Selective Inhibition of Soluble TNF using XPro1595 Improves Hippocampal Pathology to Promote Improved Neurological Recovery Following Traumatic Brain Injury in Mice

CNS Neurol Disord Drug Targets. 2023;22(9):1378-1390. doi: 10.2174/1871527321666220610104908.

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.

Keywords: TBI; TNF; TNFR1; glial reactivity; inflammation; synaptic plasticity..

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Brain Injuries, Traumatic* / complications
  • Brain Injuries, Traumatic* / diagnosis
  • Brain Injuries, Traumatic* / drug therapy
  • Brain Injuries, Traumatic* / pathology
  • Dendrites / drug effects
  • Dendrites / metabolism
  • Dendrites / pathology
  • Disease Models, Animal
  • Disks Large Homolog 4 Protein / metabolism
  • Hippocampus* / cytology
  • Hippocampus* / drug effects
  • Hippocampus* / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neuralgia / drug therapy
  • Neuralgia / etiology
  • Neuralgia / pathology
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / physiology
  • Recovery of Function / drug effects
  • Recovery of Function / physiology
  • Severity of Illness Index
  • Tumor Necrosis Factor Inhibitors* / pharmacology
  • Tumor Necrosis Factor Inhibitors* / therapeutic use
  • Tumor Necrosis Factor-alpha* / administration & dosage
  • Tumor Necrosis Factor-alpha* / metabolism

Substances

  • XENP 1595
  • Tumor Necrosis Factor-alpha
  • Tumor Necrosis Factor Inhibitors
  • Dlg4 protein, mouse
  • Disks Large Homolog 4 Protein