Dipeptidyl Peptidase‐4 Inhibitor Anagliptin Prevents Intracranial Aneurysm Growth by Suppressing Macrophage Infiltration and Activation

<jats:sec xml:lang="en"> <jats:title>Background</jats:title> <jats:p xml:lang="en"> Chronic inflammation plays a key role in the pathogenesis of intracranial aneurysms ( <jats:styled-content style="fixed-case">IA</jats:styled-content> s). DPP‐4 (dipeptidyl peptidase‐4) inhibitors have anti‐inflammatory effects, including suppressing macrophage infiltration, in various inflammatory models. We examined whether a <jats:styled-content style="fixed-case">DPP</jats:styled-content> ‐4 inhibitor, anagliptin, could suppress the growth of <jats:styled-content style="fixed-case">IA</jats:styled-content> s in a rodent aneurysm model. </jats:p> </jats:sec> <jats:sec xml:lang="en"> <jats:title>Methods and Results</jats:title> <jats:p xml:lang="en"> <jats:styled-content style="fixed-case">IA</jats:styled-content> s 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 <jats:styled-content style="fixed-case">RAW</jats:styled-content> 264.7 macrophages. In the anagliptin‐treated group, aneurysms were significantly smaller 2 to 4 weeks after <jats:styled-content style="fixed-case">IA</jats:styled-content> induction. Anagliptin inhibited the accumulation of macrophages in <jats:styled-content style="fixed-case">IA</jats:styled-content> s, reduced the expression of MCP‐1 (monocyte chemotactic protein 1), and suppressed the phosphorylation of p65. In lipopolysaccharide‐stimulated <jats:styled-content style="fixed-case">RAW</jats:styled-content> 264.7 cells, anagliptin treatment significantly reduced the production of tumor necrosis factor α, <jats:styled-content style="fixed-case">MCP</jats:styled-content> ‐1, and IL‐6 (interleukin 6) independent of GLP‐1 (glucagon‐like peptide 1), the key mediator in the antidiabetic effects of <jats:styled-content style="fixed-case">DPP</jats:styled-content> ‐4 inhibitors. Notably, anagliptin activated ERK5 (extracellular signal–regulated kinase 5), which mediates the anti‐inflammatory effects of statins, in <jats:styled-content style="fixed-case">RAW</jats:styled-content> 264.7 macrophages. Preadministration with an <jats:styled-content style="fixed-case">ERK</jats:styled-content> 5 inhibitor blocked the inhibitory effect of anagliptin on <jats:styled-content style="fixed-case">MCP</jats:styled-content> ‐1 and <jats:styled-content style="fixed-case">IL</jats:styled-content> ‐6 expression. Accordingly, the <jats:styled-content style="fixed-case">ERK</jats:styled-content> 5 inhibitor also counteracted the suppression of p65 phosphorylation in vitro. </jats:p> </jats:sec> <jats:sec xml:lang="en"> <jats:title>Conclusions</jats:title> <jats:p xml:lang="en"> A <jats:styled-content style="fixed-case">DPP</jats:styled-content> ‐4 inhibitor, anagliptin, prevents the growth of <jats:styled-content style="fixed-case">IA</jats:styled-content> s via its anti‐inflammatory effects on macrophages. </jats:p> </jats:sec>