DPP4 inhibition for the treatment of stroke
Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesisAlternative title
DPP4 inhibering för behandling av stroke (Swedish)
Diabetes is a strong risk factor for premature and severe stroke. The dipeptidyl peptidase-4 (DPP-4) enzyme inhibitor Linagliptin is a drug for the treatment of type 2 diabetes (T2D) that may also have neurprotective effects. The aim of this study was to understand whether the systemic activation of Linagliptin is efficacious against stroke via stimulation of neuroprotection. This was done y using a diabetic animal model, a drug administration paradigm and a dose that mimic a diabetic patient on chronic Linagliptin therapy. We used glimepiride, which is an insulin secretagogue sulfonylurea, as a glycemic comparator.
A total of 44 male C57B1 mice were divided in two sets of experiments. In the first sets of experiments, 21 eight-week-old mice were exposed to high-fat diet (HFD) for a total of 32 weeks so they would develop (T2D). In teh second set of experiments, 23 ten-week-old normal diet-fed mice were treated similarly to the first experiment. In both sets of experimentm, the animals were given 10mg/kg/bw Linagliptin per day, or 2 mg/kg/bw glimepiride per day, or vehicle for 4 weeks. They were then subjected to stroke by transient middle cerebral artery occlustion (MCAo) and the drug treatment continued for 3 weeks until sacrifice.
The severity of ischemic damage was measured by evaluation of stroke volume and by stereological counting of neurons in the striatum and cortex. We show a statistically significant anti-stroke efficacy in both T2D and non-diabetic mice on Linagliptin treatment. Our results provide an impetus for the further development of incretin-based drugs for the prevention and treatment of stroke in both diabetic and non-diabetic high-risk patients.
Place, publisher, year, edition, pages
Immunohistochemistry, ELISA, lignagliptin, stroke, ischemic damage
Engineering and Technology
IdentifiersURN: urn:nbn:se:kth:diva-149657OAI: oai:DiVA.org:kth-149657DiVA: diva2:744699