Oral administration of sitagliptin activates CREB and is neuroprotective in murine model of brain trauma
Introduction: Traumatic brain injury is a major cause of mortality and morbidity. We have previously shown that the injectable glucagon-like peptide-1 (GLP-1) analogue, liraglutide, significantly improved the outcome in mice after severe traumatic brain injury (TBI). In this study we are interested...
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| Main Authors: | , , , , , |
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| Format: | Book |
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Frontiers Media S.A.,
2016-12-01T00:00:00Z.
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| Summary: | Introduction: Traumatic brain injury is a major cause of mortality and morbidity. We have previously shown that the injectable glucagon-like peptide-1 (GLP-1) analogue, liraglutide, significantly improved the outcome in mice after severe traumatic brain injury (TBI). In this study we are interested in the effects of oral treatment of a different class of GLP-1 based therapy, dipeptidyl peptidase IV (DPP-IV) inhibition on mice after TBI. DPP-IV inhibitors reduce the degradation of endogenous GLP-1 and extend circulation of this protective peptide in the bloodstream. This class has yet to be investigated as a potential therapy for TBI. Methods: Mice were administrated once-daily 50 mg/kg of sitagliptin in a Nutella® ball or Nutella® alone throughout the study, beginning two days before severe trauma was induced with a stereotactic cryo-lesion. At two days post trauma, lesion size was determined. Brains were isolated for immunoblotting for assessment of selected biomarkers for pathology and protection.Results: Sitagliptin treatment reduced lesion size at day 2 post-injury by ~28% (p<0.05). Calpain-driven necrotic tone was reduced ~2-fold in sitagliptin-treated brains (p<0.001) and activation of the protective cAMP-response element binding protein (CREB) system was significantly more pronounced (~1.5-fold, p<0.05). The CREB-regulated, mitochondrial antioxidant protein manganese superoxide dismutase (MnSOD) was increased in sitagliptin-treated mice (p>0.05). Conversely, apoptotic tone (alpha-spectrin fragmentation, Bcl-2 levels) and the neuroinflammatory markers IL-6, and Iba-1 were not affected by treatment.Conclusions: This study shows, for the first time, that DPP-IV inhibition ameliorates both anatomical and biochemical consequences of TBI and activates CREB in the brain. Moreover, this work supports previous studies suggesting that the effect of GLP-1 analogues in models of brain damage relates to GLP-1 receptor stimulation in a dose-dependent manner.Keywords: GLP-1, Traumatic Brain Injury, TBI, sitagliptin, liraglutide, CREB, Oxidative Stress, GIP, DPP-IV, DPP-4 |
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| Item Description: | 1663-9812 10.3389/fphar.2016.00450 |