Ceftriaxone Treatment Affects EAAT2 Expression and Glutamatergic Neurotransmission and Exerts a Weak Anticonvulsant Effect in Young Rats

Abstract

Epilepsy is a common neurological disorder. Despite the availability of a wide range of antiepileptic drugs, these are unsuccessful in preventing seizures in 20–30% of patients. Therefore, new pharmacological strategies are urgently required to control seizures. Modulation of glutamate uptake may have potential in the treatment of pharmacoresistant forms of epilepsy. Previous research showed that the antibiotic ceftriaxone (CTX) increased the expression and functional activity of excitatory amino acid transporter 2 (EAAT2) and exerted considerable anticonvulsant effects. However, other studies did not confirm a significant anticonvulsant effect of CTX administration. We investigated the impacts of CTX treatment on EAAT expression and glutamatergic neurotransmission, as well its anticonvulsant action, in young male Wistar rats. As shown by a quantitative real-time polymerase chain reaction (qPCR) assay and a Western blot analysis, the mRNA but not the protein level of EAAT2 increased in the hippocampus following CTX treatment. Repetitive CTX administration had only a mild anticonvulsant effect on pentylenetetrazol (PTZ)-induced convulsions in a maximal electroshock threshold test (MEST). CTX treatment did not affect the glutamatergic neurotransmission, including synaptic efficacy, short-term facilitation, or the summation of excitatory postsynaptic potentials (EPSPs) in the hippocampus and temporal cortex. However, it decreased the field EPSP (fEPSP) amplitudes evoked by intense electrical stimulation. In conclusion, in young rats, CTX treatment did not induce overexpression of EAAT2, therefore exerting only a weak antiseizure effect. Our data provide new insight into the effects of modulation of EAAT2 expression on brain functioning.

Ceftriaxone Treatment Weakens Long-Term Synaptic Potentiation in the Hippocampus of Young Rats

“…CTX causes both acute and long-term increases in GLT1 expression, and it also enhances the functional activity of GLT1 [13]. In our previous study, CTX administration had mild anticonvulsant effects on pentylenetetrazole (PTZ)-induced convulsions and in a maximal electroshock threshold test [14]. Other studies revealed that CTX reduced signs of kindling in the PTZ model [15,16].…”

“…Currently, ceftriaxone (CTX), a cephalosporin antibiotic, is one of the most studied GLT1 expression enhancers [12][13][14]. CTX causes both acute and long-term increases in GLT1 expression, and it also enhances the functional activity of GLT1 [13].…”

Neuromodulation of Glial Function During Neurodegeneration

“…Recently, strategies directed towards targeting the astrocytic glutamate transporter EAAT2 proved to be beneficial in alleviating the hyperexcitability symptoms associated with some neurodegenerative diseases and decrease the level of neurodegeneration in animal models of epilepsy (Kong et al, 2012 , 2014 ; Goodrich et al, 2013 ; Zaitsev et al, 2019 ), ALS (Kong et al, 2014 ), PD (Chotibut et al, 2014 ; Hsu et al, 2015 ) and HD (Sari et al, 2010 ). Moreover, modulation of astrocytic energy metabolism via inhibition of lactate dehydrogenase (Sada et al, 2015 ; Rosati et al, 2018 ) or via ketonic diet (Valdebenito et al, 2016 ) had a neuroprotective effect in both animal models of PD (Shaafi et al, 2016 ), and patients with HD (Adanyeguh et al, 2015 ) and epilepsy (van Berkel et al, 2018 ).…”

Ceftriaxone pretreatment confers neuroprotection in rats with acute glaucoma and reduces the score of seizures induced by pentylenotetrazole in mice

“…[ 32 ] However, some studies have described conflicting data, in particular that ceftriaxone treatment had little effect on glutamatergic transmission under normal conditions, or a beneficial effect on EAAT2 expression, and a relatively small anticonvulsant effect in seizure models. [ 33,34 ]…”