Cefepime Alleviates Comorbid Pain and Depression Induced by Lipopolysaccharide in Female Mice

TL;DR

Cefepime reduces pain and depression in female mice caused by lipopolysaccharide, suggesting it could be a new treatment for these conditions.

Contribution

This is the first study to show cefepime's effects on comorbid pain and depression in female mice via glutamate transporter modulation.

Findings

Cefepime increased pain thresholds and reduced immobility in depression tests in female mice.

Cefepime reversed downregulated GLT-1 and reduced microglial Iba-1 in brain regions.

Cefepime attenuated pro-inflammatory cytokine production in the hippocampus and prefrontal cortex.

Abstract

Background/Objectives: Evidence indicates that aberrant glutamate transporter function and expression are linked to the pathophysiology of comorbid major depressive disorder (MDD) and pain. We have previously reported that cefepime (CFP) attenuates lipopolysaccharide (LPS)-evoked pain and depression by regulating hyperglutamatergic activity in male mice. However, the effects of CFP on LPS-evoked pain, depression-related anxiety, and cognitive impairment in female mice regarding sex-specific glial mechanisms remain unknown. Methods: Using behavioral paradigms, we evaluated the therapeutic potential of CFP in mitigating LPS-evoked pain, depression-related anxiety, and cognitive impairment in female mice. Furthermore, we used Western blot analysis to examine the effects of CFP on ionized calcium-binding adaptor molecule 1 (Iba-1) and glutamate transporter 1 (GLT-1) protein levels in the prefrontal cortex (PFC) and hippocampus (HPC). We also measured tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) concentrations in the HPC and PFC after CFP treatment using ELISA. Results: Pretreatment with CFP significantly increased the mechanical threshold and withdrawal latency in female mice. Additionally, systemic treatment with CFP markedly reduced immobility during the forced swim and tail suspension tests. Moreover, pretreatment with CFP remarkably augmented the open arm time during elevated plus maze test and spontaneous alternation between arms during Y-maze test. Western blot analysis indicated that systemic administration of CFP significantly reversed the downregulation of astroglial GLT-1 expression and reduced the microglial Iba-1 protein levels in the HPC and PFC. Furthermore, pretreatment with CFP significantly attenuated the LPS-evoked increase in the production of pro-inflammatory cytokines in the HPC and PFC. Conclusions: These results represent the novel inaugural report of a combined pain-MDD phenotype in female mice. The findings imply that positive glutamate transporter modulator CFP could be a novel treatment for comorbid pain and MDD in female patient population.

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