Integrative behavior analysis, oxidative stress markers determination and molecular docking to investigate proconvulsant action of betalactamic carbapenems

Abstract

Carbapenems are broad-spectrum β-lactam antibiotics widely used in critical and hospitalized patients. They are usually well tolerated; however, under certain conditions, these drugs are associated with central nervous system toxicity and proconvulsant activity. Here, we investigated the proconvulsant action of different generation carbapenems: imipenem (IMI), meropenem (MERO), and ertapenem (ERTA) in mice through behavioral analysis. We also propose possible molecular mechanisms for this side effect through an integrative experimental and computational approach. For this, male mice received carbapenems at doses of 250 and 500 mg/kg, or saline, subcutaneously, for 7 days. On the last day, the pilocarpine-induced seizure test was performed. On the last day, the pilocarpine-induced seizure test was performed, and latency to the first seizure and latency of death were recorded. Subsequently, oxidative stress markers were measured in brain areas. Additionally, using the three-dimensional structure of the drugs, we performed computational target prediction and molecular docking calculations. IMI and MERO, at both tested doses, reduced seizure latency and death latency compared to pilocarpine group. This effect occurred only with the higher dose of ERTA (500 mg/kg). Furthermore, IMI increased lipid peroxidation in all brain areas, MERO in the hippocampus and prefrontal cortex, and ERTA only in the hippocampus. The three carbapenems increased nitrite/nitrate levels in all brain areas, while only IMI at 500 mg/kg decreased GSH. Computational studies predicted that GABA_A receptor, Glutathione S-transferase Pi, Glutathione S-transferase Mu 1, and Glutathione S-transferase A2 could be promising targets for the CNS toxicity of carbapenems, related to their proconvulsant effect. Therefore, our data contribute to the current understanding of CNS toxicity associated with carbapenems and propose the participation of oxidative stress and the interaction with GABA and GSH synthesis systems in the molecular mechanism of their proconvulsant effect.