Time dependent bi-directional neuroprotection by Adenosine 2A receptor in Experimental Traumatic Brain Injury.

BACKGROUND: Traumatic Brain Injury (TBI) results in both focal and diffuse brain pathologies that are exacerbated severely after initial injury. Due to this disease complexity in nature, there is still no effective therapeutic measure aimed directly at these pathological processes. We developed a clinically relevant model of TBI and tested bidirectional neuroprotective role of adenosine 2A receptors (A2AR) at different time window periods.

METHODS: Animals (Wistar Rats) were divided into four treatment groups- Sham, TBI, A2AR agonist (CGS-21680) and A2AR antagonist (SCH-58261) with four post TBI time windows (15mins, 1, 12 and 24hrs). A2AR agonist and antagonist effects were tested with neurological functional score (NFS), levels of cAMP, Interleukin-1β, oxidative stress-antioxidant markers and caspase-3.

RESULTS: A2AR agonist treated group showed significant NFS improvement after 15mins and 1hr post TBI compared to TBI group, but no improvement observed at 12 and 24hrs. Interestingly, A2AR antagonists showed no NFS improvement at 15mins and 1hr while significant improvement observed at 12 and 24hrs. Significant neuroprotective effect with A2AR agonist were observed with cAMP, IL-1β, oxidative stress markers, catalase and caspase-3 levels at 15mins and 1hr post TBI. A2AR antagonist showed no effect at these time intervals but showed protective effect at 12 and 24hrs post TBI.

CONCLUSIONS: A2AR agonist showed beneficial neuroprotective effect at early stages of post TBI periods while A2AR antagonist showed at later stages of post TBI. This suggests that A2AR agonist and antagonist to be used depending on the time window at which TBI has occurred.