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Dipeptidyl Peptidase-4 Inhibitor Anagliptin Prevents Intracranial Aneurysm Growth by Suppressing Macrophage Infiltration and Activation. 2017

Taichi Ikedo, and Manabu Minami, and Hiroharu Kataoka, and Kosuke Hayashi, and Manabu Nagata, and Risako Fujikawa, and Sei Higuchi, and Mika Yasui, and Tomohiro Aoki, and Miyuki Fukuda, and Masayuki Yokode, and Susumu Miyamoto
Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.

BACKGROUND Chronic inflammation plays a key role in the pathogenesis of intracranial aneurysms (IAs). DPP-4 (dipeptidyl peptidase-4) inhibitors have anti-inflammatory effects, including suppressing macrophage infiltration, in various inflammatory models. We examined whether a DPP-4 inhibitor, anagliptin, could suppress the growth of IAs in a rodent aneurysm model. RESULTS IAs were surgically induced in 7-week-old male Sprague Dawley rats, followed by oral administration of 300 mg/kg anagliptin. We measured the morphologic parameters of aneurysms over time and their local inflammatory responses. To investigate the molecular mechanisms, we used lipopolysaccharide-treated RAW264.7 macrophages. In the anagliptin-treated group, aneurysms were significantly smaller 2 to 4 weeks after IA induction. Anagliptin inhibited the accumulation of macrophages in IAs, reduced the expression of MCP-1 (monocyte chemotactic protein 1), and suppressed the phosphorylation of p65. In lipopolysaccharide-stimulated RAW264.7 cells, anagliptin treatment significantly reduced the production of tumor necrosis factor α, MCP-1, and IL-6 (interleukin 6) independent of GLP-1 (glucagon-like peptide 1), the key mediator in the antidiabetic effects of DPP-4 inhibitors. Notably, anagliptin activated ERK5 (extracellular signal-regulated kinase 5), which mediates the anti-inflammatory effects of statins, in RAW264.7 macrophages. Preadministration with an ERK5 inhibitor blocked the inhibitory effect of anagliptin on MCP-1 and IL-6 expression. Accordingly, the ERK5 inhibitor also counteracted the suppression of p65 phosphorylation in vitro. CONCLUSIONS A DPP-4 inhibitor, anagliptin, prevents the growth of IAs via its anti-inflammatory effects on macrophages.

UI MeSH Term Description Entries
D008262 Macrophage Activation The process of altering the morphology and functional activity of macrophages so that they become avidly phagocytic. It is initiated by lymphokines, such as the macrophage activation factor (MAF) and the macrophage migration-inhibitory factor (MMIF), immune complexes, C3b, and various peptides, polysaccharides, and immunologic adjuvants. Activation, Macrophage,Activations, Macrophage,Macrophage Activations
D008264 Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood MONOCYTES. Main types are PERITONEAL MACROPHAGES; ALVEOLAR MACROPHAGES; HISTIOCYTES; KUPFFER CELLS of the liver; and OSTEOCLASTS. They may further differentiate within chronic inflammatory lesions to EPITHELIOID CELLS or may fuse to form FOREIGN BODY GIANT CELLS or LANGHANS GIANT CELLS. (from The Dictionary of Cell Biology, Lackie and Dow, 3rd ed.) Bone Marrow-Derived Macrophages,Monocyte-Derived Macrophages,Macrophage,Macrophages, Monocyte-Derived,Bone Marrow Derived Macrophages,Bone Marrow-Derived Macrophage,Macrophage, Bone Marrow-Derived,Macrophage, Monocyte-Derived,Macrophages, Bone Marrow-Derived,Macrophages, Monocyte Derived,Monocyte Derived Macrophages,Monocyte-Derived Macrophage
D008297 Male Males
D010766 Phosphorylation The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. Phosphorylations
D011743 Pyrimidines A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (CYTOSINE; THYMINE; and URACIL) and form the basic structure of the barbiturates.
D001921 Brain The part of CENTRAL NERVOUS SYSTEM that is contained within the skull (CRANIUM). Arising from the NEURAL TUBE, the embryonic brain is comprised of three major parts including PROSENCEPHALON (the forebrain); MESENCEPHALON (the midbrain); and RHOMBENCEPHALON (the hindbrain). The developed brain consists of CEREBRUM; CEREBELLUM; and other structures in the BRAIN STEM. Encephalon
D002465 Cell Movement The movement of cells from one location to another. Distinguish from CYTOKINESIS which is the process of dividing the CYTOPLASM of a cell. Cell Migration,Locomotion, Cell,Migration, Cell,Motility, Cell,Movement, Cell,Cell Locomotion,Cell Motility,Cell Movements,Movements, Cell
D002532 Intracranial Aneurysm Abnormal outpouching in the wall of intracranial blood vessels. Most common are the saccular (berry) aneurysms located at branch points in CIRCLE OF WILLIS at the base of the brain. Vessel rupture results in SUBARACHNOID HEMORRHAGE or INTRACRANIAL HEMORRHAGES. Giant aneurysms (>2.5 cm in diameter) may compress adjacent structures, including the OCULOMOTOR NERVE. (From Adams et al., Principles of Neurology, 6th ed, p841) Aneurysm, Cerebral,Aneurysm, Intracranial,Basilar Artery Aneurysm,Berry Aneurysm,Brain Aneurysm,Cerebral Aneurysm,Giant Intracranial Aneurysm,Mycotic Aneurysm, Intracranial,Aneurysm, Anterior Cerebral Artery,Aneurysm, Anterior Communicating Artery,Aneurysm, Basilar Artery,Aneurysm, Middle Cerebral Artery,Aneurysm, Posterior Cerebral Artery,Aneurysm, Posterior Communicating Artery,Anterior Cerebral Artery Aneurysm,Anterior Communicating Artery Aneurysm,Middle Cerebral Artery Aneurysm,Posterior Cerebral Artery Aneurysm,Posterior Communicating Artery Aneurysm,Aneurysm, Berry,Aneurysm, Brain,Aneurysm, Giant Intracranial,Aneurysm, Intracranial Mycotic,Aneurysms, Basilar Artery,Aneurysms, Berry,Aneurysms, Brain,Aneurysms, Cerebral,Aneurysms, Giant Intracranial,Aneurysms, Intracranial,Aneurysms, Intracranial Mycotic,Artery Aneurysm, Basilar,Artery Aneurysms, Basilar,Basilar Artery Aneurysms,Berry Aneurysms,Brain Aneurysms,Cerebral Aneurysms,Giant Intracranial Aneurysms,Intracranial Aneurysm, Giant,Intracranial Aneurysms,Intracranial Aneurysms, Giant,Intracranial Mycotic Aneurysm,Intracranial Mycotic Aneurysms,Mycotic Aneurysms, Intracranial
D004195 Disease Models, Animal Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases. Animal Disease Model,Animal Disease Models,Disease Model, Animal
D004789 Enzyme Activation Conversion of an inactive form of an enzyme to one possessing metabolic activity. It includes 1, activation by ions (activators); 2, activation by cofactors (coenzymes); and 3, conversion of an enzyme precursor (proenzyme or zymogen) to an active enzyme. Activation, Enzyme,Activations, Enzyme,Enzyme Activations

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