Selective inhibition of soluble TNF using XPro1595 improves hippocampal pathology to promote improved neurological recovery following traumatic brain injury in mice

Abstract BACKGROUNDSymptoms associated with traumatic brain injury (TBI) can be debilitating, and treatment without off-target side-effects remains a challenge. This study aimed to investigate the efficacy of selectively inhibiting the soluble form of TNF (solTNF) using the biologic XPro1595 in a mouse model of TBI. METHODSMild-to-moderate traumatic brain injury (CCI model) was induced in adult male C57Bl/6J mice, with XPro1595 (10 mg/kg, S.C.) or vehicle being administered in a clinically relevant window (60 minutes post-injury). The animals were assessed for differences in neurological function, and hippocampal tissue was analyzed for inflammation and glial reactivity, as well as neuronal degeneration and plasticity. RESULTSWe report that unilateral CCI over the right parietal cortex in mice promoted deficits in learning and memory, depressive-like behavior and neuropathic pain. Using immunohistochemical and Western blotting techniques, we observed the cortical injury promoted a set of expected pathophysiology’s within the hippocampus consistent with the observed neurological outcomes, including glial reactivity, enhanced neuronal dendritic degeneration (dendritic beading), and reduced synaptic plasticity (spine density and PSD-95 expression) within the DG and CA1 region of the hippocampus. These effects were prevented in the mice treated with XPro1595. CONCLUSIONOverall, we observed that selectively inhibiting solTNF using XPro1595 improved the pathophysiological and neurological sequelae of brain-injured mice, which provides support of its use in patients with TBI.