Assessing the Neurotoxic Effects of Meropenem on Behavior, Cognition, and Hippocampal Neurogenesis in Healthy Female Rats
Abstract
Introduction: Neurogenesis is the process by which new neurons are developed from neural stem cells (NSCs) in the brain. It occurs in specific regions such as the dentate gyrus of the hippocampus that is responsible for learning, memory, and cognition. This process might be affected by several factors including oxidative stress, inflammation, aging, and antibiotic administration. The latter has been shown to cause deficits in behavioral activity, cognitive function, and neurogenesis. One common antibiotic used is Meropenem which is an intravenous carbapenem antibiotic used to treat a variety of infections particularly urinary tract infections (UTIs). It works by killing the bacteria or preventing its growth through a specific mechanism. In addition, this antibiotic can cross the blood brain barrier, penetrate body fluids, and be obtained in the cerebrospinal fluid which might cause cognitive adverse effects. A previous study has been conducted to test the effect of this antibiotic on proliferating NSCs as well as cognition and behavior of healthy male rodents but not female rodents.
Objective: This project aims to investigate the effect of meropenem on healthy adult female Sprague-Dawley rodents by assessing their behavior, cognitive function, and hippocampal neural stem cells proliferation.
Methods: Intraperitoneal injections of Meropenem were administered to adult female Sprague-Dawley rats (8-weeks-old) twice daily (8 hours apart) for seven days. The rats were divided into two experimental groups, one sham group, and one naïve group. The first experimental group was injected with a low-dose (177mg/kg) of meropenem whereas the second with a high-dose (354mg/kg). The sham group received sterile saline, and the naïve group did not receive anything. The estrous cycle of all female rats was assessed by assigning a vaginal smear each day during the behavioral tests. The rats were exposed to a thermal sensitivity test on the abdomen to assess hyperalgesia, and a rotarod test to assess motricity. Moreover, various behavioral tests were done including Y-maze test to assess spatial memory and exploration, and novel object recognition (NOR) test to assess recognition memory and exploration. Bromodeoxyuridine (BrdU) analog was injected 24 hours prior to euthanasia to assess the proliferation of hippocampal neural stem cells (NSCs), which is the first step of neurogenesis. After that, the rats were euthanized, and their brains were collected for molecular and cellular testing.
Results: Meropenem administration showed altered exploratory behavior and recognition memory in the NOR test. Moreover, a significant decrease was observed in the number of proliferating NSCs in the dentate gyrus of the hippocampus in the low-dose and high-dose groups compared to the sham group.
Conclusion and future perspective: No previous studies have confirmed the neurotoxic effect of meropenem on healthy female rats, however this project has shown possible neurotoxic effect upon the administration of this antibiotic. This research will provide insights into the neurotoxic potential of meropenem, and this will launch additional studies for research into the clinical safety of this drug.