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.
Subject(s)
Metformin/therapeutic use , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/drug therapy , Stroke/drug therapy , Stroke/prevention & control , Adenylate Kinase/metabolism , Animals , Apoptosis/drug effects , Body Weight , Brain Infarction/blood , Brain Infarction/complications , Brain Infarction/drug therapy , Brain Infarction/genetics , Enzyme Activation/drug effects , Female , Gene Expression Regulation , Gliosis/blood , Gliosis/complications , Gliosis/drug therapy , Infarction, Middle Cerebral Artery/blood , Infarction, Middle Cerebral Artery/complications , Infarction, Middle Cerebral Artery/drug therapy , Infarction, Middle Cerebral Artery/genetics , Ischemic Preconditioning , Macrophages/drug effects , Macrophages/pathology , Metformin/blood , Metformin/pharmacology , Mice, Inbred C57BL , Microglia/drug effects , Microglia/pathology , Models, Biological , NF-kappa B/metabolism , Neurons/drug effects , Neurons/pathology , Renal Insufficiency, Chronic/blood , Renal Insufficiency, Chronic/genetics , Stroke/geneticsABSTRACT
Ischemic stroke is highly prevalent in chronic kidney disease (CKD) patients and has been associated with a higher risk of neurological deterioration and in-hospital mortality. To date, little is known about the processes by which CKD worsens ischemic stroke. This work aimed to investigate the cellular and molecular mechanism associated with ischemic stroke severity in an in vivo model of CKD. CKD was induced through right kidney cortical electrocautery in 8-week-old female C57BL/6 J mice followed by left total nephrectomy. Transient middle cerebral artery occlusion (tMCAO) was performed 6 weeks after left nephrectomy. Twenty-four hours after tMCAO, the infarct volumes were significantly wider in CKD than in SHAM mice. CKD mice displayed decreased neuroscore, impaired ability to remain on rotarod device, weaker muscular strength and decreased prehensile score. Apoptosis, neuronal loss, glial cells recruitment and microglia/macrophages M1 signature genes CD32, CD86, IL-1ß, IL-6, MCP1 and iNOS were significantly increased within ischemic lesions of CKD mice. This effect was associated with decreased AMP kinase phosphorylation and increased activation of the NFΚB pathway. Pharmacological targeting of AMP kinase activity, which is known to block microglia/macrophages M1 polarization, appears promising to improve stroke recovery in CKD.
