Imipenem in the Rat Brain: A Multidimensional Study on Hippocampal Behavior, GABAergic System, Astrocyte Response, and Neurogenesis

<b>Background:</b> After imipenem was introduced in clinical practice, neurologic adverse effects led to recommendations against its use in patients with neurologic conditions. However, these conclusions were drawn without considering pharmacokinetic variations in such patients. Furthermore, animal studies lack the use of clinically relevant doses and supporting morphological studies in both naïve and disease models. <b>Objectives</b>: We aim to study the effects of imipenem in the hippocampus of naïve animals, evaluating potential behavioral and morphological alterations. <b>Methods</b>: Naïve Wistar rats received a 10-day course of intraperitoneal imipenem (40 mg/kg) while controls received a saline injection. After that, they were put through the Morris water maze, elevated plus maze, open-field test, and then euthanized. We analyzed neurogenesis (using doublecortin immunoreactivity), astrogliosis, and the γ-Aminobutyric acid (GABA)ergic system (using parvalbumin (PV), calretinin (CR) and calbindin (CB) immunoreactive (IR) neurons) in the hippocampus. <b>Results</b>: Interestingly, our results showed no significant alterations in both short and long-term memory, nor in anxiety. There were also no significant changes in the neuronal density of doublecortin-immunoreactive (IR) neurons nor in astrogliosis. Furthermore, the areal density of PV- and CR-IR was preserved in all hippocampal subfields. The density of CB-IR neurons also showed no changes in the dentate gyrus, CA3, and subiculum; however, a significant increase was found in the CA1 region. <b>Conclusions</b>: Our results indicate that in naïve individuals, a clinically relevant dose of imipenem does not seem to cause overt behavioral deficits or widespread morphological alterations in the hippocampus. However, a specific increase in the CB-IR neuronal population in the CA1 region highlights a localized cellular alteration/plasticity induced by the imipenem. Hence, pharmacokinetic factors seem to be the potential contributors of imipenem side effects. Further studies should focus on this as a possible cause and focus on individuals with brain diseases.