BACKGROUND

Traumatic brain injury (TBI) is a common pathological condition that presently lacks a specific pharmacological treatment. Adenosine levels rise following TBI, which is thought to be neuroprotective against secondary brain injury. Evidence from stroke and inflammatory disease models suggests that adenosine signaling through the G protein-coupled A adenosine receptor (AAR) can provide antiinflammatory and neuroprotective effects. However, the role of AAR in TBI has not been investigated.

METHODS

Using the selective AAR agonist, MRS5980, we evaluated the effects of AAR activation on the pathological outcomes and cognitive function in CD1 male mouse models of TBI.

RESULTS

When measured 24 h after controlled cortical impact (CCI) TBI, male mice treated with intraperitoneal injections of MRS5980 (1 mg/kg) had reduced secondary tissue injury and brain infarction than vehicle-treated mice with TBI. These effects were associated with attenuated neuroinflammation marked by reduced activation of nuclear factor of kappa light polypeptide gene enhancer in B cells (NFκB) and MAPK (p38 and extracellular signal-regulated kinase (ERK)) pathways and downstream NOD-like receptor pyrin domain-containing 3 inflammasome activation. MRS5980 also attenuated TBI-induced CD4 and CD8 T cell influx. Moreover, when measured 4-5 weeks after closed head weight-drop TBI, male mice treated with MRS5980 (1 mg/kg) performed significantly better in novel object-placement retention tests (NOPRT) and T maze trials than untreated mice with TBI without altered locomotor activity or increased anxiety.

CONCLUSION

Our results provide support for the beneficial effects of small molecule AAR agonists to mitigate secondary tissue injury and cognitive impairment following TBI.