What are the implications of sex differences in cell death for treatment after neonatal hypoxia-ischemia, if any?

Our understanding of the mechanisms by which cells die during and after neonatal hypoxic-ischemic (HI) brain injury continues to be elucidated, and currently involves a wide range of overlapping pathways that include necrosis, apoptosis, necroptosis, ferroptosis, and autophagy. 1 The predominant pathway seems to depend on several factors, including the severity of HI, the stage in the evolution of injury, the developmental age, and the availability of adenosine triphosphate. 2 Importantly, there is evidence of a sexual dimorphism in the predominant cell death pathway after HI. For example, in the Rice−Vannucci murine model of HI brain injury, there is extensive evidence that cell death primarily occurs via caspase-3 dependent pathways in females, 3 , 4 whereas in males it occurs via caspase-independent, poly [adenosine diphosphate ribose] polymerase 1 (PARP-1) dependent pathways. 4 , 5 In this volume, Alonso-Alconada et al. confirm that this sex difference is not unique to rodents and is also seen in a piglet model of neonatal brain injury. In that study, although necrosis was the predominant form of cell death in both sexes, female piglets exposed to carotid artery occlusion and hypoxia had more apoptotic cell death than males, who had an increased prevalence of necrotic cell death, at 48 hours after HI. 6 The underlying mechanisms of these differences between males and females are unclear, but likely include differences in the vulnerability to oxidative stress, production of reactive oxygen species, and mitochondrial dysfunction. 7 Furthermore, speculatively given that overall cell loss was greater in males than females in the piglet study, potentially this drove more cell death through the necrotic pathway.