REPURPOSING RIBOSE, ADENINE AND ALLOPURINOL AS AN ATP-ELEVATING NEUROPROTECTIVE THERAPY FOR ISCHEMIC STROKE

Stroke is the second leading cause of death and the third leading cause of adult disability worldwide. Interruption of cerebral blood flow leads to rapid depletion of adenosine triphosphate (ATP), triggering a cascade of pathophysiological processes that worsen brain injury. Both the brain and heart rely on the purine salvage pathway to resynthesize ATP. During ischaemia, ATP loss is exacerbated because its metabolites enter the bloodstream, leaving the brain without the adenine and ribose necessary for ATP regeneration. Previous studies have shown that treatment with ribose and adenine (RibAde) restores cellular ATP to physiological levels in in vitro models of brain injury. In vivo, post-insult treatment with RibAde, alone or in combination with allopurinol (RibAdeAll), which prevents the formation of non-salvageable purine metabolites, showed a trend to reduce brain lesion volume and improved neurological recovery. These findings are supported by the present hyperacute study, in which a two-hour administration of RibAde following two hours of middle cerebral artery occlusion (MCAO) significantly reduced infarct volume. Given the narrow therapeutic window of current stroke treatments (thrombolysis and/or mechanical thrombectomy), RibAdeAll represents a promising strategy to preserve salvageable brain tissue and reduce neurological dysfunction. Next steps will be to evaluate RibAdeAll beneficial effects in the context of prolonged (~2 week) recovery after 1 hr of transient MCAO.