In vitro and in vivo effects of a novel dimeric inhibitor of PSD-95 on excitotoxicity and functional recovery after experimental traumatic brain injury.

ABSTRACT

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 of PSD-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 of TBI, we also investigated the neuroprotective effects of UCCB01-147 and related compounds on NMDA-induced cell death in cultured cortical neurons. Anesthetized rats were given a CCI or sham injury, and were randomized to receive an injection of either UCCB01-147 (10 mg/kg), the non-competitive NMDAR-receptor antagonist MK-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 with UCCB01-147 nor MK-801 resulted in significant improvements of cognition and histopathology after CCI. Although MK-801 provided robust neuroprotection against NMDA-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 of PSD-95 inhibition in stroke and TBI that should be investigated further in future studies taking important experimental factors such as timing of treatment, dosage, and anesthesia into consideration.