AUTHOR=DellaValle Brian , Brix Gitte S. , Brock Birgitte , Gejl Michael , Rungby Jørgen , Larsen Agnete 

TITLE=Oral Administration of Sitagliptin Activates CREB and Is Neuroprotective in Murine Model of Brain Trauma

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 7 - 2016

YEAR=2016

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2016.00450

DOI=10.3389/fphar.2016.00450

ISSN=1663-9812

ABSTRACT=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