Sex-Specific Differences in Autophagic Responses to Experimental Ischemic Stroke

Area of Science:

• Neuroscience
• Cell Biology
• Pathophysiology

Background:

• Ischemic stroke induces complex pathophysiological processes, including autophagy.
• Autophagy activation exhibits sexual dimorphism in neurons under stress.
• The role of autophagy in ischemic stroke and its sex-dependent nature remain unclear.

Purpose of the Study:

• To investigate the sex-specific role of autophagy in ischemic brain injury.
• To evaluate the effects of autophagy inhibition on infarct volume in a male and female mouse model.
• To explore the impact of estrogen on autophagy and neuronal survival post-stroke.

Main Methods:

• Cerebral ischemia was induced using the middle cerebral artery occlusion (MCAO) mouse model.
• Autophagy inhibition was pharmacologically administered.
• Infarct volume, autophagy marker levels (Beclin1, LC3, pULK1, p62, ATG7), and neuronal survival were assessed.
• In vitro studies used male and female neurons subjected to oxygen and glucose deprivation, with and without estrogen (E2) supplementation.

Main Results:

• Autophagy inhibition reduced infarct volume in males and ovariectomized females.
• Conversely, autophagy inhibition increased infarct size in females and estrogen-supplemented ovariectomized females.
• Males exhibited increased Beclin1/LC3 and decreased pULK1/p62; females showed decreased Beclin1 and increased ATG7.
• Male neurons displayed higher basal and stress-induced autophagy marker levels than female neurons.
• Estrogen supplementation inhibited autophagy in male neurons but improved survival in female neurons.

Conclusions:

• Autophagy plays a sex-dependent role in ischemic stroke pathology.
• Autophagy regulators exert differential effects in a sex-specific manner.
• Targeting autophagy for stroke treatment requires consideration of patient sex and hormonal status.