Purines include the DNA base pairs adenine and guanine. These are the A and G of the CAG repeat that defines the mutant HD gene. Purines are also potent anti-inflammatory agents that may be useful for the treatment of HD. Inotek seems to be the industry leader of recent purine research.

Inotek has found the purine hypoxanthine to be a most potent cytoprotective agent and investigated the mechanism of its cytoprotective effect. The anti-inflammatory effects were unexpected.

From the Inotek web site: Inotek is a world leader in the development of novel inhibitors of the cell death producing nuclear enzyme poly(ADP-ribose) synthese (PARS or PARP). By targeting a late event in the cascade of cell and organ injury, these agents provide remarkable protection hours after reperfusion injury and oxidant-induced DNA damage. As a consequence, Inotek's PARS inhibitors are protective in models of stroke and myocardial infarction when administered hours after the initial insult. This mechanism of protection is expected to translate into clinical candidates that are effective hours after the presentation of myocardial and cerebrovascular ischemia. Clinical trials of Inotek's ultrapotent PARS inhibitors (IC50<50 nM) in stroke and myocardial infarction are scheduled for 2001. PARS inhibitors have also shown unexpected efficacy in reducing pro-inflammatory gene expression in a variety of experimental models of inflammation, including arthritis, multiple sclerosis, colitis, diabetes, uveitis, and sepsis. The Company is actively developing a series of PARS inhibitors intended for treatment of chronic inflammatory clinical conditions. Clinical Phase I trials for the firm's lead oral candidate PARS inhibitor are scheduled for late 2001.

Hypoxanthine crosses the blood brain barrier and is available from chemical supply sources. I have posted a request for information on the pharmacology of hypoxanthine on the sci.med.pharmacy news group.

The HDLighthouse is on the rocky shore of what is known and not known about HD. There are dangers in alternative treatment. See While We Wait.--Jerry 13-Apl-2001
FASEB J 2001 Jan;15(1):99-107, Virag L., et al.Inotek Corporation,

Purines such as adenosine, inosine, and hypoxanthine are known to have potent antiinflammatory effects.

These effects generally are believed to be mediated by cell surface adenosine receptors. Here we provide evidence that purines protect against oxidant-induced cell injury by inhibiting the activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP). Upon binding to broken DNA, PARP cleaves NAD+ into nicotinamide and ADP-ribose and polymerizes the latter on nuclear acceptor proteins such as histones and PARP itself.

Overactivation of PARP depletes cellular NAD+ and ATP stores and causes necrotic cell death. We have identified some purines (hypoxanthine, inosine, and adenosine) as potential endogenous PARP inhibitors. We have found that purines (hypoxanthine > inosine > adenosine) dose-dependently inhibited PARP activation in peroxynitrite-treated macrophages and also inhibited the activity of the purified PARP enzyme.

Consistently with their PARP inhibitory effects, the purines also protected interferon gamma + endotoxin (IFN/LPS) -stimulated RAW macrophages from the inhibition of mitochondrial respiration and inhibited nitrite production from IFN/LPS-stimulated macrophages.

We have selected hypoxanthine as the most potent cytoprotective agent and PARP inhibitor among the three purine compounds, and investigated the mechanism of its cytoprotective effect. We have found that hypoxanthine protects thymocytes from death induced by the cytotoxic oxidant peroxynitrite. In line with the PARP inhibitory effect of purines, hypoxanthine has prevented necrotic cell death while increasing caspase activity and DNA fragmentation.

As previously shown with other PARP inhibitors, hypoxanthine acted proximal to mitochondrial alterations as hypoxanthine inhibited the peroxynitrite-induced mitochondrial depolarization and secondary superoxide production. Our data imply that purines may serve as endogenous PARP inhibitors.

We propose that, by affecting PARP activation, purines may modulate the pattern of cell death during shock, inflammation, and reperfusion injury.