Oxidation of K+ Channels in TBI

The delayed rectifier potassium (K+) channel KCNB1 (Kv2.1), which conducts a major somatodendritic current in cortex and hippocampus, is known to undergo oxidation in the brain but whether this can cause neurodegeneration and cognitive impairment is not known. Here, we used transgenic mice harboring human KCNB1 wild type (Tg-WT) or non-oxidable C73A mutant (Tg-C73A) in cortex and hippocampus, to determine whether oxidized KCNB1 channels affect brain function. Animals were subjected to moderate traumatic brain injury (TBI), a condition characterized by extensive oxidative stress. Dasatinib, an FDA-approved inhibitor of Src tyrosine kinases was used to impinge on the pro-apoptotic signaling pathway activated by oxidized KCNB1 channels. Thus, typical lesions of brain injury, namely inflammation (astrocytosis), neurodegeneration and cell death were markedly reduced in Tg-C73A and dasatinib-treated non-Tg animals. Accordingly, Tg-C73A mice and non-Tg mice treated with dasatinib exhibited improved behavioral outcomes in motor (rotarod) and cognitive (Morris Water Maze) assays compared to control. Moreover, the activity of Src kinases, along with oxidative stress, were significantly diminished in Tg-C73A brains. Together, these data demonstrate that oxidation of KCNB1 channels is a contributing mechanism to cellular and behavioral deficits in vertebrates and suggest a new therapeutic approach to TBI.