Alogliptin, a dipeptidylpeptidase-4 inhibitor, for patients with diabetes mellitus type 2, induces tolerance to focal cerebral ischemia in non-diabetic, normal mice.

Abstract

Effective interventions that provide obvious neuroprotection are currently fairly limited. Glucagon-like peptide-1 (GLP-1), an enhancer of insulin production with a trophic effect on β cells in the islets, has been found to be trophic for neuronal cells. Alogliptin benzoate (AGL), a selective inhibitor of dipeptidylpeptidase-4 (DPP-4) functioning as a long-acting agonist of GLP-1, is in clinical use worldwide for patients with diabetes mellitus type 2. To clarify whether administration of AGL, independent of the insulinotropic effect, protects the brain against focal ischemia, we investigated the effect of AGL on the development of cerebral infarction in non-diabetic normal mice. Male C57BL/6J mice were administered AGL (7.5, 15, or 30μg) once a day for three weeks by intragastric gavage. After the induction of temporary focal ischemia, volumes of infarcted lesions and neurological deficits were analyzed at 24h (acute phase) and seven days (chronic phase). In the acute phase, significant reductions were observed in the volumes of infarcted lesions (p=0.009), and in the severity of neurological deficits (p=0.004), in the group treated with 15μg of alogliptin benzoate, but not the 7.5 or 30μg-treated groups. This significant reduction in volumes of infarcted lesions persisted into the chronic phase. At the end of the AGL treatment; before the induction of ischemia, the levels of brain-derived neurotrophic factor (BDNF), a potent neuroprotectant in the brain, were elevated in the cortex (p=0.008), or in the whole forebrain (p=0.023). AGL could be used as a daily neuroprotectant or an enhancer of BDNF production aiming to attenuate cerebral injuries, for the growing number of people who have the risk of ischemic stroke.

• Authors: Dong Yang, Yukako Nakajo, Koji Iihara, Hiroharu Kataoka, Hiroji Yanamoto
• Journal: Brain research (Brain Res) Vol. 1517 Pg. 104-13 (Jun 23 2013) ISSN: 1872-6240 [Electronic] Netherlands
• PMID: 23602966 (Publication Type: Journal Article)
• Copyright: Copyright © 2013 Elsevier B.V. All rights reserved.

Chemical References

• Brain-Derived Neurotrophic Factor
• Dipeptidyl-Peptidase IV Inhibitors
• Piperidines
• Uracil
• alogliptin

Topics

• Analysis of Variance
• Animals
• Brain Edema (etiology, prevention & control)
• Brain Infarction (etiology, prevention & control)
• Brain Ischemia (complications, drug therapy, pathology, prevention & control)
• Brain-Derived Neurotrophic Factor (metabolism)
• Dipeptidyl-Peptidase IV Inhibitors (therapeutic use)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Gene Expression Regulation (drug effects)
• Laser-Doppler Flowmetry
• Male
• Mice
• Mice, Inbred C57BL
• Microcirculation (physiology)
• Nervous System Diseases (etiology, prevention & control)
• Piperidines (therapeutic use)
• Prosencephalon (blood supply, drug effects, metabolism)
• Time Factors
• Uracil (analogs & derivatives, therapeutic use)