Beneficial Effects of Ceftriaxone Against Pentylenetetrazole-Evoked Convulsions

Abstract

Although considered to be generally safe, a number of beta-lactam antibiotics have been associated with epileptic seizures in humans. Furthermore, some beta-lactam antibiotics, including ceftriaxone, are used to evoke convulsions under experimental conditions. Recently it was demonstrated that ceftriaxone increased expression of the glutamate transporter (GLT1) and its biochemical and functional activity in the brain of rodents. GLT1 regulates extracellular concentrations of glutamate, an excitatory amino acid involved in the pathogenesis of seizures and epilepsy. Because of its rapid transfer of glutamate into neurons and adjacent glial cells, GLT1 diminishes glutamate toxicity. We investigated whether ceftriaxone (200 mg/kg body wt) administered intraperitoneally (ip) for 6 days could modify the convulsant effects of pentylenetetrazole (PTZ, 100 mg/kg ip) in inbred male BALBcAnNCR and C57 black (BL)/6 mice aged 4 and 12 weeks. Ceftriaxone pretreatment provided significant protective effects against PTZ-evoked generalized clonic convulsions (GCCs), generalized clonic-tonic convulsions (GCTCs), and convulsion-induced mortality during a period of 30 mins after PTZ administration. The incidence of GCCs, GCTCs, and death was statistically significantly lower for BALBcAnNCR mice of both ages, particularly younger mice. The latency time for each of the three parameters was significantly greater, with the exception of GCCs in adult mice. Protective effects of ceftriaxone were also noticed in adult C57BL/6 mice but not in prepubertal C57BL/6 mice. This is the first demonstration of anticonvulsant effects of ceftriaxone or any other beta-lactam antibiotic, which are not uniform across the mouse population. Our results provide new insight into the effects of ceftriaxone, which need further investigation.

Glutamatergic Mechanisms Associated with Seizures and Epilepsy

“…Moreover, GLT-1-overexpressing mice show a significant reduction in disease severity following pilocarpine-induced SE , suggesting that targeting glutamate transporters through transcriptional or translational regulation processes could represent an as-yet untapped therapeutic strategy for excitotoxic injury, including epilepsy . Efforts are now underway to use ceftriaxone to increase expression of glutamate transporters in a variety of preclinical models and clinical disorders associated with glutamate-mediated excitotoxic injury, including ALS (Simantov et al 1999;Berry et al 2013), Huntington's disease (Miller et al 2008), substance-abuse disorders (Sari et al 2009;Abulseoud et al 2012), traumatic brain injury (Goodrich et al 2013), and epilepsy (Jelenkovic et al 2008;Rawls et al 2010;Zeng et al 2010). As interest in, and understanding of, glial function in pathological conditions grows, efforts to capitalize on this knowledge will provide significant potential for "glia-centric" therapeutics.…”

Genetic deletion of the neuronal glutamate transporter, EAAC1, results in decreased neuronal death after pilocarpine-induced status epilepticus

“…Conversely, over-expression of GLT-1 in transgenic mice using the GFAP promoter to drive astrocytic expression results in decreased mortality and decreased cell death due to pilocarpine-induced status epilepticus (Kong et al, 2012). Up-regulation of GLT-1 induced by the beta-lactam antibiotic, ceftriaxone, increases latency to seizure onset and decreases mortality associated with administration of pentylenetetrazole (Jelenkovic et al, 2008). Genetic deletion of GLAST results in a more severe pentylenetetrazole-induced seizure phenotype compared to controls (Watanabe et al, 1999) and more intraictal spikes as a result of kindling, though more stimulations were required to obtain kindling and a shorter after-discharges were observed (Tsuru et al, 2002).…”

Glutamate transporter EAAT2: regulation, function, and potential as a therapeutic target for neurological and psychiatric disease

“…Reducing glutamate-mediated excitotoxicity may prevent epileptogenesis and, subsequently, spontaneous-recurrent seizures. Ceftriaxone shows protective effects by reducing seizure activity and the acute mortality in a pentylenetetrazole model of epilepsy [168], a model of tuberous sclerosis [169], and a traumatic brain injury-induced epilepsy model [170]. We have investigated pilocarpine-induced status epilepticus in EAAT2 transgenic mice and the pyridazine-derivative EAAT2 translational-activator-treated mice [56,171].…”