Clioquinol “ Sweetens the Pot ” for Drug-Resistant Epilepsy—With an After Taste

Clioquinol as a New Therapy in Epilepsy: From Preclinical Evidence to a Proof-of-Concept Clinical Study Thevissen K, Ny A, Copmans D, Tits J, Kamata K, Gielis E, Longin K, Sourbron J, Thergarajan P, Tan TH, Ali I, Jones NC, O’Brien TJ, Monif M, Semple BD, Germeys C, Frizzi B, Minniti V, Perrone S, Linster CL, Elia I, Van Den Bosch L, Cammue BPA, Voet A, Lagae L, de Witte P. Epilepsia . 2025. doi:10.1111/epi.18536. Online ahead of print Objective: Drug-resistant epilepsy (DRE) affects >25 million people worldwide and is often associated with neuroinflammation. Increasing evidence links deficiency or malfunctioning of the enzyme phosphoglycerate dehydrogenase (PHGDH), which converts 3-phosphoglycerate to generate serine and the neurotransmitter glycine, with (drug-resistant) epilepsy. Moreover, PHGDH, which is primarily expressed in astrocytes within the brain, has been identified as a critical enzyme in driving macrophage polarization toward an anti-inflammatory state. Hence, PHGDH activators may be beneficial for treating DRE by exhibiting both antiseizure and anti-inflammatory activity. The objective of this study was to identify such PHGDH activators. Methods: We screened a drug repurposing library for PHGDH activators and assessed their antiseizure and anti-inflammatory properties using various zebrafish and mouse epilepsy models and explored the mechanistic consequences of activating PHGDH in a cell line, in astrocytes, and in zebrafish heads. Finally, we assessed the efficacy of clioquinol as add-on treatment in three severe DRE patients in a clinical open pilot proof-of-concept study. Results: We identified haloquinolines from a drug repurposing library as potent activators of PHGDH. The most promising haloquinoline clioquinol can increase the catalytic activity of PHGDH up to 2.5-fold, thereby increasing de novo glycine biosynthesis and resulting in reduced glutamate levels. Moreover, we show that clioquinol has PHGDH-dependent antiseizure activity as well as anti-inflammatory properties in vivo using various zebrafish and mouse epilepsy models. Finally, we demonstrate the efficacy of clioquinol as add-on treatment in severe DRE patients; two patients showed a 37%-47% reduction in seizure frequency, and all three patients noted a positive impact on quality of life and seizure severity.