UCCB01-147

PSD‐95 inhibitors have been shown to be neuroprotective in stroke, but have only to a very limited extent been evaluated in the treatment of traumatic brain injury (TBI) that has pathophysiological mechanisms in common with stroke. The aims of the current study were to assess the effects of a novel dimeric inhibitor ofPSD‐95,UCCB01‐147, on histopathology and long‐term cognitive outcome after controlled cortical impact (CCI) in rats. As excitotoxic cell death is thought to be a prominent part of the pathophysiology ofTBI, we also investigated the neuroprotective effects ofUCCB01‐147 and related compounds onNMDA‐induced cell death in cultured cortical neurons. Anesthetized rats were given aCCIor sham injury, and were randomized to receive an injection of eitherUCCB01‐147 (10 mg/kg), the non‐competitiveNMDAR‐receptor antagonistMK‐801 (1 mg/kg) or saline immediately after injury. At 2 and 4 weeks post‐trauma, spatial learning and memory were assessed in a water maze, and at 3 months, brains were removed for estimation of lesion volumes. Overall, neither treatment withUCCB01‐147 norMK‐801 resulted in significant improvements of cognition and histopathology afterCCI. AlthoughMK‐801 provided robust neuroprotection againstNMDA‐induced toxicity in cultured cortical neurons,UCCB01‐147 failed to reduce cell death and became neurotoxic at high doses. The data suggest potential differential effects ofPSD‐95 inhibition in stroke andTBIthat should be investigated further in future studies taking important experimental factors such as timing of treatment, dosage, and anesthesia into consideration.