Metformin prevents stroke damage in non-diabetic female mice with chronic kidney disease

• Main Authors: Maria Grissi, Cédric Boudot, Maryam Assem, Alexandre Candellier, Mathilde Lando, Sabrina Poirot-Leclercq, Agnès Boullier, Youssef Bennis, Gaëlle Lenglet, Carine Avondo, Jean-Daniel Lalau, Gabriel Choukroun, Ziad A. Massy, Saïd Kamel, Jean-Marc Chillon, Lucie Hénaut
• Format: Article
• Language: English
• Published: Nature Publishing Group 2021-04-01
• Series: Scientific Reports
• Online Access: https://doi.org/10.1038/s41598-021-86905-9

Abstract Chronic kidney disease (CKD) worsens ischemic stroke severity in both patients and animals. In mice, these poorer functional outcomes are associated with decreased brain activity of AMP-activated protein kinase (AMPK), a molecule that recently emerged as a potential therapeutic target for ischemic stroke. The antidiabetic drug metformin, a well-known activator of AMPK, has improved stroke outcomes in diabetic patients with normal renal function. We investigated whether chronic metformin pre-conditioning can rescue AMPK activity and prevent stroke damage in non-diabetic mice with CKD. Eight-week-old female C57BL/6J mice were assigned to CKD or SHAM groups. CKD was induced through right kidney cortical electrocautery, followed by left total nephrectomy. Mice were then allocated to receive metformin (200 mg/kg/day) or vehicle for 5 weeks until stroke induction by transient middle cerebral artery occlusion (tMCAO). The infarct volumes were lower in CKD mice exposed to metformin than in vehicle-treated CKD mice 24 h after tMCAO. Metformin pre-conditioning of CKD mice improved their neurological score, grip strength, and prehensile abilities. It also enhanced AMPK activation, reduced apoptosis, increased neuron survival and decreased microglia/macrophage M1 signature gene expression as well as CKD-induced activation of the canonical NF-κB pathway in the ischemic lesions of CKD mice.