Selective Inhibition of Soluble TNF Attenuates Hippocampal Neuroinflammation and PSD-95 Expression to Improve Neurological Functions in a Rat Model of Gulf War Illness

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BACKGROUND Systemic inflammation is a major contributor to poor brain pathology across many disease conditions. Specifically, the upregulation of the pro-inflammatory cytokine TNF in the hippocampus activates its receptor TNFR1, reducing AMPA receptor trafficking to impair LTP and associated behavioral outcomes. Studies using animal models of GWI have shown both a chronic upregulation of TNF and impaired neurological function. Therefore, this study aimed to investigate whether selectively inhibiting only the soluble form of TNF (solTNF) that preferentially activates TNFR1 can reverse neuroinflammation to improve neuroplasticity and neurological function. METHODS GWI was induced in rats by treating with DFP (or vehicle) for 5 consecutive days. Six months later, the rats were treated with XPro1595 (or vehicle) for 2 weeks to selectively inhibit solTNF, after which they were subjected to a battery of behavioral tests (cognition, anxiety-related, depressive-like behavior, and neuropathic pain). MRI brain scans were performed, and the animals were euthanized for brain pathological analysis. RESULTS The hippocampus of the GWI rats had significantly increased neuroinflammatory levels, resulting in edema and reduced AMPA receptor trafficking to the post-synaptic membrane that collectively promoted impairments in memory, anxiety, depressive-like behavior, and neuropathic pain. However, treating the rats with XPro1595 in the chronic environment attenuated the neuroinflammatory response, that reduced edema and impaired AMPA receptor trafficking, allowing for improvements in all areas of neurological function. CONCLUSION Overall findings suggest that selectively inhibiting solTNF using XPro1595 reduces neuroinflammation, synaptic plasticity, and overall function when administered in the chronic setting of a rat model of GWI. This data supports the use of XPro1595 in Veterans with GWI.