Adenosine and neurotrauma: therapeutic perspectives

Cerebral ischemia studies demonstrating that stimulation of adenosine A1 receptors by either endogenously released adenosine or the administration of selective receptor agonists causes significant reductions in the morbidity and mortality associated with focal or global brain ischemias have triggered interest in the potential of purinergic therapies for the treatment of traumatic injuries to the brain and spinal cord. Preliminary findings indicate that activation of A1 adenosine receptors can ameliorate trauma-induced death of central neurons. Other avenues of approach include the administration of agents which elevate local concentrations of adenosine at injury sites by inhibiting its metabolism to inosine by adenosine deaminase, rephosphorylation to adenosine triphosphate by adenosine kinase; or re-uptake into adjacent cells. Amplification of the levels of endogenously released adenosine in such a 'site and event specific' fashion has the advantage of largely restricting the effect of such inhibitors to areas of injury-induced adenosine release. Another approach involving purinergic therapy has been applied to the problem of respiratory paralysis following high spinal cord injuries. In this instance, the adenosine antagonist theophylline has been used to enhance residual synaptic drive to spinal respiratory neurons by blocking adenosine A1 receptors. Theophylline induced, and maintained, hemidiaphragmatic recovery for prolonged periods after C2 spinal cord hemisection in rats and may prove to be beneficial in assisting respiration in spinal cord injury patients.