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It is not known whether simultaneously increasing GABAergic and decreasing glutamatergic activity using valproic acid and ceftriaxone, respectively, leads to better seizure control.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p><jats:bold>What is the central question of this study?<\/jats:bold><\/jats:p>\n<jats:p>Ceftriaxone suppressed seizure and cognitive deficits and restored neuronal density and the number of newborn cells in the hippocampus in a rat model of epilepsy. Combined treatment with ceftriaxone and valproic acid showed additive effects in seizure suppression.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>The pathophysiology of epilepsy is typically considered as an imbalance between inhibitory GABA and excitatory glutamate neurotransmission. Valproic acid (Val), a GABA agonist, is one of the first\u2010line antiepileptic drugs in the treatment of epilepsy, but it exhibits adverse effects. Ceftriaxone (CEF) elevates expression of glutamate transporter\u20101, enhances the reuptake of synaptic glutamate, increases the number of newborn cells and exhibits neuroprotective effects in animal studies. In this study, we evaluated effects of the combination of CEF and Val on behavioural and neuronal measures in a rat epilepsy model. Male Wistar rats were injected i.p. with pentylenetetrazol (35\u00a0mg\/kg, every other day for 13\u00a0days) to induce the epilepsy model. Ceftriaxone (10 or 50\u00a0mg\/kg), Val (50 or 100\u00a0mg\/kg) or the combination of CEF and Val were injected daily after the fourth pentylenetetrazol injection for seven consecutive days. Epileptic rats exhibited seizure and impairments in motor and cognitive functions. Treatment with CEF and Val reduced the seizure and enhanced motor and cognitive functions in a dose\u2010dependent manner. The combination of CEF (10\u00a0mg\/kg) and Val (50\u00a0mg\/kg) improved behaviours considerably. Histologically, compared with control animals, epileptic rats exhibited lower neuronal density and a reduction in hippocampal newborn cells but higher apoptosis in the basolateral amygdala, all of which were restored by the treatment with CEF, Val or the combination of CEF and Val. The study findings demonstrated that the combination of low doses of CEF and Val has beneficial effects on seizure suppression, neuroprotection and improvement in motor and cognitive functions in epilepsy.<\/jats:p><\/jats:sec>","DOI":"10.1113\/ep089624","type":"journal-article","created":{"date-parts":[[2021,6,4]],"date-time":"2021-06-04T14:24:46Z","timestamp":1622816686000},"page":"1814-1828","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Treatment effects of the combination of ceftriaxone and valproic acid on neuronal and behavioural functions in a rat model of epilepsy"],"prefix":"10.1113","volume":"106","author":[{"given":"Hsin\u2010Hua","family":"Li","sequence":"first","affiliation":[{"name":"Department of Medical Research Institute of Medicine Chung Shan Medical University Hospital Chung Shan Medical University  Taichung Taiwan Republic of 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