The Many Roles of Adenosine in Traumatic Brain Injury

Abstract

Many secondary mechanisms regulate the evolution of damage and repair after traumatic brain injury (TBI). Bench-to-bedside studies from our team have shown that adenosine plays a key role in several secondary injury pathways in the brain, namely, excitotoxicity, neuroinflammation, and cerebral blood flow (CBF) dysregulation. Studies of adenosine A1-receptor (A1R) knockout (KO) mice strongly support a key role for adenosine-dependent effects at this receptor in attenuating posttraumatic excitotoxicty. A1R KO mice develop lethal status epilepticus after experimental TBI. Evidence also supports a role of the A1R in human TBI since A1R gene variants are associated with posttraumatic seizures in patients with TBI. A1R also modulates the neuroinflammatory response to TBI. A1R KO mice exhibit enhanced microglial proliferation early after TBI. Adenosine acting at A2A and/or A2B receptors also modulates posttraumatic CBF. Local injection of either the nonselective AR agonist 2-chloroadenosine or the A2AR agonist CGS21680 markedly increases CBF in naive or brain-injured rats. However, whether the effects of adenosine on CBF after TBI are beneficial or detrimental is controversial. Mitigation of ischemia by adenosine produced from breakdown of ATP after TBI has been suggested, and consistent with this hypothesis, we reported increases in brain interstitial adenosine levels in patients with severe TBI during episodes of ischemia. However, in studies of CBF in patients after severe TBI, we also noted an association between cerebrospinal fluid (CSF) adenosine levels and uncoupling of CBF and metabolism (cerebral metabolic rate for oxygen [CMRO2]). Uncoupling of CBF and CMRO2 is associated with intracranial hypertension. Thus, adenosine may represent a two-edged sword after TBI. Additional evidence supporting a protective role of adenosine in TBI comes from clinical studies showing a powerful association between CSF caffeine levels and favorable outcome after TBI—given the interplay between caffeine and adenosine in neuroprotection. Finally, our work also suggests that the newly discovered 2,3-cyclic AMP pathway represents an important component of the adenosine response to TBI.