Does sex matter in neurons response to hypoxic stress?

Abstract

BackgroundStroke exhibits significant sex differences in incidence, response to treatment and outcome. Preclinical studies suggest that hormones, particularly estrogens, are key to differential sensitivity, as female neurons demonstrate enhanced resilience compared to males in both in vivo and in vitro models. This study investigates whether these sex-specific differences in neuronal vulnerability extend to the ischemic penumbra and explores the effects of estrogens under such conditions. MethodsPrimary cortical neuronal networks were generated from male and female new-born Wistar rats and cultured on micro-electrode arrays or glass coverslips. Male and female networks were subjected to hypoxic conditions, followed by a recovery phase, with or without exogenous estrogen treatment. Electrophysiological activity, including spikes and bursts, was monitored and analyzed. Apoptosis was assessed through immunocytochemistry, focusing on caspase-dependent and apoptosis inducing factor (AIF)-dependent pathways. ResultsUnder hypoxic conditions, male and female neuronal networks exhibited a similar decrease in firing and network burst rates, with an associated increase in network burst durations. Estrogen treatment altered these dynamics, leading to increased network burst rates and decreased network burst duration for both sexes. During recovery, no significant differences were observed between estrogen-treated and untreated networks. Immunocyto-chemistry revealed that estrogen significantly influenced caspase-dependent apoptosis, and to a lesser extent AIF-dependent apoptosis. ConclusionsIn our model of the ischemic penumbra, sex-dependent differences in neuronal responses to hypoxic injury are primarily driven by estrogen, rather than intrinsic neuronal characteristics. Although our electrophysiological data demonstrated that estrogen influenced network activity, it did not offer long-term neuroprotection after hypoxia.