Lactate: Beyond a mere fuel in the epileptic brain

Epilepsy, a prevalent neurological disorder characterized by spontaneous recurrent seizures, significantly impacts physiological and cognitive functions. Emerging evidence suggests a crucial role for metabolic factors, particularly lactate, in epilepsy. We discuss the applicability of the astrocyte-neuron lactate shuttle (ANLS) model during acute seizure events and examine lactate's metabolic adaptation in epilepsy progression. Additionally, the roles of lactate metabolism in microglia and oligodendrocytes are considered, aiming to supplement our understanding of neuro-glial metabolic interactions as extensions of the ANLS model. Additionally, lactate modulates neuronal excitability via its interaction with hydroxycarboxylic acid receptor 1 (HCAR1), alongside additional mechanisms involving acid-sensing ion channels (ASICs) and ATP-sensitive potassium (KATP) channels, which contribute as secondary modulatory pathways. In conclusion, we propose that lactate functions as more than a mere fuel source in the epileptic brain, offering potential insights into new therapeutic targets for seizure control.