they could be involved in the pathogenesis of HD, and that A(2A)R antagonists could be neuroprotective. This was further sustained by the demonstration that A(2A)Rs and underlying signaling systems undergo profound changes in cellular and animal models of HD. More recently, however, the equation A(2A) receptor blockade=neuroprotection has appeared too simplistic. First, it is now definitely clear that, besides mediating 'bad' responses (for example, stimulation of glutamate outflow and excessive glial activation), A(2A)Rs also promote 'good' responses (such as trophic and antinflammatory effects). This implies that A(2A)R blockade results either in pro-toxic or neuroprotective effects according to the mechanisms involved in a given experimental model. Second, since HD is a chronically progressive disease, the multiple mechanisms involving A(2A)Rs may play different relative roles along the degenerative process. Such different mechanisms can be influenced by A(2A)R activation or blockade in different ways, even leading to opposite outcomes depending on the time of agonist/antagonist administration. The number, and the complexity, of the possible scenarios is further increased by the influence of mutant Huntingtin on both the expression and functions of A(2A)Rs, and by the strikingly different effects mediated by A(2A)Rs expressed by different cell populations within the brain. # # #

Source: Progress in Neurobiology 2007 Jan 9; [Epub ahead of print]

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