The Neurotrophic/Neuroprotective Role of Gip in Cellular and Rodent Models of Mild Traumatic Brain Injury.( I )

Mild traumatic brain injury (mTBI) represents 70-90% of all treated traumatic brain injuries. The symptoms, including mood disorders and impaired attention and memory, usually resolve without intervention, but sometimes persistent symptoms develop. Reactive oxygen species (ROS) plays major role in the pathogenesis of TBI, resulting in neuronal damage, and loss of cortical excitability and synaptic plasticity. Therefore, the potential of neuroprotection is a novel treatment strategy. Research have demonstrated that pretreatment with the endogenous incretin, glucagon-like peptide-1 (GLP-1) may provide neurotrophic and neuroprotective effects in many acute and chronic neurodegenerative models through GLP-1 receptor activation. Glucose-dependent insulinotropic polypeptide (GIP) is another incretin similar to GLP-1, showing potential for halting or reversing neurodegenerative processes in CNS disorders. This is to further demonstrate the neuroprotective role of GIP in cellular and rodent models of mild traumatic brain injury. In the first year, we will identify the neuroprotective effect of GIP-R expression in PC12 cell model and primary rat cortical neuron by estimating the cell viability, proliferation, and survival. In addition, the (pro3)GIP, a specific GIP-R antagonist, will be utilized to confirm GIP-induced neurotrophic/neuroprotective actions are mediated via GIP-R. Consequently, we will figure out the regulatory mechanisms of GIP on the gene expression of mTBI animal model via using cDNA microarrays. The quantitative real time PCR and Western blotting will be used to further confirm the regulated gene expression. In the last year, the synaptic and cognitive function in mild traumatic brain injury animal model after GIP treatment will be investigated. The cognitive testing will be performed in a Morris water maze (MWM). The hippocampus tissues from mTBI animals, the mRNA expression of ARP2, Nrxn3, Tgm2 and Fcgr3 will be observed by QPCR. The protein expression of synapsin I and CREB will be determined by Western blotting. The BDNF protein in the hippocampus will be further quantified using ELISA. In the near future, we hope to clarify whether GIP may play a role in neuroprotection in mTBI animals. It will provide a novel strategy for mTBI treatment.