Pharmacological upregulation of GLT-1 alleviates the cognitive impairments in the animal model of temporal lobe epilepsy

Abstract

It is known that hippocampal epileptogenesis is accompanied by hyperexcitability, glutamate-related neuronal dysfunctions and consequently cognitive deficits. However, the neuroprotective role of astrocytic glutamate uptake through the Glutamate Transporter-1 (GLT-1) remains to be unknown in these processes. Therefore, to assess the effect of glutamate uptake, pharmacological upregulation of GLT-1 using ceftriaxone administration (200 mg/kg/day, i.p, 5 days) was utilized in Li-PIL animal models of temporal lobe epilepsy (TLE). Glutamate concentration and glutamine synthetase activity were analyzed using biochemical assays. In addition, GLT-1 gene expression was assessed by RT-qPCR. Finally, cognitive function was studied using Morris water maze (MWM) test and novel object recognition task (NORT). Our results demonstrated that the acute phase of epileptogenesis (first 72 hours after Status Epilepticus) was accompanied by an increase in the hippocampal glutamate and downregulation of GLT-1 mRNA expression compared to controls. Ceftriaxone administration in epileptic animals led to a reduction of glutamate along with elevation of the level of glutamine synthetase activity and GLT-1 expression in the acute phase. In the chronic phase of epileptogenesis (4 weeks after Status Epilepticus), glutamate levels and GLT-1 expression were decreased compared to controls. Ceftriaxone treatment increased the levels of GLT-1 expression. Furthermore, impaired learning and memory ability in the chronic phase of epileptogenesis was rescued by Ceftriaxone administration. This study shows that astrocytic glutamate uptake can profoundly impact the processes of hippocampal epileptogenesis through the reduction of glutamate-induced excitotoxicity and consequently rescuing of cognitive deficits caused by epilepsy.

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

“…It should also be noted that CTX treatment can restore hippocampus-dependent behavioral disorders in various models of disease. For example, learning and memory ability in the Morris water maze was rescued by CTX administration during the phase of epileptogenesis in the lithium-pilocarpine model of temporal lobe epilepsy [48]. Administration of CTX for 7 days and 14 days during hypoxic exposure ameliorated hypobaric hypoxia-induced cognitive impairment in the Morris water maze and GLT1 expression [49].…”

Solute carrier transporter disease and developmental and epileptic encephalopathy

“…Recombinant forms of interleukin 1 receptor antagonists, LDN/OSU-0212320, ceftriaxone, and Parawixin10 all act by enhancing EAAT2 expression ( 18 – 20 ). Among them, ceftriaxone has been applied to one clinical patient, but no significant efficacy was found ( 16 , 24 , 25 ). Therefore, more clinical studies are needed to validate the efficacy of ceftriaxone in SLC1A2 -associated epilepsy.…”

“…However, tamoxifen and growth factor α-selective agonists enhance EAAT1 and EAAT2 expression through the activation of the NF-κB pathway ( 21 , 22 ). In addition, ceftriaxone, a β-lactam antibiotic, is one of the well-studied SLC1A2 modulators, and it is an EAAT2 protein enhancer that reduces neuronal death and seizure frequency ( 23 , 24 ). An animal study also showed that low doses of ceftriaxone with valproate increased GABAergic activity and decreased glutamatergic activity, favoring seizure suppression and improved cognitive function ( 25 ).…”

Baicalin Rescues Cognitive Dysfunction, Mitigates Neurodegeneration, and Exerts Anti-Epileptic Effects Through Activating TLR4/MYD88/Caspase-3 Pathway in Rats

“…56 The hippocampus has long been thought to be crucial for learning and memory in rodents, and since it is highly susceptible to injury, these functions can be easily impaired in patients with epilepsy. 57,58 Hence, neuronal damage and disorder in this area will cause cognitive deficits. Besides, numerous findings demonstrate that epilepsy, neurodegeneration and inflammatory cytokines are not autonomous, but mutually influence each other.…”