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DPP-4 Inhibitor Linagliptin is Neuroprotective in Hyperglycemic Mice with Stroke via the AKT/mTOR Pathway and Anti-apoptotic Effects

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Abstract

Dipeptidyl peptidase 4 (DPP-4) inhibitors have been shown to have neuroprotective effects in diabetic patients suffering from stroke, but less research has focused on patients with mild hyperglycemia below the threshold for a diagnosis of diabetes. In this investigation, a hyperglycemic mouse model was generated by intraperitoneal injection of streptozotocin and then subjected to focal cerebral ischemia. We demonstrated that the DPP-4 inhibitor linagliptin significantly decreased the infarct volume, reduced neuronal cell death, decreased inflammation, and improved neurological deficit compared with control mice. Linagliptin up-regulated the expression of p-Akt and p-mTOR and regulated the apoptosis factors Bcl-2, Bax, and caspase 9. Taken together, these results suggest that linagliptin exerts a neuroprotective action likely through activation of the Akt/mTOR pathway along with anti-apoptotic and anti-inflammatory mechanisms. Therefore, linagliptin may be considered as a therapeutic treatment for stroke patients with mild hyperglycemia.

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Acknowledgements

This work was supported by the John E. Steinhaus Endowment fund.

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Authors and Affiliations

  1. Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, 30322, USA

    Gang Zhang, Samuel Kim, Xiaohuan Gu, Shan Ping Yu & Ling Wei

  2. Department of Neurology, Children’s Hospital of Nanjing Medical University, Nanjing, 210000, China

    Gang Zhang

  3. Department of Neurology, Emory University School of Medicine, Atlanta, GA, 30322, USA

    Ling Wei

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Correspondence to Ling Wei.

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Zhang, G., Kim, S., Gu, X. et al. DPP-4 Inhibitor Linagliptin is Neuroprotective in Hyperglycemic Mice with Stroke via the AKT/mTOR Pathway and Anti-apoptotic Effects. Neurosci. Bull. 36, 407–418 (2020). https://doi.org/10.1007/s12264-019-00446-w

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