{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,14]],"date-time":"2026-03-14T06:03:09Z","timestamp":1773468189708,"version":"3.50.1"},"reference-count":75,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T00:00:00Z","timestamp":1773273600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"South Dakota State University (SDSU) College of Pharmacy and Department of Pharmaceutical Sciences"},{"name":"Great Plains Veterans Research Foundation and Research Service"},{"name":"Sioux Falls VA Healthcare System"},{"DOI":"10.13039\/100006379","name":"VA Office of Research and Development","doi-asserted-by":"crossref","award":["I01BX004712"],"award-info":[{"award-number":["I01BX004712"]}],"id":[{"id":"10.13039\/100006379","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>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-\u03b1 (TNF-\u03b1) and interleukin-1\u03b2 (IL-1\u03b2) 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.<\/jats:p>","DOI":"10.3390\/brainsci16030306","type":"journal-article","created":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T14:46:31Z","timestamp":1773326791000},"page":"306","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cefepime Alleviates Comorbid Pain and Depression Induced by Lipopolysaccharide in Female Mice"],"prefix":"10.3390","volume":"16","author":[{"given":"Amna","family":"Khan","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings, SD 57007, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick J.","family":"Ronan","sequence":"additional","affiliation":[{"name":"Research Service, Sioux Falls VA Healthcare System, Sioux Falls, SD 57105, USA"},{"name":"Department of Psychiatry and Basic Biomedical Sciences, University of South Dakota Sanford School of Medicine, Sioux Falls, SD 57105, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6289-5386","authenticated-orcid":false,"given":"Shafiqur","family":"Rahman","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings, SD 57007, USA"},{"name":"Research Service, Sioux Falls VA Healthcare System, Sioux Falls, SD 57105, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1097\/j.pain.0000000000003056","article-title":"Co-Occurrence of Chronic Pain and Anxiety\/Depression Symptoms in U.S. Adults: Prevalence, Functional Impacts, and Opportunities","volume":"165","author":"Jennifer","year":"2024","journal-title":"Pain"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11682-012-9179-y","article-title":"Brain Regions Associated with Psychological Pain: Implications for a Neural Network and Its Relationship to Physical Pain","volume":"7","author":"Meerwijk","year":"2013","journal-title":"Brain Imaging Behav."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"99","DOI":"10.3389\/fnbeh.2014.00099","article-title":"Common Mechanisms of Pain and Depression: Are Antidepressants Also Analgesics?","volume":"8","author":"Nekovarova","year":"2014","journal-title":"Front. 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