Sunday, May 11, 2025
5/11/2025
Axonoprotection in pediatric cardiac arrest - Pediatric cardiac arrest affects 10-‐15,000 children each year. Fewer than 1 in 10 children survive, and the majority of deaths occur due to severe neurologic injury. At present, no therapy exists for brain injury in children after cardiac arrest, and new approaches are needed. The current proposal focuses on one under-‐appreciated aspect of brain injury after cardiac arrest – injury to long-‐range axons. Using a clinically-‐realistic model of severe pediatric cardiac arrest and resuscitation in immature rats, we have generated new preliminary data showing that axonal injury occurs early after resuscitation and is associated with depletion of nicotinamide adenine dinucleotide (NAD+) specifically in the white matter. We propose that the mechanism of axonal NAD+ depletion after cardiac arrest involves injury-‐dependent activation of the protein SARM1. SARM1 is the only known injury-‐activated NAD-‐cleaving enzyme in axons, and its activation effects axonal degeneration in several injury paradigms. To determine the role of SARM1 in post-‐arrest axonal injury while preserving the clinical realism of the cardiac arrest model in developing rats, we generated SARM1 knockout (SARM1-‐/-‐) rats. Our central hypothesis is that SARM1-‐mediated NAD+ depletion contributes to axonal injury and poor neurologic outcomes after pediatric cardiac arrest. We propose three Specific Aims to test our hypothesis. In Aim 1, we will determine whether SARM1 deletion a) prevents white matter NAD+ depletion and b) preserves axonal function and structure after cardiac arrest. In Aim 2, we will determine whether SARM1 deletion improves motor behavioral outcomes after cardiac arrest. In Aim 3, we will determine if nicotinamide riboside – a safe NAD+ precursor that penetrates the blood-‐brain barrier – maintains NAD+ levels and improves motor behavior after cardiac arrest. If successful, the proposed experiments will identify SARM1 activation and NAD+ depletion as mechanisms contributing to axonal injury after cardiac arrest and establish a pre-‐ clinical basis for a novel therapeutic approach to a devastating, and currently untreatable, neurologic injury in children.
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