Effects of Metformin in Experimental Stroke

• Published in: Stroke (1970) 2010-11, Vol.41 (11), p.2645-2652
• Main Authors: JUN LI, BENASHSKI, Sharon E, VENUGOPAL REDDY VENNA, MCCULLOUGH, Louise D
• Format: Article
• Language: English
• Subjects: AMP-Activated Protein Kinases - drug effects; AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; Animals; Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Dose-Response Relationship, Drug; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Hormones. Endocrine system; Hypoglycemic Agents - adverse effects; Hypoglycemic Agents - pharmacology; Incidence; Infarction, Middle Cerebral Artery - metabolism; Infarction, Middle Cerebral Artery - pathology; Lactates - metabolism; Male; Medical sciences; Metformin - adverse effects; Metformin - pharmacology; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Animal; Nervous system (semeiology, syndromes); Neurology; Nitric Oxide Synthase - genetics; Nitric Oxide Synthase - metabolism; Pharmacology. Drug treatments; Stroke - epidemiology; Stroke - metabolism; Stroke - pathology; Time Factors; Vascular diseases and vascular malformations of the nervous system
• ISSN: 0039-2499; 1524-4628; 1524-4628
• DOI: 10.1161/strokeaha.110.589697

Adenosine 5'-monophosphate-activated protein kinase (AMPK) is an important sensor of energy balance. Stroke-induced AMPK activation is deleterious because both pharmacological inhibition and genetic deletion of AMPK are neuroprotective. Metformin is a known AMPK activator but reduces stroke incidence in clinical populations. We investigated the effect of acute and chronic metformin treatment on infarct volume and AMPK activation in experimental stroke. Male mice were subjected to middle cerebral artery occlusion after acute (3 days) or chronic (3 weeks) administration of metformin. Infarct volumes, AMPK activation, lactate accumulation, and behavioral outcomes were assessed. The roles of neuronal nitric oxide synthase and AMPK were examined using mice with targeted deletion of AMPK or neuronal nitric oxide synthase. Acute metformin exacerbated stroke damage, enhanced AMPK activation, and led to metabolic dysfunction. This effect was lost in AMPK and neuronal nitric oxide synthase knockout mice. In contrast, chronic metformin given prestroke was neuroprotective, improved stroke-induced lactate generation, and ameliorated stroke-induced activation of AMPK. Similarly, the neuroprotective effect of chronic prestroke metformin was lost in neuronal nitric oxide synthase knockout mice. AMPK is an important potential target for stroke treatment and prevention. These studies show that the timing, duration, and amount of AMPK activation are key factors in determining the ultimate downstream effects of AMPK on the ischemic brain.