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.

DPP‐4 inhibitor reduces striatal microglial deramification after sensorimotor cortex injury induced by external force impact

“…Previous studies have shown that the neuroprotective effect of gliptins is glucose‐independent and is associated with activation of the GLP‐1 system 12‐16,28 . Enhanced incretin by gliptins results in attenuation of inflammatory responses, oxidative stress, mitochondrial dysfunction, tau phosphorylation, and disease‐related pathologies 12‐13,15‐16,19,27,28 . We found that blood and brain levels of active GLP‐1 are both increased after sitagliptin treatment.…”

“…Gliptins reduce neurodegeneration after acute focal cerebral ischemia 14 or chronic cerebral hypo‐perfusion 18 in nondiabetic animals. A recent study in a stereotactic cryo‐lesion model indicates that presurgical treatment with sitaglipin reduced lesioned size and activated the neuroprotective cAMP response element binding protein system in brain of female C57B16/j mice 19 . Taken together, these data suggest that gliptins have preventive neuroprotective effects in both diabetic and nondiabetic animals.…”

“…Neuroprotection by gliptins has been reported in many studies. Sitagliptin treatment prior to and continued after cryogenic lesions reduced cortical lesion size in nondiabetic animals 19 . Chronic and prophylactic administration of vildagliptin prevented neurodegeneration in animal models of Alzheimer's disease, 16 Parkinson's disease, 17 diabetic vascular dementia, 27 and high‐fat diet‐mediated insulin resistance 12,13 .…”

“…The changes in cytokine expression by sitagliptin treatment observed in the present study may be attributed to the reduction of inflammation and maintenance of axon connectivity, together to contribute to the pathological attenuation and neurological recovery. The often seen axonal pathology and corticostriatal connectivity disruption in human TBI and the therapeutic effects of sitagliptin on these aspects would not be possible in the cryogenic lesion model by DellaValle et al, 19 since the model mainly produces focal pathological responses 41 …”

The Emerging Role of GLP-1 Receptors in DNA Repair: Implications in Neurological Disorders

“…The DPP-4 inhibitors have not been extensively investigated for TBI treatment. A recent study from DellaValle et al [ 131 ] demonstrated that oral administration of sitagliptin reduces brain lesion size and brain cell death via activation of the CREB-mediated signaling pathway in the TBI mouse model; moreover, CREB-regulated expression of manganese superoxide dismutase (MnSOD) was increased in sitagliptin-treated mice. All these lines of evidence from previous studies indicate agonists of GLP-1R have potential as pharmacological-based therapies for TBI.…”