Urolithin A mitigates behavioural and synaptic deficits associated with epilepsy

The persistence of drug-resistant epilepsy highlights the need for new therapeutic interventions that target novel mechanisms with homeostatic regulations while minimizing side effects. Slow-acting drugs, particularly small molecules of natural origin with anti-epileptogenic potential, can contribute to this regulation by influencing the processes that drive epileptogenesis and seizure-susceptibility. One promising approach involves modifying the underlying pathophysiological mechanisms of synaptic plasticity leading to a reduced seizure threshold. We show that the administration of Urolithin-A (UA), a small molecule of natural origin, mitigates behavioural and synaptic dysfunctions under chemically and genetically induced epileptic conditions in Drosophila. Additionally, chronic treatment with UA attenuates the altered basal synaptic transmission and single-cell post-synaptic currents, curtailing the deleterious consequences of PTZ-induced chronic kindling of mice. However, UA exerts no seizure-suppressive effects in in-vitro epileptic conditions, implying the absence of acute symptomatic anti-epileptic effects. Here, we identify the direct interactor of UA as the complex of tubulin dimer and VDAC1 through affinity-purification with synthesized UA-attached beads and transcriptomics studies. Finally, neuron specific VDAC1 knockdown in Drosophila mimics UA supplementation effects. VDAC1 inhibition through UA offers new hope as a distinct neuroprotective therapeutic intervention for refractory epilepsy.