Cephalosporin antibiotics are weak blockers of GABAa receptor-mediated synaptic transmission in rat brain slices
- Sechenov Institute of Evolutionary Physiology and Biochemistry of RAS, 44, Toreza prospekt, Saint Petersburg 194223 (Russian Federation)
Highlights: • Millimolar concentrations of cephalosporins are required to block eIPSCs. • Cefepime and ceftriaxone have different mechanisms of GABAa receptor inhibition. • Cephalosporins alone fail to induce consistent epileptiform activity in brain slices. Cephalosporins are beta-lactam antibiotics that are extensively used in medical practice and are reported to cause epileptic seizures in some patients. The primary cause of cephalosporin-induced convulsions is believed to be their ability to block GABAa receptors. However, direct evidence for the involvement of this mechanism has not yet been provided. The present study aims to investigate the ability of two cephalosporins – cefepime and ceftriaxone – to block inhibitory synaptic transmission in entorhinal cortex slices of rats. Using the whole-cell patch-clamp method, we found that millimolar concentrations of cefepime (IC{sub 50} = 1.6 ± 0.1 mM) and ceftriaxone (2.0 ± 0.1 mM) were required to block the evoked inhibitory postsynaptic currents (IPSCs). These concentrations are almost two orders of magnitude higher than cerebrospinal fluid concentrations of antibiotics achieved during treatment. We also found that while ceftriaxone did not affect the IPSC decay kinetics, cefepime significantly slowed the decays of the evoked currents, which may be attributed to the diverse mechanisms of the GABAa receptor inhibition of cefepime and ceftriaxone. The experiments involving the fast application of GABA at various concentrations to isolated neurons suggests that cefepime blocks receptors competitively, while ceftriaxone does so noncompetitively. Cefepime, at a concentration of up to 4 mM, was unable to produce seizure-like events in brain slices. However, this antibiotic could induce epileptiform activity in combination with the altered ionic composition of the perfusing media, which may be the case for patients with renal insufficiency. Our results suggest that cefepime and ceftriaxone are weak GABAa receptor blockers and that it is unlikely that the inhibition of GABAa receptors by antibiotics is the primary cause of the seizures.
- OSTI ID:
- 23137133
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 499, Issue 4; Other Information: Copyright (c) 2018 Elsevier Inc. All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
Similar Records
Ethanol inhibits epileptiform activity and NMDA receptor-mediated synaptic transmission in rat amygdaloid slices
Enhancement of endocannabinoid signaling protects against cocaine-induced neurotoxicity