Modulation of intracellular ATP determines adenosine release and functional outcome in response to metabolic stress in rat hippocampal slices and cerebellar granule cells

Cerebral ischaemia rapidly depletes cellular ATP. Whilst this deprives brain tissue of a valuable energy source, the concomitant production of adenosine mitigates the damaging effects of energy failure by suppressing neuronal activity. However, the production of adenosine and other metabolites, and their loss across the blood-brain barrier, deprives the brain of substrates for the purine salvage pathway, the primary means by which the brain makes ATP. Because of this, cerebral ATP levels remain depressed after brain injury. To test whether manipulating cellular ATP levels in brain tissue could affect functional neuronal outcomes in response to oxygen/glucose deprivation (OGD), we examined the effects of creatine and d-ribose and adenine (RibAde). In hippocampal slices creatine delayed ATP breakdown, reduced adenosine release, retarded both the depression of synaptic transmission and the anoxic depolarization caused by OGD, and improved the recovery of transmission. In contrast, RibAde increased cellular ATP, caused increased OGD-induced adenosine release and accelerated the depression of synaptic transmission, but did not improve functional recovery. However, RibAde improved the viability of cerebellar granule cells when administered after OGD. Our data indicate that RibAde may be effective in promoting recovery of brain tissue after injury, potentially via enhancement of salvage-mediated ATP production. The mammalian brain requires the purine salvage pathway to make ATP. However, at times of metabolic stress or traumatic injury, ATP metabolites are lost across the blood-brain barrier to the general circulation impairing both the resynthesis of ATP and compromising the ATP-derived reservoir of neuroprotective and anticonvulsant adenosine. By providing creatine, we can reduce ATP metabolism during metabolic stress, but at the expense of adenosine release, whilst d-ribose and adenine (RibAde) improve ATP levels and adenosine release, and protects neurones when given after metabolic stress. Creatine may thus have some neuroprophylactic value, whilst RibAde may promote metabolic and functional recovery after brain injury.