TXA after severe TBI: Learning and memory benefits are prominent only in males.

Abstract

Tranexamic acid (TXA), a commonly used pharmacotherapy, appears to preserve blood brain barrier integrity after traumatic brain injury (TBI) in males, but whether TXA confers equivalent neurocognitive benefit in female and male subjects after TBI remains unknown. We hypothesized that TXA unequally affects male and female learning and memory post-TBI. CD1 male (M, n = 24) and female (F, n = 24) mice underwent controlled cortical impact (TBI) or sham craniotomy (Sh), receiving either TXA (60 mg/kg) or saline (placebo [P]) i.v., 1 hour later. For 14 days, mice underwent Morris water maze testing where improved learning/memory was indicated by traveling a shorter distance/reaching or crossing into target zones with greater frequency (Z1, platform quadrant; Z5, platform, Z6; Z7, concentric peri-platform zones). Brains were collected for tissue water determinations and neurological recovery was quantified daily using the Garcia neurological test and Neurological Severity Score across 14 days. Post-TBI TXA improved male spatial learning (crossing frequency into Z6 and Z7 [p < 0.01]; latency to Z1 [p < 0.01], Z5 [p < 0.01], Z6 [p < 0.01], and Z7 [p < 0.01]). Tranexamic acid improved female learning solely in one parameter (Z7 latency; p < 0.01). Tranexamic acid improved male memory (frequency into Z5 [p = 0.02] and Z6; duration in Z1 [p = 0.01] and Z7 [p = 0.04] and swimming velocity [p < 0.01]). In females, TXA improved memory solely in one parameter (Z1 duration; p = 0.02). Tranexamic acid reduced only male cerebral edema. Tranexamic acid enhanced male mice Garcia Neurological Test scores early (first 3 days) and female mice scores, late (Day 11). Tranexamic acid only improved male Neurological Severity Score on Days 8 to 11. Post-TBI TXA benefits males more than females. Traumatic brain injury should be studied separately in males and females to identify sex-specific mechanisms of injury and recovery.