Deshpande, L. S. | Search bioRxiv

bioRxiv2022

SELECTIVE INHIBITION OF SOLUBLE TNF ATTENUATES HIPPOCAMPAL NEUROINFLAMMATION AND PSD-95 EXPRESSION TO IMPROVE NEUROLOGICAL FUNCTIONS IN A RAT MODEL OF GULF WAR ILLNESS

BACKGROUNDSystemic 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. METHODSGWI 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. RESULTSThe 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. CONCLUSIONOverall 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.

neuroscience↗

bioRxiv2021

Repeated exposure to chlorpyrifos is associated with a dose-dependent chronic neurobehavioral deficit in adult rats

Organophosphate (OP) chemicals include commonly used pesticides and also chemical warfare agents, and mechanistically they are potent inhibitors of the cholinesterase (ChE) enzyme. While a chronic low-dose OP exposure does not produce acute cholinergic crises, epidemiological studies report long-term neuropsychiatric issues including depression and cognitive impairments in OP-exposed individuals. Chlorpyrifos (CPF) is one of the most widely used pesticides worldwide. Multiple laboratory studies have reported on either the long-term behavioral effect of a single, high-dose CPF or studied sub-chronic behavioral effects particularly the motor and cognitive effects of repeated low-dose CPF exposure. However, studies on chronic mood and depression-related morbidities following repeated sub-threshold CPF doses that would mimic occupationally-relevant OP exposures are lacking. Here, adult male rats were injected with CPF (1, 3, 5, or 10 mg/kg/d, s.c.) for 21-days. Dependent on the CPF dose, ChE activity was inhibited approximately 60-80% in the blood and about 20-50% in the hippocampus at 2-days after the end of CPF exposures. Following an 11-week washout period, CPF-treated rats exhibited a dose-dependent increase in signs of anhedonia (sucrose preference test), anxiety (open-field and elevated plus-maze), and despair (forced swim test) despite a complete recovery of ChE activity at this stage. We speculate that both cholinergic and non-cholinergic mechanisms could play a role in the development of chronic OP-related depressive outcomes. The proposed CPF exposure paradigm could provide an ideal model to further study molecular mechanisms underlying cause and effect relationships between environmental OP exposures and the development of chronic behavioral deficits.

pharmacology and toxicology↗