Harnessing the purine salvage pathway to treat ATP deficit in cerebral ischemia.

Stroke is a global health problem affecting ~14 million people per year, with ischemic stroke accounting for 85% of cases. Ischemic stroke results from disruption of blood flow in part of the brain. Without ample oxygen supply from the blood, the cells can be irreversibly damaged or die causing a number of neurological deficits.
The key mechanism which triggers cell death during a stroke is the loss of ATP synthesis mechanisms and the subsequent depletion of ATP. When the energy demands of the brain cannot be met and the membrane homeostasis and ionic gradient, which regulate synaptic transmission, are disrupted. This causes a metabolic crisis resulting in rapid cell death at the site of the ischemic episode. Over time, this cell death can spread to otherwise salvageable cells meaning stroke treatments must be administered as soon as possible to be effective. Currently the only method of treatment is effective in just 10% of patients due to these time constraints.
This project will investigate a novel method of stroke treatment which utilises metabolites of the purine salvage pathway (PSP), ribose and adenine, to generate ATP and restore energy balance in the brain.
The PSP is the primary route of adenine nucleotide synthesis in the brain via the production of AMP, a precursor to ATP. The addition of ribose and adenine to brain slices, which mimic the ischemic brain in terms of ATP content, has been shown to restore ATP to in vivo values. This approach has also been shown to be beneficial in a rodent model of stroke. Theoretically, this is due to the incorporation of these molecules into the PSP, increasing the production of AMP and subsequently ATP. This is a promising method of treatment as both ribose and adenine are safe for intravenous administration. Additionally, the PSP enzymes are cytosolic, eliminating any need to target organelles. This could allow for more rapid treatment and increase patient outcome should this be approved as a stroke therapeutic.