The Effect of Meropenem on Behavior, Cognition, and Hippocampal Neurogenesis in Adult Rats

Abstract

Introduction: Neurogenesis is the process by which neural stem cells (NSCs) develop into functional neurons in the brain. It is comprised of five major phases: proliferation, differentiation, migration, axonal and dendritic targeting, and synaptic integration. It is a process that may be affected by multiple factors including stress, aging, brain injury, infection, and inflammation. Moreover, antibiotic administration may also be a negative factor as recent studies indicate. Meropenem (Merrem) is a broad-spectrum carbapenem antibiotic used to treat various inflammatory diseases. It causes inhibition of cell wall synthesis, hence targeting bacterial growth and halting it. Meropenem can penetrate most body fluids and tissues, cross the blood–brain barrier, and obtain a concentration within the cerebrospinal fluid close to that of blood plasma. However, no research has been conducted establishing a clear link between meropenem and its neurotoxic effects on neurogenesis. Objective: This project aimed to investigate the neurotoxic effects of meropenem on rodents’ motricity, cognitive function, and hippocampal proliferation of neural stem cells. Methods: Adult male Sprague-Dawley rats received two intraperitoneal injections of meropenem every 8 hours for 1 week. The experimental group was divided into two groups: low-dose (177 mg/kg) and high-dose (354 mg/kg). The sham group was divided into two groups: low-dose and high-dose and received sterile saline, and the naïve group did not receive anything. Bromodeoxyuridine (BrdU) was injected 24 hours prior to euthanasia to assess hippocampal NSC proliferation. A thermal sensitivity test was performed on the abdomen to assess hyperalgesia. The rota-rod test was performed to assess motricity, and other behavioral tests were performed including the Y-maze test to assess spatial memory and novel object recognition (NOR) test to assess long-term memory of rats.

Results: High dose meropenem administration showed altered exploratory behavior in the NOR test and possible induction of anxiety-like behavior. Moreover, a significant decrease was observed in the number of proliferating NSCs and expression levels of the neurotrophic factor FGF2 and the receptor TrkB.

Conclusion/Future Perspectives: This study demonstrated that meropenem administration is associated with decreased proliferation of NSCs, hence altering neurogenesis. Clinically, this may provide insight to improve meropenem administration in humans and shed light on its possible negative side effects on the central nervous system.