Enriched Environment Suppresses Neuronal Ferroptosis Through SIRT1/AKT/GSK3β-Dependent Glycogen Metabolic...

Area of Science:

• Neuroscience
• Metabolic pathways
• Cellular biology

Background:

• Neuronal ferroptosis contributes to brain injury after cerebral ischemia.
• The metabolic mechanisms of ferroptosis and enriched environment (EE) neuroprotection are unclear.
• EE may protect against ischemia-induced ferroptosis via glycogen metabolism.

Purpose of the Study:

• To investigate if EE influences ferroptosis-associated pathways through Sirtuin 1 (SIRT1)/protein kinase B (AKT)/glycogen synthase kinase-3β (GSK3β) mediated glycogen metabolism.
• To elucidate the molecular mechanisms of EE-induced cerebroprotection.

Main Methods:

• Mouse model of middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation/reoxygenation (OGD/R) cellular model.
• Behavioral assessments, molecular and biochemical analyses, and pharmacological interventions.
• Sirtuin 1 (SIRT1) inhibition and overexpression studies.

Main Results:

• EE improved neurological outcomes and reduced infarct volume post-ischemia.
• EE activated the SIRT1/AKT pathway, increased GSK3β inhibitory phosphorylation, and elevated brain glycogen levels.
• SIRT1 inhibition reduced EE's neuroprotective effects; SIRT1 overexpression attenuated ferroptosis in vitro.

Conclusions:

• EE attenuates ferroptosis possibly through SIRT1/AKT/GSK3β-dependent glycogen metabolic remodeling.
• SIRT1-centered regulation of glycogen metabolism is a potential therapeutic target for ischemic stroke.
• EE-induced cerebroprotection offers a novel metabolic perspective.