Mammalian target of rapamycin (mTOR) inhibition: potential for antiseizure, antiepileptogenic, and epileptostatic therapy

Abstract

New epilepsy treatments are needed that not only inhibit seizures symptomatically (antiseizure) but also prevent the development of epilepsy (antiepileptogenic). The mammalian target of rapamycin (mTOR) pathway may mediate mechanisms of epileptogenesis and serve as a rational therapeutic target. mTOR inhibitors have antiepileptogenic and antiseizure effects in animal models of the genetic disease, tuberous sclerosis complex. The mTOR pathway is also implicated in epileptogenesis in animal models of acquired epilepsy and infantile spasms, although the effects of mTOR inhibitors are variable depending on the specific conditions and model. Furthermore, beneficial effects on seizures are lost when treatment is withdrawn, suggesting that mTOR inhibitors are "epileptostatic" in only stalling epilepsy progression during treatment. Clinical studies of rapamycin in human epilepsy are limited, but suggest that mTOR inhibitors at least have antiseizure effects in tuberous sclerosis patients. Further studies are needed to assess the full potential of mTOR inhibitors for epilepsy treatment.

Figure 1

Regulation of the mTOR signaling pathway. The serine-threonine protein kinase, mTOR, forms two complexes, mTORC1, which is rapamycin sensitive, and mTORC2 (not shown). The mTOR pathway activates downstream signaling mechanisms primarily involved in regulating protein synthesis related to multiple functions, such as cell growth and proliferation, as well as other processes that may relate directly to epileptogenesis. In turn, the mTOR pathway may be activated or inhibited by various physiological or pathological stimuli via various upstream signaling pathways and intermediary proteins (TSC1, TSC2, Rheb). AMPK - 5' adenosine monophosphate-activated protein kinase; eIF4E, elongation initiation factor 4E; ERK – extracellular-signal-regulated kinases; IGF - insulin growth factor; mTOR - mammalian target of rapamycin; PI3K - phosphoinositide-3 kinase; PTEN, phosphatase and tensin homolog on chromosome 10; Rheb - Ras homolog enriched in brain; STRADα – STE20-related kinase adapter alpha; S6 - ribosomal protein S6; S6K - ribosomal S6 kinase; TSC1 - tuberous sclerosis complex 1 protein; TSC2 - tuberous sclerosis complex 2 protein; 4E-BP1 - elongation factor 4E binding protein 1.