Ghrelin Prevents TBI‐induced Neuronal Apoptosis via Induction of Mitochondrial Uncoupling Protein 2 (UCP2)

Abstract

Traumatic brain injury (TBI) is a significant cause of morbidity and mortality in humans. Presently, no pharmacologic agent exists to prevent neuronal loss; however, the second wave of cellular death that follows TBI occurs within a timeframe amenable to therapeutic intervention. Previous research has demonstrated that transient mitochondrial uncoupling may help prevent initiation of apoptosis via the intrinsic pathway. Among the several endogenous mitochondrial uncoupling proteins identified, UCP2 has been shown to be expressed throughout the central nervous system and to provide a protective role in a variety of neural injury models. Moreover, production of UCP2 is upregulated when levels of ghrelin, a protein with anti‐inflammatory and anti‐apoptotic properties, are elevated. Our study sought to correlate these two observations in an experimental model of TBI. We hypothesized that ghrelin administration would inhibit neuronal apoptosis via induction of UCP2. BALB/c mice were divided into sham, TBI, and TBI/ghrelin treatment groups, and TBI was induced with a weight drop model following anesthesia. Neuronal apoptosis was characterized by staining coronal brain sections with the TUNEL method, and relative expression levels of UCP2 and the apoptotic protein caspase‐3 were analyzed with immunohistochemistry. We found that increased UCP2 expression in response to TBI/ghrelin treatment correlated with decreased neuronal apoptosis, suggesting that ghrelin treatment may provide an amenable therapeutic target for reducing neurodegeneration following TBI.