Protective effects of β-Funaltrexamine against LPS-induced CCL2 expression and behavioral deficits

Abstract

Background: Inflammation is present in both neurological and peripheral disorders. Specifically, inflammation is one of the common factors in diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), mood disorders which include anxiety and depression, and even inflammatory bowel disease (IBD). Thus, exploring potential treatments geared toward the assessment of inflammation is crucial to the continuation of treatment development. One pharmacological agent researched for its antiinflammatory effects is β-funaltrexamine (β-FNA), a selective mu-opioid receptor antagonist. Preclinical studies using in vitro human astroglial cells showed that β-FNA inhibited inflammatory signaling, NF-κB signaling, and chemokine expression in a mechanism unrelated to MOR. Also, β-funaltrexamines neuroprotective effects were discovered in a preclinical model of lipopolysaccharide (LPS)-induced neuroinflammation and sickness-like behavior when administered before LPS.

Methods: This study determines the effects of β-FNA (50 mg/kg, i.p.) on LPS-induced (0.83 mg/kg, i.p.) sickness-like behavior using a 10 min open field test, and anxiety-like behavior, using a 5 min elevated plus maze in male and female C57BL/6J. It also assesses the effects on LPS-induced neuro and peripheral inflammation when β-FNA is administered immediately or 10 h post-LPS. Tissue collected included whole brain, hippocampus, prefrontal cortex, cerebellum/brain stem, spleen, liver, small intestine, large intestine, and plasma.

Results and Conclusions: Levels of inflammatory chemokine Monocyte Chemoattractant Protein-1 (MCP1, also known as CCL2) was measured using an enzyme-linked immunosorbent assay (ELISA). Two-way analysis of variance revealed that at 24 hours, LPS increased chemokines, and β-FNA treatment was protective depending on the dosing schedule and had region-specific effects. Also, to our knowledge, this is the first time β-FNAs effect on female mice has been assessed. Differential effects of β-FNA were found between the whole brain vs. brain regions, central vs. peripheral, and sexes. This study provides insight into the inflammatory protection offered by β-FNA in both the central and peripheral systems and further knowledge of the potential therapeutic options for inflammatory disorders.