Adenosine and neurotrauma: Therapeutic perspectives

Cerebral ischemia studies demonstrating that stimulation of adenosine A(1) receptors by either endogenously released adenosine or the administration o f selective receptor agonists causes significant reductions in the morbidit y and mortality associated with focal or global brain ischemias have trigge red interest in the potential of purinergic therapies for the treatment of traumatic injuries to the brain and spinal cord. Preliminary findings indic ate that activation of A(1) adenosine receptors can ameliorate trauma-induc ed death of central neurons. Other avenues of approach include the administ ration of agents which elevate local concentrations of adenosine at injury sites by inhibiting its metabolism to inosine by adenosine deaminase, repho sphorylation to adenosine triphosphate by adenosine kinase or re-uptake int o adjacent cells. Amplification of the levels of endogenously released aden osine in such a 'site and event specific' fashion has the advantage of larg ely restricting the effect of such inhibitors to areas of injury-induced ad enosine release. Another approach involving purinergic therapy has been app lied to the problem of respiratory paralysis following high spinal cord inj uries. In this instance, the adenosine antagonist theophylline has been use d to enhance residual synaptic drive to spinal respiratory neurons by block ing adenosine Al receptors. Theophylline induced, and maintained, hemidiaph ragmatic recovery for prolonged periods after C-2 spinal cord hemisection i n rats and may prove to be beneficial in assisting respiration in spinal co rd injury patients.