62 - Acute 4-aminopyridine (4-AP) Does Not Increase Seizure Risk After Experimental Traumatic Brain Injury With Dosing That Mitigates Axon Damage and Node of Ranvier Disruption

Abstract Text: A traumatic brain injury (TBI) event can disrupt the structural organization of axons in white matter tracts resulting in long-term functional connectivity deficits. Currently, no treatment is available that can prevent the progression of axonal injury to late-stage neurodegeneration. To address this need, we identified 4-aminopyridine (4-AP) as a promising small molecule candidate to attenuate TBI-induced axon damage. 4-AP is an FDA-approved therapy used for chronic neurological disorders as an inhibitor of voltage-gated potassium (Kv1) channel activity to improve function at nodes of Ranvier (NoR) that are disrupted by demyelination. Using a well-characterized model of closed-skull TBI in adult male and female mice, we previously demonstrated that a low, clinically reasonable therapeutic dose of 4-AP reduced axon damage, myelin pathology, and NoR disruption in the corpus callosum. To further evaluate repurposing of 4-AP as an acute treatment for TBI, the current studies test whether TBI effects the seizure threshold during acute 4-AP therapy. Following TBI or sham procedures, 8 week old male and female C57BL/6 mice received intraperitoneal injections of either a pro-convulsant 4-AP dose (5 mg/kg), a therapeutic 4-AP dose (0.5 mg/kg) or saline vehicle, twice daily for 6 days, starting 24 hours after TBI/sham procedures. Seizure threshold was tested on days 1 and 7 post-TBI/sham using a modified Racine scale as a sensitive measure of seizure behavior in mice. The pro-convulsant 4-AP dose confirmed the Racine scale detection of seizure behavior in all sham and TBI mice. In contrast, neither the therapeutic 4-AP dose nor the saline vehicle induced seizure behavior in sham or TBI mice. These results advance the pre-clinical evidence of the safety profile for repurposing 4-AP acute therapy for patients after TBI.

Keywords: axonal injury, seizure, behavior, demyelination, white matter, therapeutics