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

Maria Grissi,Maryam Assem,Lucie Hénaut,Carine Avondo,Ziad A Massy,Sabrina Poirot-Leclercq,Mathilde Lando,Gaëlle Lenglet,Gabriel Choukroun,Jean-Marc Chillon,Agnès Boullier,Jean-Daniel Lalau,Cédric Boudot,Saïd Kamel,Alexandre Candellier,Youssef Bennis

doi: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.

Highlights

Chronic kidney disease (CKD) worsens ischemic stroke severity in both patients and animals
Plasma metformin concentrations were significantly higher in CKD-Met than in SHAM-Met mice (0.53 ± 0.21 mg/L vs. 0.27 ± 0.14 mg/L, p < 0.01)
We show that chronic metformin pre-conditioning rescued adenosine monophosphate‐activated protein kinase (AMPK) activation in CKD mice, an effect that was associated with a reduction of CKD-induced NF-κB pathway and a subsequent decrease in the level of the macrophage/microglia M1 markers CD32, CD16, CD86, iNOS, and IL-1β

Summary

Introduction

Chronic kidney disease (CKD) worsens ischemic stroke severity in both patients and animals. A first-line drug for glycemic control in patients with type-2 diabetes mellitus (T2DM)[7], has been shown to markedly reduce the risk of ischemic stroke in diabetic patients with normal renal function[8,9] In these patients, glycemic control with metformin prior to the development of stroke is associated with reduced neurological severity and improved acute-phase o utcomes[9]. Preclinical studies evaluating the effect of metformin on stroke recovery in the CKD setting have never been undertaken due to the fear of lactic acidosis[25] In this context, the recent observations that metformin can be safely used in patients with advanced CKD without increasing the risk of lactic acidosis, provided that the dose of metformin is adapted to kidney function, opened up new perspectives in the prevention of stroke severity in this population[26,27]. The present work aimed to evaluate whether metformin can be used in non-diabetic CKD mice to rescue AMPK activity and prevent stroke severity

Methods

Results

Conclusion