Mitigation of acute seizures and neuropathology after traumatic brain injury by structure-based discovery-identified drugs

Abstract

Our objective was to test the hypothesis that structure-based identified or designed compounds exhibiting neuroprotective, antioxidant, and anti-inflammatory properties in vitro will mitigate early seizures and neuropathology after traumatic brain injury (TBI) in vivo. The neuroprotective and antiinflammatory effects of 11 compounds identified by computer-assisted approximations were tested in vitro in neuronal microglial co-cultures. Among these, compound FBA exhibited the best neuroprotective (MAP-2, a neuronal damage biomarker), antioxidative (nitrite production), and antiinflammatory (TNF-α) effects in vitro [all p<0.01]. Consequently, its neuroprotective and antiseizure effects were assessed in vivo in adult male Sprague-Dawley rats exposed to severe lateral fluidpercussion-induced TBI. Rats under continuous video-electroencephalogram (vEEG) monitoring received prophylactic treatment with an intraperitoneal (i.p.) injection of FBA (FBApro, 30 mg/kg) or vehicle (VEH, 48% PEG in 0.9% saline, 3 ml/kg) at 2 and 24 h post-TBI. Rats that developed status epilepticus received 1-2 additional on-demand FBA doses (FBApro+, 100 mg/kg, i.p.) to stop epileptiform activity. FBApro treatment reduced the cortical lesion area (18.9 ± 4.1 mm2 , n=7) compared with VEH treatment (24.8 ± 5.7 mm2 , n=10, p<0.05). FBApro treatment also showed a favorable effect on white matter by reducing plasma levels of pNF-H, a biomarker of axonal injury, compared with VEH treatment (Cohen’s delta 0.657). Both FBApro (368 ± 407 s) and FBApro+ (256 ± 327 s) treatments reduced the average cumulative seizure duration compared with VEH (896 ± 703 s, both p<0.05). The FBApro+ treatment regimen also reduced the mean relative theta and alpha power and increased the mean relative gamma power in the EEG (p<0.05). Our data identified FBA as a novel structure-based discovered compound with promising favorable effects on structural and functional recovery after TBI.