Systemic davunetide provides sex-specific neuroprotection during Coronary Artery Bypass Grafting (CABG)

Coronary artery bypass grafting (CABG) is a surgical procedure commonly employed to treat severe coronary artery disease by improving blood flow to the heart. Despite its effectiveness, CABG is an open-heart surgery associated with potential complications, including cognitive decline, a currently unmet need. Discovered in our laboratory, activity-dependent neuroprotective protein (ADNP) is essential for brain formation as well as heart development and embryogenesis and the ADNP-derived investigational drug, davunetide, ameliorates partly ADNP-linked deficiencies. Specifically, davunetide was found to be efficacious in a rat pre-clinical model of ischemic stroke, a potential unwanted side effect of CABG, which may lead to a neurodegenerative process, culminating in cognitive dysfunction. Here, leveraging acute administration of intravenous davunetide (AL-208, ClinicalTrials.gov ID NCT00404014), we implicated, for the first time, a differential drug metabolism/bioavailability between men and women, with a potential dose-dependent accumulation in men and an opposite decline/no concentration change in women over time. These findings, while requiring caution due to the small cohort size, were linked with an apparent protection against brain cell death/disease progression by davunetide (AL-208) neuroprotective effects (neuron-specific enolase - NSE blood content). In men, also for the first time under these circumstances, neuroprotection was coupled to cognitive function increases in the treated group versus placebo, reaching healthy control levels in the Verbal Paired Associates II test, emphasizing the importance of sex-specific brain medicine.