Finding a better drug for epilepsy: The mTOR pathway as an antiepileptogenic target

Abstract

Summary The mTOR signaling pathway regulates cell growth, differentiation, proliferation and metabolism. Loss of function mutations in upstream regulators of mTOR have been highly associated with dysplasias, epilepsy and neurodevelopmental disorders. These include tuberous sclerosis, which is due to mutations in TSC1 or TSC2 genes, mutations in phosphatase and tensin homolog (PTEN) as in Cowden syndrome, polyhydramnios, megalencephaly, symptomatic epilepsy syndrome (PMSE) due to mutations in the STE20-related kinase adaptor alpha (STRADalpha), and neurofibromatosis type 1 attributed to neurofibromin 1 mutations. Inhibition of the mTOR pathway with rapamycin may prevent epilepsy and improve the underlying pathology in mouse models with disrupted mTOR signaling, due to PTEN or TSC mutations. However the timing and duration of its administration appear critical in defining the seizure and pathology-related outcomes. Rapamycin application in human cortical slices from patients with cortical dysplasias reduces the 4-aminopyridine induced oscillations. In the multiple-hit model of infantile spasms, pulse high dose rapamycin administration can reduce the cortical overactivation of the mTOR pathway, suppresses spasms and has disease-modifying effects by partially improving cognitive deficits. In post-status epilepticus models of temporal lobe epilepsy, rapamycin may ameliorate the development of epilepsy-related pathology and reduce the expression of spontaneous seizures, but its effects depend on the timing and duration of administration, and possibly the model used. The observed recurrence of seizures and epilepsy-related pathology after rapamycin discontinuation suggests the need for continuous administration to maintain the benefit. However, the use of pulse administration protocols may be useful in certain age-specific epilepsy syndromes, like infantile spasms, whereas repetitive pulse rapamycin protocols may suffice to sustain a long-term benefit in genetic disorders of the mTOR pathway. In summary, mTOR dysregulation has been implicated in several genetic and acquired forms of epileptogenesis. The use of mTOR inhibitors can reverse some of these epileptogenic processes although their effects depend upon the timing and dose of administration as well as the model used.

Recent Advances in the Pharmacotherapy of Infantile Spasms

“…Rapamycin inhibits seizures and mTOR pathway activation in a mouse model of the TS complex [101,[103][104][105], And also improved cognitive outcome in a rat model of infantile spasms [104].…”

“…rapamycin) may challenge the role of vigabatrin as the preferred drug for infantile spasms caused by TS [104]. High-dose, pulse rapamycin treatment is also a promising, well-tolerated and disease-modifying new therapy for infantile spasms, including those not linked to TS [104,105]. Clinical trials are ongoing to explore the benefits of this treatment to control other severe symptoms, such as epilepsy and skin lesions.…”

“…In a mouse model of TS, vigabatrin inhibits seizure activity and mTOR pathway activation [103]. Rapamycin, currently being evaluated within animal models for TS, is emerging therapy under investigation for infantile spasms [104,105].…”

Epilepsy Related to Developmental Tumors and Malformations of Cortical Development

“…Accordingly, mTOR has been shown to influence both the innate and adaptive immune response [80][81][82], and selectively regulate microglial activation in response to pro-inflammatory cytokines, influencing microglial viability [83]. The prominent upregulation of the mTOR pathway observed in GNT, particularly in GG, is especially interesting in view of the observations supporting the role of mTOR as a key regulator of cellular changes involved in epileptogenesis (for reviews see [84][85][86][87]). Recent observations suggest a prognostic value for BRAF V600E and pS6 (as marker of mTOR activation) as potential indicators of worse postoperative seizure outcome in GNT [31].…”

“…The secretion of growth factors, such as vascular endothelial growth factor (VEGF), in the microenvironment of these tumors has been also suggested to contribute to the activation of the mTOR pathway [122][123][124]. Whether seizure activity contributes to mTOR activation also has to be taken into consideration (for reviews see [84][85][86]). Mutational analysis of TSC1 and TSC2 demonstrated TSC1 sequence alterations in FCD IIb [125].…”