Inhibition of MEK-ERK signaling reduces seizures in two mouse models of tuberous sclerosis complex

• Published in: Epilepsy research 2022-03, Vol.181, p.106890-106890, Article 106890
• Main Authors: Nguyen, Lena H., Leiser, Steven C., Song, Dekun, Brunner, Daniela, Roberds, Steven L., Wong, Michael, Bordey, Angelique
• Format: Article
• Language: English
• Subjects: Animals; Disease Models, Animal; Epilepsy; Humans; MAPK; MEK inhibitor; MEK-ERK signaling; Mice; Mitogen-Activated Protein Kinase Kinases - metabolism; Seizures; Seizures - drug therapy; Signal Transduction; Tuberous Sclerosis - complications; Tuberous Sclerosis - drug therapy; Tuberous sclerosis complex
• ISSN: 0920-1211; 1872-6844
• DOI: 10.1016/j.eplepsyres.2022.106890

Tuberous sclerosis complex (TSC) is a monogenic disorder characterized by hyperactivation of the mTOR signaling pathway and developmental brain malformations leading to intractable epilepsy. Although treatment with the recently approved mTOR inhibitor, everolimus, results in clinically relevant seizure suppression in up to 40% of TSC patients, seizures remain uncontrolled in a large number of cases, underscoring the need to identify novel treatment targets. The MEK-ERK signaling pathway has been found to be aberrantly activated in TSC and inhibition of MEK-ERK activity independently of mTOR rescued neuronal dendrite overgrowth in mice modeling TSC neuropathology. Here, we evaluated the efficacy of MEK-ERK inhibition on seizures in two mouse models of TSC. We found that treatment with the MEK inhibitor PD0325901 (mirdametinib) significantly reduced seizure activity in both TSC mouse models. These findings support inhibiting MEK-ERK activity as a potential alternative strategy to treat seizures in TSC. •Inhibition of MEK-ERK activity with PD0325901 treatment reduces seizures in Tsc1 conditional knockout mice.•PD0325901 treatment decreases phospho-ERK1/2 levels in a dose-dependent manner in Tsc1 conditional knockout mice.•PD0325901 treatment reduces seizures in a Rheb in utero electroporation-based mouse model of TSC.•PD0325901 treatment reduces phospho-ERK1/2 levels in a Rheb in utero electroporation-based mouse model of TSC.