Department 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.
Department of Translational EEG, PsychoGenics, Inc., Paramus, NJ, USA.
Epilepsy Res. 2022 Mar;181:106890. doi: 10.1016/j.eplepsyres.2022.106890. Epub 2022 Feb 18.
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.
结节性硬化症复合征（TSC）是一种单基因疾病，其特征是 mTOR 信号通路的过度激活和导致难治性癫痫的发育性脑畸形。尽管最近批准的 mTOR 抑制剂依维莫司治疗可使高达 40%的 TSC 患者的癫痫发作得到临床相关抑制，但在大量病例中，癫痫发作仍未得到控制，这突显了需要确定新的治疗靶点。在 TSC 中发现 MEK-ERK 信号通路异常激活，并且独立于 mTOR 抑制 MEK-ERK 活性可挽救模拟 TSC 神经病理学的小鼠中的神经元树突过度生长。在这里，我们评估了 MEK-ERK 抑制对两种 TSC 小鼠模型中癫痫发作的疗效。我们发现，用 MEK 抑制剂 PD0325901（mirdametinib）治疗可显著减少两种 TSC 小鼠模型中的癫痫发作活动。这些发现支持抑制 MEK-ERK 活性作为治疗 TSC 中癫痫发作的潜在替代策略。
