Treatment with the combination of clavulanic acid and valproic acid led to recovery of neuronal and behavioral deficits in an epilepsy rat model.

Epilepsy, which is caused by abnormal neuronal firing in the brain, is a common neurological disease and affects motor and cognitive functions. Excessive levels of glutamate and insufficient levels of inhibitory GABA are involved in its pathophysiology. Valproic acid (Val), a GABAergic agonist, is one of the first-line antiepileptic drugs, but it shows many adverse side effects at the clinical dose. Clavulanic acid (CA), a ß-lactamase inhibitor, has been demonstrated to increase glutamate transporter-1 expression. This study evaluated the effects of CA and Val in an epilepsy rat model. Male Wistar rats received intraperitoneal injections of pentylenetetrazol (PTZ, 35 mg/kg, every other day, IP, for 13 days) to induce kindling epilepsy. After four times of PTZ injection, rats received daily treatment with CA (1 or 10 mg/kg, IP), Val (50 or 100 mg/kg, IP), or the combination of CA (1 mg/kg) and Val (50 mg/kg) for 7 consecutive days. Motor, learning, and memory functions were measured. Rats with PTZ-induced kindling exhibited seizures, motor dysfunction, cognitive impairment, and cell loss and reduction of neurogenesis in the hippocampus. Neither 1 mg/kg CA nor 50 mg/kg Val treatment was effective in alleviating behavioral and neuronal deficits. However, treatment with 10 mg/kg CA, 100 mg/kg Val, and the combination of 1 mg/kg CA and 50 mg/kg Val improved these behavioral and neuronal deficits. Particularly, the combination of CA and Val showed synergistic effects on seizure suppression, suggesting the potential for treating epilepsy and related neuronal damage and motor and cognitive deficits.

Treatment effects of the combination of ceftriaxone and valproic acid on neuronal and behavioural functions in a rat model of epilepsy.

NEW FINDINGS: What is the central question of this study? Imbalance of activities between GABAergic and glutamatergic systems is involved in epilepsy. It is not known whether simultaneously increasing GABAergic and decreasing glutamatergic activity using valproic acid and ceftriaxone, respectively, leads to better seizure control. What is the central question of this study? 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. ABSTRACT: 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-line antiepileptic drugs in the treatment of epilepsy, but it exhibits adverse effects. Ceftriaxone (CEF) elevates expression of glutamate transporter-1, 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 mg/kg, every other day for 13 days) to induce the epilepsy model. Ceftriaxone (10 or 50 mg/kg), Val (50 or 100 mg/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-dependent manner. The combination of CEF (10 mg/kg) and Val (50 mg/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.

A new avenue for treating neuronal diseases: Ceftriaxone, an old antibiotic demonstrating behavioral neuronal effects.

Several neurodegenerative disorders, namely Parkinson's disease dementia, dementia with Lewy bodies, and Alzheimer's disease, share common pathophysiological features, such as (1) cognitive deficits, (2) glutamatergic hyperactivity-related excitotoxicity, and (3) deposition of α-synuclein (α-syn) and ß-amyloid (Aß). Ceftriaxone (CEF) is a well-tested and safe drug that has been used as an antibiotic for several decades. Recent studies have demonstrated the following effects of CEF: (1) increasing glutamate transporter-1 expression and glutamate reuptake and suppressing excitotoxicity, (2) binding well with α-syn and inhibition of α-syn polymerization, (3) modulating expression of genes related to Aß metabolism, and (4) enhancing neurogenesis and recovery of neuronal density. In addition, our data revealed that CEF ameliorates seizure and abnormal neuronal firing in the brain. These results suggest the potential of CEF in treating neuronal disorders. This paper addresses the effects and pharmacology of CEF.