Assessing the Neurotoxic Effects of Fosfomycin on Cognition and Hippocampal Neurogenesis in Adult Female Rats
Abstract
Introduction: Neurogenesis is the process by which new functional neurons arise from neural stem cells (NSCs). Comprised of four major phases (proliferation, fate specification, differentiation and maturation, and synaptic integration), this highly dynamic process takes place in several areas in the brain including the dentate gyrus (DG) of the hippocampus, an important area for learning, memory, and mood regulation. It can be affected by multiple factors including brain injury, inflammation, aging, oxidative stress, and antibiotic administration, which has been associated with behavioral deficits and neurotoxicity. Fosfomycin is a broad-spectrum antibiotic widely prescribed in the treatment of uncomplicated urinary tract infections (UTIs). It has an important bactericidal activity, irreversibly inhibiting bacterial cell wall synthesis at an early stage.
A previous study published by our laboratory has revealed neurotoxic activity upon injecting Fosfomycin to treat induced UTIs in male Sprague Dawley rats. Further studies in our laboratory have focused on highlighting the neurotoxic effects of this antibiotic on healthy male rats, but the effects on female rats have not been investigated. This constitutes an important research gap due to the higher incidence of UTIs in females, which makes female rats a model worth investigating.
Objective: This project aims to investigate the neurotoxic effects of Fosfomycin on motricity, pain sensitivity, cognitive functions, as well as hippocampal neurogenesis of adult female rats.
Methods: In this study, adult female Sprague Dawley rats aged 8 weeks were divided into four groups. The antibiotic-injected group received two daily intraperitoneal injections of Fosfomycin, 8 hours apart, over 7 days. This group was divided into two groups: one received a low dose (177 mg/kg), and the other a high dose (354 mg/kg). The sham group was instilled with saline instead of the antibiotic, and the naïve group was not subjected to any injections. A series of behavioral assessments were conducted before (baseline) and after (end) antibiotic injections. These tests include the Y-Maze, novel object recognition (NOR), as well as the Rotarod test. This allows the assessment of spatial memory, recognition memory, and motricity, respectively. In addition, the thermal sensitivity test was performed on the abdomen of the rats to identify the occurrence of hyperalgesia. The rats’ estrous cycle was also tracked. Finally, rats received 3 injections, 2 hours apart, of Bromodeoxyuridine (BrdU) analog 24 hours prior to euthanasia to assess hippocampal NSCs proliferation (the first step in neurogenesis).
Results: Fosfomycin administration did not affect motricity, thermal sensitivity, or spatial working memory. However, Fosfomycin-injected groups demonstrated a significantly lower number of entries to the novel object zone in the NOR test compared to control groups, and travelled a significantly shorter distance in the NOR apparatus, suggesting that this antibiotic might negatively impact recognition memory and exploratory behavior. Additionally, a significant decrease in the number of proliferating NSCs in the DG of the hippocampus was recorded in the group receiving a high dose of Fosfomycin compared to the sham. At the molecular level, FGF2, NGF and TrkB mRNA levels were significantly increased in the low dose group compared to the sham, suggesting the occurrence of a certain compensatory mechanism following the administration of low doses of Fosfomycin.
Conclusion & future perspectives: Our data have shown neurotoxic activity upon administration of Fosfomycin in adult female rats, as well as cognitive and memory deficits. These findings will help in better understanding the neurotoxicity of Fosfomycin, and for the first time in female rats specifically, paving the way for further research into safer clinical applications of this antibiotic.