Amphiphilic Ebselen Conjugate Suppresses Tripartite Motif-Containing 21-Glutathione Peroxidase 4 Axis-Dependent Neuronal Ferroptosis and Ameliorates Epilepsy.

There has been a lack of effective and safe therapies for temporal lobe epilepsy (TLE), a typical refractory epilepsy. Lipid peroxidation, a critical ferroptotic event, is key for TLE, and targeting this ferroptotic process represents a promising therapeutic approach. However, selective suppression of ferroptosis in neural cells is challenging because of the plasma instability of canonical ferroptosis inhibitors and the presence of the blood-brain barrier (BBB). Here, we report an amphiphilic glycerylphosphoryl choline-ebselen conjugate (GPC-EBS), a biomimic of glutathione peroxidase 4 (GPX4), for effective suppression of ferroptosis and alleviation of TLE. The conjugate addressed the poor water solubility of EBS well and self-assembled with a helper lipid (DSPE-PEG 2000), forming a nanoscale micelle (mGPC-EBS). mGPC-EBS could efficiently suppress lipid peroxidation in neural cell lines. Following nasal delivery that bypasses the blood-brain barrier, mGPC-EBS micelles showed potent antiseizure and neuroprotective effects in an acute epilepsy mouse model. Meanwhile, mGPC-EBS suppressed spontaneous recurrent seizures and ameliorated cognitive deficits in a chronic epilepsy mouse model. Mechanistic investigation revealed that mGPC-EBS, apart from its GPX4-mimic role, downregulated tripartite motif-containing 21 (TRIM21) and led to an increase in GPX4 as TRIM21 can ubiquitylate and degrade GPX4. The current work provides a strategy to manipulate GPX4 activity using tailored organoselenium conjugates for the effective management of refractory TLE.