Histological and electrophysiological effects of sulbactam and valproate in the PTZ-induced epileptic rat model

An imbalance between excitatory glutamate and inhibitory gamma-aminobutyric acid (GABA) neurotransmitters is a key mechanism in epilepsy. Astrocytic glutamate transporter-1 (GLT-1) helps reuptake glutamate in the synaptic cleft to maintain glutamate concentration and prevent neuronal hyperactivity. Sulbactam (SUL), a β-lactam drug, increases GLT-1 expression. Valproate (VPA) is a first-line antiepileptic drug. The current study evaluated the effects of SUL and VPA on histology and electroencephalography in a pentylenetetrazol (PTZ)-induced epilepsy rat model. Male Wistar rats received intraperitoneal injection of PTZ (20-35 mg/kg, every other day) for 25 days (13 injections in total) to establish an epilepsy model. From day 26, saline, SUL (50 or 150 mg/kg), VPA (50 mg/kg), or a combination of SUL and VPA was intraperitoneally administered daily for 25 days. Electroencephalography recordings were taken on day 46 or 47. Brains were used for histological analyses. Electrophysiological results indicated that during the PTZ challenge session, the epilepsy group had significantly more spikes and seizures and higher delta, theta, and beta power compared with the control group. SUL at 150 mg/kg and the combination of SUL (50 mg/kg) and VPA (50 mg/kg) significantly reduced the numbers of spikes and seizures. SUL at both 50 and 150 mg/kg and the combination of SUL (50 mg/kg) and VPA (50 mg/kg) significantly inhibited the increase in delta, theta, and beta power. In terms of histology, the epilepsy group exhibited lower neuronal density in the hippocampus, lower GLT-1 expression in astrocytes, lower GABAergic density, and hyperactivity in the subthalamic nucleus. These neurophysiological impairments were restored by treatment with SUL and a combination of SUL and VPA. The results suggest that SUL increases GLT-1 expression in astrocytes and the number of GABAergic neurons, indicating it holds potential as an antiepileptic treatment.