Title:Selective Inhibition of Soluble TNF using XPro1595 Improves Hippocampal
Pathology to Promote Improved Neurological Recovery Following
Traumatic Brain Injury in Mice
Volume: 22
Issue: 9
Author(s): Katelyn Larson, Melissa Damon, Rajasa Randhi, Nancy Nixon-Lee and Kirsty J. Dixon*
Affiliation:
- Department of Surgery, Virginia Commonwealth University, 1101 E. Marshall Street, Richmond VA, 23298, USA
Keywords:
TBI, inflammation, TNF, TNFR1, glial reactivity, synaptic plasticity.
Abstract:
Aims: To determine the efficacy of XPro1595 to improve pathophysiological and functional
outcomes in a mouse model of traumatic brain injury (TBI).
Background: Symptoms associated with 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.
Objectives: Use XPro1595 to determine whether injury-induced solTNF promotes hippocampal inflammation
and dendritic plasticity and associated functional impairments.
Methods: Mild-to-moderate traumatic brain injury (CCI model) was induced in adult male C57Bl/6J
WT and Thy1-YFPH 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.
Results: We 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, that were
prevented in mice treated with XPro1595.
Conclusion: Overall, we observed that selectively inhibiting solTNF using XPro1595 improved the
pathophysiological and neurological sequelae of brain-injured mice, which provides support for its use
in patients with TBI.
