Dual mechanisms of GABA_a response inhibition by β‐lactam antibiotics in the pyramidal neurones of the rat cerebral cortex

Abstract

1 The effects of fi-lactam antibiotics on the y-aminobutyric acid (GABA)-induced Cl-current were investigated in pyramidal neurones freshly dissociated from the rat frontal cortex by the use of a nystatin-perforated patch recording mode under voltage-clamp conditions.2 The GABA-induced inward current increased in a concentration-dependent manner with an EC5o of 6.7 x 10-6 M at a holding potential of -40 mV. The GABA response was accompanied by an increase in the membrane conductance and reversed at near the Cl-equilibrium potential. 3 All f-lactams (penicillin, imipenem, aztreonam and cefotiam) inhibited the I0-5 M GABA-induced response in a concentration-dependent manner with an IC"o and Hill coefficient of 1.3 x 10-M and 0.64 for penicillin, 9.6 x 1O' M and 0.83 for imipenem, 2.5 x 10-3 M and 9.99 for aztreonam, and 2.9 x l0-' M and 1.03 for cefotiam. 4 Imipenem inhibited the GABA-response competitively while penicillin inhibited the same response in a noncompetitive fashion. 5The inhibitory action of imipenem showed no voltage-dependency, whereas the effect of penicillin was voltage-dependent. 6 It is thus proposed that some classes of ,B-lactams, including imipenem, may have a mechanism that is different from penicillin and competitively affects the GABAA receptor.

Replacement of asparagine with arginine at the extracellular end of the second transmembrane (M2) region of insect GABA receptors increases sensitivity to penicillin G

“…1c). Although PCG is a voltage-dependent antagonist of vertebrate GABA A receptors (Fujimoto et al 1995), no voltage-dependency was observed on wild-type RDL (Fig. 1d).…”

“…Despite the high degree of conservation between the ion channels of insect and vertebrate GABA A receptors, differences in the penicillin sensitivity of vertebrate and insect GABA receptors have been reported. Millimolar IC 50 s have been quoted for penicillin antagonism of vertebrate GABA A receptors (Horne et al 1992;Fujimoto et al 1995) whereas similar concentrations of the (b-lactam antibiotic had no effect on native or recombinant insect GABA receptors (Scott and Duce 1987). To date a single residue at the 6¢ position in M2 has been identified in vertebrate receptors whose mutation profoundly reduced the potency of both PCG and PTXN (Sugimoto et al 2002).…”

“…At millimolar concentrations, PCG effects a voltage-dependent open channel block of GABA A receptors (Pickles and Simmonds 1980;Twyman et al 1992;Fujimoto et al 1995;Behrens 2000). However, native and recombinant insect GABA receptors are insensitive to concentrations of PCG which block vertebrate GABA A receptors (Scott and Duce 1987).…”

Involvement of Multidrug Resistance-Associated Protein 4 in Efflux Transport of Prostaglandin E2 across Mouse Blood-Brain Barrier and Its Inhibition by Intravenous Administration of Cephalosporins

“…It is known that ␤-lactam antibiotics, including cefmetazole and cefazolin, inhibit the GABA A receptor response in rat cerebral cortex and cause seizure (Schliamser et al, 1991;Fujimoto et al, 1995). PGE 2 in the brain enhances excitatory neuronal response and induces a pain response (Oliveira et al, 2009).…”

Cefixime-induced nonconvulsive status epilepticus

“…Penicillins and cephalosporins bind GABA receptors noncompetitively and competitively, respectively; so the latter shows greater neurotoxicity [21]. The fact that benzodiazepines, as in our case, and barbiturates are effective in treating cephalosporin-associated epileptiform activity also supports the theory of a GABA-mediated mechanism [22]. The potential relationship between cephalosporin-induced neurotoxicity and glutamate was studied by Ohtaki and colleagues [23].…”