Sulbactam: A β–Lactam Compound with Neuroprotective Effects in Epilepsy

Background: The pathophysiology of epilepsy is characterized by increased neuronal activity due to an excess of the excitatory neurotransmitter glutamate and a deficiency in the inhibitory neurotransmitter gamma–aminobutyric acid (GABA). Epilepsy presents with seizures, neuronal loss, and hyperactivity in the subthalamic nucleus (STN). Astrocytes play a crucial role by absorbing extracellular glutamate through glutamate transporter–1 (GLT–1), thereby reducing neuronal excitation. Upregulating the expression of astrocytic GLT–1 is a promising therapeutic strategy for epilepsy. Sulbactam (SUL), a β–lactam antibiotic, has been demonstrated to exert neuroprotective effects by upregulating GLT–1 expression. Objectives: This study investigated the impact of SUL on neuronal and behavioral changes in epilepsy by using a pentylenetetrazol (PTZ)-induced rat model of epilepsy. Methods: Rats were treated with saline, SUL (50 and 150 mg/kg), or a combination of SUL and the GLT–1 blocker dihydrokainate (DHK) for 20 days. Subsequently, behavioral tasks were conducted to assess recognition, anxiety, and memory. Results: Histological analyses revealed that SUL ameliorated neuronal deficits, increased astrocytic GLT–1 expression, and reduced hyperactivity in the STN. Additionally, SUL promoted astrocyte proliferation, indicating a new dimension of its neuroprotective properties. However, the beneficial effects of SUL were prevented by DHK. Conclusions: This pioneering study highlights multiple benefits of SUL, including seizure suppression, increased GLT–1 expression, and astrocyte proliferation, underscoring its high potential as a treatment for epilepsy.