title: Oral Administration of Sitagliptin Activates CREB and Is Neuroprotective in Murine Model of Brain Trauma.
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) analog, 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 2 days before severe trauma was induced with a stereotactic cryo-lesion. At 2 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 analogs in models of brain damage relates to GLP-1 receptor stimulation in a dose-dependent manner.
authors.affiliation: Department of Biomedicine/Pharmacology, Aarhus UniversityAarhus, Denmark; Centre of Medical Parasitology, Department of Clinical Microbiology, Copenhagen University HospitalCopenhagen, Denmark.
authors.forename: Brian
authors.initials: B
authors.lastname: DellaValle
authors.affiliation: Department of Biomedicine/Pharmacology, Aarhus University Aarhus, Denmark.
authors.forename: Gitte S
authors.initials: GS
authors.lastname: Brix
authors.affiliation: Department of Biomedicine/Pharmacology, Aarhus UniversityAarhus, Denmark; Department of Clinical Biochemistry, Aarhus University HospitalAarhus, Denmark.
authors.forename: Birgitte
authors.initials: B
authors.lastname: Brock
authors.affiliation: Department of Biomedicine/Pharmacology, Aarhus UniversityAarhus, Denmark; Department of Clinical Biochemistry, Aarhus University HospitalAarhus, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Gejl
authors.affiliation: Department of Biomedicine/Pharmacology, Aarhus UniversityAarhus, Denmark; Department of Endocrinology, Bispebjerg University HospitalCopenhagen, Denmark.
authors.forename: Jørgen
authors.initials: J
authors.lastname: Rungby
authors.affiliation: Department of Biomedicine/Pharmacology, Aarhus University Aarhus, Denmark.
authors.forename: Agnete
authors.initials: A
authors.lastname: Larsen
keywords: CREB; DPP-IV; GIP; GLP-1; TBI; liraglutide; sitagliptin; traumatic brain injury