Omarigliptin Protects the Integrity of the Blood–Brain Barrier After Intracerebral Hemorrhage in Mice

Abstract

Yan Zhang,1,2 Yang Liu,1,2 Xiangyu Zhang,1,2 V Wee Yong,3 Mengzhou Xue1,2 1Department of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 2Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 3Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, CanadaCorrespondence: V Wee Yong, Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada, Email [email protected] Mengzhou Xue, Department of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450001, People’s Republic of China, Email [email protected]: Intracerebral hemorrhage (ICH) is a fatal disease without effective treatment. The damage of the blood–brain barrier (BBB) is a key cause of brain edema and herniation after ICH. Omarigliptin (also known as MK3102) is a potent antidiabetic that inhibits dipeptidyl peptidase (DPP4); the latter has the ability to bind and degrade matrix metalloproteinases (MMPs). The present study aims to investigate the protective effects of omarigliptin against the destruction of BBB following ICH in mice.Methods and Materials: Collagenase VII was used to induce ICH in C57BL/6 mice. MK3102 (7 mg/kg/day) was administered after ICH. The modified neurological severity scores (mNSS) were carried out to assess neurological functions. Nissl staining was applied to evaluate neuronal loss. Brain water content, Evans blue extravasation, Western blots, immunohistochemistry and immunofluorescence were used to study the protective effects of BBB with MK3102 at 3 days after ICH.Results: MK3102 reduced DPP4 expression and decreased hematoma formation and neurobehavioral deficits of ICH mice. This was correspondent with lowered activation of microglia/macrophages and infiltration of neutrophils after ICH. Importantly, MK3102 protected the integrity of the BBB after ICH, associated with decreased expression of MMP-9, and preservation of the tight junction proteins ZO-1 and Occludin on endothelial cells through putative degradation of MMP-9, and inhibition of the expression of CX43 on astrocytes.Conclusion: Omarigliptin protects the integrity of the BBB in mice after ICH injury.Keywords: intracerebral hemorrhage, dipeptidyl peptidase, blood–brain barrier, omarigliptin

Keywords

• intracerebral hemorrhage
• dipeptidyl peptidase
• blood-brain barrier
• omarigliptin