Agmatine attenuate brain edema through lessening the expression of aquaporins after traumatic brain injury

Background and aims: Brain edema is a pathophysiological condition of increased water content due to a variety of brain injuries, including trauma, ischemia and progression results in major focal brain dysfunction. The cold injury model is one of the established models for the study of vasogenic brain edema development and secondary rain injury[1]. The aquaporins are a family of water-selective membrane channels. Aquaporin-1, -4 and -9 have been identified as the three major water channels in the brain[2]. Agmatine is a primary amine formed by the arginine decarboxylase and is known as an antagonist at N-methyl-D-aspartate (NMDA) receptors and an inhibitor for NOS. Previously we reported the neuroprotective effect of agmatine on infarct volume and brain edema following cerebral ischemia[3]. In this study, we investigate that administration of agmatine regulates aquaporin expression and attenuates brain edema after TBI. Materials and methods: For the cold traumatic injury model, the skull of the rat was mounted in a stereotactic device for trephination (diameter for 4mm) above the right parietal cortex leaving dura mater intact. Cortical lesion was induced by attachment of metal probe (diameter 3mm) cooled by liquid nitrogen onto the brain surface 5 times for 30 seconds. Agmatine was treated 30min after traumatic cold injury (100mg/kg, IP). Water content was analyzed in 24hours after TBI. The expression of aquaporins was examined with immunohistochemistry and immunoblotting. Results: The physiological parameters before cold traumatic injury were monitored and maintained throughout the experiment. Trauma-induced loss of brain volume and the number of eosinophilic neurons were reduced and improved neurological deficits in agmatine treatment group. The water content in cold traumatic injured brains at 24hours after insults was measured and decreased in agmatine treatment group. We examined the expression of aquaporin-1,-4 and -9 using immunohistochemistry and immunoblotting in cerebral cortex and hippocampus. In all time point, aquaporin-1 was decreased in agmatine treatment group compared to experimental control after TBI. Aquaporin -4, -9 were similar expressed in agmatine treatment group and experimental control 1, 2 day after TBI. But 1week after TBI, the expressions of aquaporin -4,-9 were decreased in agmatine treatment group. Conclusion: Agmatine could attenuate brain edema through lessening water content by suppression of the expression of aquaporins. These results may suggest agmatine as a novel therapeutic material for vasogenic and cytosolic edema including traumatic brain injury and brain tumor.