BACKGROUND: Traumatic brain injury (TBI) is a major contributor to trauma-related deaths and disability worldwide. Management of TBI is currently limited to supportive care. We have previously shown that global knockout of PAD2 confers neuroprotection, but its therapeutic potential was unclear. This study was designed to test the hypothesis that selective inhibition of PAD2 following TBI would improve neurological outcomes. METHODS: Male mice (c57bl6/j, 11-14 wk) were subjected to controlled cortical impact-induced TBI, and 5 to 10 minutes later, randomly given either PAD2 inhibitor ("loading dose" 60 mg/kg AFM41a dissolved in dimethyl sulfoxide (DMSO) or vehicle (DMSO), (n=6/group). One day post-TBI, frozen brain sections were Nissl-stained to determine lesion size. In a separate experiment, the long-term impact of AFM41a treatment on motor, sensory, and cognitive recovery after TBI was evaluated. In addition to the loading dose, animals received a "maintenance dose" of 30 mg/kg of AFM41a or vehicle on postinjury days (PIDs) 2 to 5. Neurologic Severity Scores (NSS on PIDs 1-8) and visuospatial learning via Morris water maze test (MWM on PIDs 21-30) were assessed. RESULTS: Mice treated with AFM41a had significantly smaller lesion sizes compared with the control group (p<0.05). Treatment with AFM41a also increased the rate of sensory and motor recovery, as evidenced by reduced NSS on PIDs 1 to 5 (p<0.05), and improved visuospatial learning and memory as shown by MWM (p<0.05). CONCLUSIONS: PAD 2 is a promising therapeutic target in TBI, and its inhibition with AFM41a, a first-in-class PAD2-selective inhibitor, confers early neuroprotection as well as sustained cognitive benefits.
Dawood et al. (Thu,) studied this question.