Dipeptidyl peptidase 4 deficiency improves survival after focal cerebral ischemia in mice and ameliorates microglia activation and specific inflammatory markers.

Autor: Höfling C; Paul Flechsig Institute for Brain Research, University of Leipzig, 04103 Leipzig, Germany; Department of Neurology, University of Leipzig, 04103 Leipzig, Germany., Donkersloot P; Paul Flechsig Institute for Brain Research, University of Leipzig, 04103 Leipzig, Germany., Ulrich L; Paul Flechsig Institute for Brain Research, University of Leipzig, 04103 Leipzig, Germany., Burghardt S; Paul Flechsig Institute for Brain Research, University of Leipzig, 04103 Leipzig, Germany., Opitz M; Paul Flechsig Institute for Brain Research, University of Leipzig, 04103 Leipzig, Germany., Geissler S; Fraunhofer Institute for Cell Therapy and Immunology, Department of Molecular Drug Design and Target Validation, 06120 Halle (Saale), Germany., Schilling S; Fraunhofer Institute for Cell Therapy and Immunology, Department of Molecular Drug Design and Target Validation, 06120 Halle (Saale), Germany; Anhalt University of Applied Sciences, Faculty of Applied Biosciences and Process Engineering, 06366 Köthen, Germany., Cynis H; Fraunhofer Institute for Cell Therapy and Immunology, Department of Molecular Drug Design and Target Validation, 06120 Halle (Saale), Germany; Junior Research Group 'Immunomodulation in Pathophysiological Processes' Faculty of Medicine, Martin Luther University Halle-Wittenberg, Germany., Michalski D; Department of Neurology, University of Leipzig, 04103 Leipzig, Germany., Roßner S; Paul Flechsig Institute for Brain Research, University of Leipzig, 04103 Leipzig, Germany. Electronic address: steffen.rossner@medizin.uni-leipzig.de.
Jazyk: angličtina
Zdroj: Neurobiology of disease [Neurobiol Dis] 2024 Oct 15; Vol. 201, pp. 106671. Date of Electronic Publication: 2024 Sep 16.
DOI: 10.1016/j.nbd.2024.106671
Abstrakt: Dipeptidyl peptidase 4 (DPP4; CD26) is involved in the regulation of various metabolic, immunological, and neurobiological processes in healthy individuals. Observations based on epidemiological data indicate that DPP4 inhibition by gliptins, typically used in patients with diabetes, may reduce the risk for cerebral ischemia and may also improve related outcomes. However, as DPP4 inhibitor application is neither complete nor specific for suppression of DPP4 enzymatic activity and DPP4 has non-enzymatic functions as well, the variety of consequences is a matter of debate. Therefore, we here used DPP4 knock-out (KO) mice to analyze the specific contribution of DPP4 to cellular, immunological, and functional consequences of experimental focal cerebral ischemia. We observed a significantly higher survival rate of DPP4 KO mice after ischemia, which was accompanied by a lower abundance of the pro-inflammatory chemokine CCL2 and reduced activation of Iba1-positive microglia cells in brain tissue of DPP4 KO mice. In addition, after ischemia for 24 h to 72 h, decreased concentrations of CCL5 and CCL12 in plasma and of CCL17 in brain tissue of DPP4 KO mice were observed when compared to wild type mice. Other aspects analyzed, such as the functional Menzies score, astrocyte activation and chemokine levels in plasma and brain tissue were affected by ischemia but appeared to be unaffected by the DPP4 KO genotype. Taken together, experimental ablation of DPP4 functions in mice improves survival and ameliorates aspects of cellular and molecular inflammation after focal cerebral ischemia.
Competing Interests: Declaration of competing interest The authors declare that they have no competing interests.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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