CMX-2043 Treatment Limits Neural Injury Pathophysiology and Promotes Neurological and Cognitive Recovery in a Pediatric Porcine Traumatic Brain Injury Model.

Abstract

Traumatic brain injury (TBI) represents a major global health issue contributing to significant disability and mortality. The TBI-induced secondary injury cascade, characterized by neuroinflammation, neural cell death, and tissue damage, results in lifelong functional deficits. Alpha--[(R)-1, 2-dithiolane-3-pentanoyl]l-glutamyl-l-alanine (CMX-2043) is a novel alpha lipoic acid (ALA)-based therapeutic that has neuroprotective, anti-apoptotic, and anti-inflammatory properties that mitigate cellular, tissue, and functional deficits following TBI. In this study, we evaluated the therapeutic efficacy of CMX-2043 on neural injury severity and functional recovery in a clinically relevant porcine TBI model. CMX-2043 was administered 1-h post-TBI subcutaneously (SQ;= 8) or intravenously (IV;= 8) for a total of 5 days. Control piglets (placebo;= 11) received saline subcutaneously. Magnetic resonance imaging (MRI), immunohistochemistry analysis, modified Rankin Scale (mRS) neurological evaluation, and social recognition testing (SRT) were evaluated up to 42 days post-TBI. MRI revealed that SQ and IV CMX-2043 administration reduced hemispheric swelling and atrophy, lesion volume, midline shift, and intracerebral hemorrhage and preserved diffusivity, cerebral blood flow, and white matter integrity. CMX-2043-mediated neuroprotection and regeneration were indicated by increased neural cell density, decreased neuroinflammation, and enhanced neurogenesis following SQ and IV administration. These cellular and tissue-level changes corresponded with reduced neurological deficits and rapid cognitive recovery as indicated by improved mRS and SRT results, respectively. Collectively, these results observed in a translational large animal porcine model suggest that CMX-2043 holds significant clinical value to potentially mitigate TBI pathophysiology and promote functional recovery.