A3Adenosine Receptor Agonists: Novel Therapeutics for Neuroprotection after Traumatic Brain Injury

Abstract ID 130535 Poster Board 208 For survivors of traumatic brain injury (TBI), a key factor in maintaining quality of life is cognitive function. TBI-induced cognitive impairment (CI) can include decreased concentration, slowed thinking, and inconsistent learning and memory. Long-term CI resulting from mild TBI (mTBI) has no FDA-approved pharmacotherapy and is a risk factor for age-related dementia, representing a growing public health concern. We demonstrated previously that MRS5980, a highly selective A3 adenosine receptor (A3AR) agonist, given to mice 1h after TBI prevented CI measured 4 weeks later. Preserved cognitive performance corresponded with reduced markers of neuroinflammation. In another set of our past experiments, TBI induced a spike in active glycogen synthase kinase-3b (GSK-3b) that when blocked prevented memory impairment. GSK-3b is a known driver of neuroinflammation through proinflammatory cytokines and the A3AR modulates its phosphorylation status (activity). To expand clinical relevance and further probe the mechanism of the observed cognitive benefits, the present study aimed to answer how long post-injury MRS5980 treatment could be delayed with retention of benefits and what signaling pathways are involved. Mice were subjected to either a sham procedure or a closed-head weight-drop TBI. Injured experimental groups received vehicle or MRS5980 (1 mg/kg I.P.) at 1h, 24h, or 72h post-procedure and control sham mice received vehicle. Dosing continued every 48h for the duration of the study. Behavioral testing commenced 4 weeks later, revealing no differences in activity, anxiety, or depressive behavior between groups. Novel object recognition (NOR) and T-maze testing revealed the 1h and 24h MRS-treated injured animals had conserved learning and memory compared to vehicle-treated injured animals, correlating with increased phosphorylated GSK-3b at serine 9 (inactive) and decreased hyperphosphorylated tau in MRS-treated animals. Our previous use of MRS5980 in chronic pain models has revealed that A3AR stimulation drives interleukin-10 (IL-10) release from CD4+ cells; ongoing TBI pilot studies also suggest that IL-10 is the critical mediator of our cognitive and biochemical results. Excitingly, highly selective A3AR agonists like MRS5980 are currently in advanced clinical trials for inflammatory, painful, and cancerous conditions, displaying excellent safety and efficacy profiles. These data support another indication for this class of medications, specifically MRS5980 as a candidate therapeutic for neuroprotection against TBI-induced CI. These studies are funded by NINDS grant 5R01NS111120-04 awarded to DS and SF. MG is supported by NINDS 5F30NS124254-02 and SLU Diversity Fellowship.