Gender-based differences in neuroprotective effects of hydrogen gas against intracerebral hemorrhage-induced...

Post-stroke depression (PSD) severely affects recovery in patients with intracerebral hemorrhage (ICH). Although hydrogen gas (H₂) exerts excellent neuroprotective effects in patients with ICH, there are sex-based differences in H₂ efficacy in several diseases. Herein, we determined whether estrogen increases susceptibility to the neuroprotective effects of H₂ in males with ICH-induced depression.

A rodent model of ICH in the basal ganglia was established using autologous blood injection (30 μL). Mice were treated with 2.9% H₂ for 2 h daily for 3 days post-ICH. Estrogen (1 mg/kg) was administered by subcutaneous injection daily for 3 days to male mice post-ICH. Thirty days post-ICH, PSD was evaluated by sucrose preference, forced swimming, and 3-chamber social tests. Following the completion of behavioral tests, levels of superoxide dismutase (SOD) and reactive oxygen species (ROS), astrocytic activation, phosphorylated (p)-NF-κB-positive astrocytes, p-NF-κB, p-IKKβ, IL-1β, and IL-6 expression were determined.

Compared with female mice, H₂ administration post-ICH exhibited fewer neuroprotective effects, including decreased sucrose consumption and time spent sniffing a novel mouse, increased immobility time, downregulated total SOD content, upregulated ROS content and p-NF-κB levels, and elevated astrocyte branches, whereas estrogen enhanced the neuroprotective effects of H₂ in male mice. A reduced number of p-NF-κB-positive astrocytes, downregulated expression of p-NF-κB, p-IKKβ, IL-1β, and IL-6 in the amygdala were demonstrated in ICH-males treated with estrogen plus H₂.

Estrogen was responsible for increased H₂ sensitivity in male mice with ICH. The underlying mechanism may be associated with the suppression of NF-κB signaling in astrocytes.