Abstract WP245: Casein Kinase 2 Preconditions White Matter Against Ischemic Injury

Abstract

White matter injury (WMI) causes debilitating neurological impairments observed in stroke patients. Ischemic preconditioning (IPC) has been investigated as a protective mechanism against stroke in experimental studies. However, mechanisms of IPC have been mainly studied in gray matter and in vivo rodent models of IPC are not clinically relevant. There is a need to develop clinically-applicable pharmacologically preconditioning approaches that protect the brain against ischemia. Casein kinase 2 (CK2) is upregulated during WMI. Consequently, we have previously reported that application of CX-4945, a CK2 selective inhibitor, protects axon function in young and aged in ex vivo WM stroke model. However, whether CX-4945 preconditioning exerts similar axon function protection and alleviates behavior deficits in ex vivo and in vivo of WMI models remains to be investigated. We hypothesize that pharmacologically preconditioning with CX-4945 protects young and old WM against ischemic injury and alleviates behavioral deficits. Mouse optic nerves (MONs), a pure white matter tract, were used to measure axon function in an ex vivo stroke model. Compound action potentials (CAPs) were evoked and recorded from control and treated MONs. CX-4945 preconditioning did not alter axon function at baseline but protected axon function during recovery against oxygen-glucose deprivation. Behavioral deficits were assessed using cylinder tests and pasta eating tests. At baseline, mice preferentially used both paws; while injured mice showed a biased use of contralateral paw over bilateral paw. Additionally injured mice spent longer time eating pasta and with higher frequency of drops indicating the loss of paw dexterity. Mice were administered orally either CX-4945 (75mg/kg) or vehicle twice/day for 5 days before undergoing WMI. Treated mice showed improved bilateral paw use, and maintained paw dexterity. This behavioral protective effects of CK2 inhibition correlated with survival of oligodendrocyte, preservation of axonal integrity and axonal mitochondrial dynamics. We demonstrated that WM preconditioning with CX-4945 protects axon function, WM integrity, and alleviates behavior deficits in young and age mice.