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

Lena H Nguyen1, Steven C Leiser2, Dekun Song2

  • 1Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA; Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA.

Epilepsy Research
|February 26, 2022
PubMed

Insights

Tuberous sclerosis complex (TSC) causes epilepsy due to mTOR pathway overactivation. MEK-ERK pathway inhibition with PD0325901 effectively reduced seizures in TSC mouse models, offering a potential new treatment strategy.

Area of Science:

  • Neuroscience
  • Genetics
  • Pharmacology

Background:

  • Tuberous sclerosis complex (TSC) is a genetic disorder linked to mTOR pathway hyperactivation and brain malformations causing epilepsy.
  • Current mTOR inhibitor treatments like everolimus offer limited seizure control in many TSC patients, necessitating new therapeutic targets.

Purpose of the Study:

  • To investigate the efficacy of MEK-ERK pathway inhibition as a novel therapeutic strategy for intractable epilepsy in Tuberous sclerosis complex.
  • To evaluate the anti-seizure effects of the MEK inhibitor PD0325901 (mirdametinib) in established mouse models of TSC.

Main Methods:

  • Utilized two distinct mouse models engineered to recapitulate Tuberous sclerosis complex neuropathology.
  • Administered PD0325901 (mirdametinib), a selective MEK inhibitor, to assess its impact on seizure activity.
  • Monitored and quantified seizure frequency and severity in treated and control groups.

Main Results:

  • Treatment with PD0325901 significantly reduced seizure activity in both Tuberous sclerosis complex mouse models.
  • MEK-ERK pathway inhibition demonstrated efficacy independent of mTOR signaling modulation.
  • Observed rescue of neuronal dendrite overgrowth in prior TSC mouse models with MEK-ERK inhibition.

Conclusions:

  • MEK-ERK pathway inhibition represents a promising therapeutic avenue for managing intractable epilepsy associated with Tuberous sclerosis complex.
  • PD0325901 (mirdametinib) shows potential as an alternative or adjunctive treatment for TSC-related seizures.
  • Targeting the MEK-ERK pathway offers a novel strategy distinct from mTOR inhibition for TSC epilepsy treatment.
Keywords:
EpilepsyMAPKMEK inhibitorMEK-ERK signalingSeizuresTuberous sclerosis complex

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