Metformin Ameliorates Early Brain Injury After Subarachnoid Hemorrhage Via Improving Endoplasmic Reticulum Stress and Mitochondrial Stress-Mediated Ca2+ Imbalance

Subarachnoid hemorrhage (SAH) is a destructive subtype of stroke characterized by a high mortality and morbidity rate (45-50%) and a poor neurologic prognosis, encompassing both neurological and psychiatric impairments. It will be more imperative to explore new therapeutic strategies for early brain injury (EBI) to enhance the prognosis of patients with SAH. First, we investigated the role of endoplasmic reticulum stress (ERS) and mitochondrial stress (MS) in mediating the IP3R1-GRP75-VDAC1 Ca²⁺ channeling complex within the first 72 h following SAH in mice. Neurological function was assessed prior to euthanasia, and brain water content was measured post-sacrifice in each group. The ultrastructural composition of mitochondria-associated membrane (MAM) was examined using transmission electron microscopy (TEM). Protein expressions related to ERS, MS, and apoptosis were evaluated by immunofluorescence and Western blot. Metformin (Met) administration improved neurological scores and reduced brain edema at 24 h post-SAH, likely through ameliorating ERS- and MS-mediated Ca²⁺ dysregulation. Finally, the beneficial effect of Met was further confirmed in an in vitro SAH model, yielding consistent results. Stimulation of arterial blood aggravates the ERS and MS through the PTP1B/AKT axis, further affecting the structure and function of the MAM following SAH. The MAM formation mediates the IP3R1-GRP75-VDAC1 complex, playing an important role in Ca²⁺ transport. The Met treatment could ameliorate ER stress, MS, and Ca²⁺ overload, further alleviating the EBI of SAH.