POST-TBI ANTITHROMBIN III RECOVERS MORRIS WATER MAZE COGNITIVE PERFORMANCE, IMPROVING CUED AND SPATIAL LEARNING.

BACKGROUND Neuroinflammation and cerebral edema development following severe TBI affect subsequent cognitive recovery. Independent of its anticoagulant effects, antithrombin III (AT-III) has been shown to block neurovascular inflammation after severe TBI, reduce cerebral endothelial-leukocyte interactions and decrease blood brain barrier permeability. We hypothesized that AT-III administration after TBI would improve post-TBI cognitive recovery, specifically enhancing learning, and memory. METHODS Fifteen CD1 male mice were randomized to undergo severe TBI (controlled cortical impact, CCI: 6 m/sec velocity, 1 mm depth, 3 mm diameter) or sham craniotomy (SHAM) and received either intravenous AT-III (250 IU/kg) or vehicle (VEH:saline) 15 minutes and 24 hours post-TBI. Animals underwent Morris water maze testing from 6-14 days post-injury consisting of cued learning trials (platform visible), spatial learning trials (platform invisible, spatial cues present), and probe (memory) trials (platform removed, spatial cues present). Intergroup differences were assessed by the Kruskal-Wallis test (p < 0.05). RESULTS Morris water maze testing demonstrated that cumulative cued learning (overall mean time in seconds to reach the platform on days 6-8) was worst in CCI+VEH animals (26.1 ± 2.4s) compared to CCI+ATIII counterparts (20.3 ± 2.1s, p<0.01). Cumulative non-cued spatial learning was also worst in the CCI+VEH group (23.4 ± 1.8s) but improved with AT-III (17.6 ± 1.5s, p<0.01. In probe trials, AT-III failed to significantly improve memory ability. SHAM animals demonstrated preserved learning and memory compared to all CCI counterparts (p < 0.05). CONCLUSIONS AT-III improves neurocognitive recovery weeks after TBI. This improvement is particularly related to improvement in learning but not memory function. Pharmacologic support of enhanced learning may support new skill acquisition or re-learning to improve outcomes after TBI. STUDY TYPE Original Article (Basic Science). LEVEL OF EVIDENCE Level II Evidence (Therapeutic / care management).