Carnosine Is Neuroprotective Against Traumatic Brain Injury In Mice Model

Background:Traumatic brain injury (TBI) is a common neurosurgery disease with high incidence, high mortality and high disability rate. It often causes obvious economic burden of family and society. The brain damage caused by TBI includes primary injury and secondary injury. Secondary brain injury is progressive and can last several hours, days, or even months after TBI. It is mainly due to the complex pathophysiological process, including cerebral edema, blood brain barrier (BBB) damage, the release of excitatory amino acids toxicity, inflammation, oxidative stress and apoptosis, etc. So the key to reduce mortality and improve prognosis of TBI patients is to inhibit or relieve the secondary brain injury. In recent years, many scholars and clinicians at home or abroad have made significant progress in the pathology and diagnosis of TBI, radiology in the nervous system, neurosurgery nursing and treatment of TBI. However, there is still no real effective drug treatment, which urges us to find a nerve protective agent at present stage.As is known to all, carnosine (β-alanyl-i-histidine), a naturally compound dipeptide, almost exists in all human organizations, the central nervous system included. It is well tolerated in high doses with minimal side effects. What’s more, it has been illustrated to have multiple neuroprotective properties in various models. Previous studies showed that it plays anti-oxidative and anti-apoptotic roles in animals with ischemic brain injuries and neurodegenerative diseases. However, the potential effect of carnosine in traumatic brain injury (TBI) remains unknown. So this study explored the protective effect of carnosine on cerebral injury in the mice TBI model.Methods:The mice we used are the male Institute of Cancer Research (ICR) mice (all weighing 25-28 g) and the model we used is the modified heavy hammer model. L-carnosine was bought from Sigma and was dissolved in sterile saline (0.9% NaCl) just before experiment. Either carnosine or an equal volume (0.15 ml) of sterile saline was administrated 30 minutes after the surgery by intraperitoneal injection. The experiment has the following two parts.In the first part of the experiment, using the random number table method, the mice were divided into six groups:sham group, TBI group, TBI+saline group, TBI+ low dose carnosine group (500 mg/kg), TBI+moderate dose carnosine group (1000 mg/kg) and TBI+high dose carnosine group (1500 mg/kg). Neurologic scores were detected 24 hours and 72 hours after TBI by the neurologic severity score (NSS), while the brain water content was determined 24 hours after TBI with the wet and dry weight ratio method.According to the first part of the experiment, we got the best dose group, so in the second part of the experiment, the mice were divided into four groups:sham group, TBI group, TBI+saline group and TBI+best dose carnosine group. BBB permeability, neuronal cell apoptosis, and the levels of caspase-3, Bcl-2 and Bax were detected respectively using Evans blue (EB) staining, terminal-deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining and protein imprinting analysis 24 hours after TBI. In addition, oxidative stress was evaluated based on changes of malondialdehyde (MDA) and superoxide dismutase (SOD) expressions.Results:In the three different dose groups, the middle dose (1000 mg/kg) carnosine group works best. The optimal dose of carnosine markedly improved neurological function and attenuated cerebral edema as well as BBB disruption. It significantly reduced the number of TUNEL-positive cells in the damaged brain. Besides, it inhibited expressions of caspase-3 and Bax, while promoted the expression of Bcl-2. What’s more, the protective role of camosine was also accompanied by decreased MDA level and increased SOD level.Conclusions:Carnosine plays a critical role in neuroprotection after TBI.