title: Glucagon-like peptide-1 receptor activation reduces ischaemic brain damage following stroke in Type 2 diabetic rats.
abstract: Diabetes is a strong risk factor for premature and severe stroke. The GLP-1R (glucagon-like peptide-1 receptor) agonist Ex-4 (exendin-4) is a drug for the treatment of T2D (Type 2 diabetes) that may also have neuroprotective effects. The aim of the present study was to determine the efficacy of Ex-4 against stroke in diabetes by using a diabetic animal model, a drug administration paradigm and a dose that mimics a diabetic patient on Ex-4 therapy. Furthermore, we investigated inflammation and neurogenesis as potential cellular mechanisms underlying the Ex-4 efficacy. A total of seven 9-month-old Type 2 diabetic Goto–Kakizaki rats were treated peripherally for 4 weeks with Ex-4 at 0.1, 1 or 5 μg/kg of body weight before inducing stroke by transient middle cerebral artery occlusion and for 2–4 weeks thereafter. The severity of ischaemic damage was measured by evaluation of stroke volume and by stereological counting of neurons in the striatum and cortex. We also quantitatively evaluated stroke-induced inflammation, stem cell proliferation and neurogenesis. We show a profound anti-stroke efficacy of the clinical dose of Ex-4 in diabetic rats, an arrested microglia infiltration and an increase of stroke-induced neural stem cell proliferation and neuroblast formation, while stroke-induced neurogenesis was not affected by Ex-4. The results show a pronounced anti-stroke, neuroprotective and anti-inflammatory effect of peripheral and chronic Ex-4 treatment in middle-aged diabetic animals in a preclinical setting that has the potential to mimic the clinical treatment. Our results should provide strong impetus to further investigate GLP-1R agonists for their neuroprotective action in diabetes, and for their possible use as anti-stroke medication in non-diabetic conditions.
authors.affiliation: Diabetes Research Unit, Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Vladimer
authors.initials: V
authors.lastname: Darsalia
authors.forename: Shiva
authors.initials: S
authors.lastname: Mansouri
authors.forename: Henrik
authors.initials: H
authors.lastname: Ortsäter
authors.forename: Anna
authors.initials: A
authors.lastname: Olverling
authors.forename: Nino
authors.initials: N
authors.lastname: Nozadze
authors.forename: Camilla
authors.initials: C
authors.lastname: Kappe
authors.forename: Kerstin
authors.initials: K
authors.lastname: Iverfeldt
authors.forename: Linda M
authors.initials: LM
authors.lastname: Tracy
authors.forename: Nina
authors.initials: N
authors.lastname: Grankvist
authors.forename: Åke
authors.initials: Å
authors.lastname: Sjöholm
authors.forename: Cesare
authors.initials: C
authors.lastname: Patrone
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy*; D004353:Drug Evaluation, Preclinical; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D006943:Hyperglycemia / Q000188:drug therapy; D008297:Male; D017628:Microglia / Q000187:drug effects; D055495:Neurogenesis / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010455:Peptides / Q000627:therapeutic use*; D051381:Rats; D018027:Receptors, Glucagon / Q000819:agonists*; D020521:Stroke / Q000188:drug therapy*; D013318:Stroke Volume / Q000187:drug effects; D014688:Venoms / Q000627:therapeutic use*
chemical_list: C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D018696:Neuroprotective Agents; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D000077270:Exenatide