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.

Potentials of incretin‐based therapies in dementia and stroke in type 2 diabetes mellitus

“…Post‐stroke treatment with peripherally‐administered exendin‐4 in diabetic rodents resulted in a reduction of infarct volume in a dose‐dependent manner117. Combined pre‐ and post‐treatment with peripherally‐administered linagliptin in diabetic rodents showed a trend toward a decrease in infarct volume118.…”

“…After stroke, microglial activation, an inflammatory response, induces various neurotoxic free radicals, cytotoxic and pro‐inflammatory mediators, and contributes to infarct progression114, 116. Rodent models showed inhibited microglial activation and microglial migration, thereby suppressing the inflammatory response induced by ischemic stroke116, 117. In addition, rodent models of ischemic stroke showed that incretin‐based therapies might protect against oxidative stress and neuronal cell death114, 115, 117.…”

“…Rodent models showed inhibited microglial activation and microglial migration, thereby suppressing the inflammatory response induced by ischemic stroke116, 117. In addition, rodent models of ischemic stroke showed that incretin‐based therapies might protect against oxidative stress and neuronal cell death114, 115, 117.…”

Mechanisms of neuroprotective action of incretin mimetics

“…Существует ряд работ, в которых продемонстриро-вано защитное действие ГПП-1 в условиях транзиторной фокальной ишемии головного мозга у животных [21][22][23][24][25][26].…”

“…Не менее показательно исследование, проведенное в 2012 г. V. Darsalia [26]. Крысам линии Goto-Kakizaki в течение 4 недель внутрибрюшинно вводился эксен-дин-4 в дозах 0,1, 1 и 5 мкг/кг 2 раза в день, что сопо-ставимо с дозами, используемыми для лечения СД2 у человека, в пересчете на массу тела.…”