Beta-lactam Antibiotic Cefepime Attenuates Lipopolysaccharide-induced Pain and Depression By Modulating Inflammatory Response and Astroglial Glutamate Transporter in Mice.

Emerging evidence suggests that the brain glutamatergic system has a critical role in the pathophysiology of comorbid pain and depression. Cefepime is a widely used fourth-generation beta-lactam cephalosporin antibiotic and it has been shown to have neuroprotective properties in various animal models. In this study, cefepime is hypothesized to exert anti-nociceptive, anti-depressant, anxiolytic, and procognitive-like effects by modulating microglial activation and excessive glutamatergic neurotransmission in mice. Therefore, we have investigated the effects of cefepime on tactile allodynia, thermal hyperalgesia, depression, anxiety, and cognitive deficit-like behaviors in a mouse model of comorbid pain-depression induced by LPS. In addition, we have determined the effects of cefepime on astroglial expression of GLT-1 and microglial expression of Iba-1 in the hippocampus and prefrontal cortex using the Western blot analysis. We also evaluated the effects of cefepime on TNF-α and IL-1β levels in the hippocampus and prefrontal cortex using ELISA. Our results demonstrated that cefepime (50 mg/kg and 200 mg/kg i.p.) significantly attenuated LPS-induced nociceptive pain, depression, anxiety, and cognitive deficit-like behaviors in mice. In contrast, selective blockade of astroglial GLT-1 with dihydrokainic acid (10 mg/kg i.p.) significantly abolished the anti-nociceptive, anti-depressant, anxiolytic, and procognitive-like effects of cefepime (200 mg/kg i.p.), suggesting that these effects are mediated by the astroglial GLT-1 transporter. Western blot analysis indicated that cefepime (200 mg/kg) significantly reversed the LPS-reduced GLT-1 expression in the hippocampus and prefrontal cortex. Moreover, cefepime (200 mg/kg) effectively modulated the LPS-induced microglial activation as evidenced by decreased expression of Iba-1 in the hippocampus and prefrontal cortex. Notably, cefepime (200 mg/kg) significantly prevented the LPS-induced increased TNF-α and IL-1β levels in the hippocampus and prefrontal cortex by targeting glial mechanisms. Overall, these results suggest that novel glutamate transporter modulator cefepime could be developed as potential therapeutic utility for comorbid pain and depression.