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Advanced Neurology mTOR inhibition in epilepsy

onset of neurological abnormalities, prevented epilepsy, seizures. Targeting mTOR signaling represents a novel
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and premature death. However, the neurological therapeutic strategy for epilepsy, with ongoing research
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phenotype and histopathological abnormalities reappeared focused on optimizing the use of mTOR inhibitors for
after rapamycin cessation, resulting in death within treating this disorder.
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approximately 2 months. Similar findings were observed To date, at least 60 mTOR inhibitors have been
in PTEN-knockout mice with cortical dysplasia. 43 developed and are at various stages of clinical trials.
Unlike its effects on genetic models of mTOR Thus far, three mTOR inhibitors, namely rapamycin
hyperactivity, mTOR inhibition exhibited significantly (also known as sirolimus), everolimus, and temsirolimus,
variable anti-seizure and anti-epileptogenic effects in have been approved by the United States Food and Drug
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acquired models of epilepsy. 14,20 Zeng et al. reported Administration (U.S. FDA) for variable indications.
that biphasic mTOR activities peaked 3 – 6 h after acute However, only everolimus is specifically licensed for use
kainate-induced seizure and returned to baseline by 24 h in epilepsy, whereas rapamycin is used off-label for certain
in the neocortex and hippocampus, with a second peak neurology-related conditions (Table 1). 16,51-55
5 – 10 days later only in the hippocampus, in an animal 6.1. mTOR inhibitors used in tuberous sclerosis
model of status epilepticus-induced temporal lobe epilepsy complex
(TLE). Early rapamycin use has been shown to prevent
epilepsy, while late treatment reduces seizures. In a mouse 6.1.1. Rapamycin (sirolimus)
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model of pilocarpine-induced status epilepticus and TLE, Rapamycin was the first mTOR inhibitor identified. It
a 2-month treatment with rapamycin reduced mossy fiber was discovered by Vézina et al. in 1975, isolated from
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sprouting – a common neuropathology of mesial TLE – but Streptomyces hygroscopius in a soil sample from Rapa Nui,
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did not reduce seizure frequency. Sliwa et al. similarly and initially demonstrated anti-fungal properties before its
found that rapamycin did not prevent epileptogenesis in immunosuppressive effects were recognized.
a mouse model of amygdala stimulation-induced TLE. In
rats with hypoxia-induced neonatal seizures, rapamycin Rapamycin is an allosteric inhibitor that binds to
reversed the early rise of glutamate neurotransmission intracellular FKBP12 receptors, which in turn binds
and seizure susceptibility, reducing subsequent autistic- to the FRB domain of the mTOR protein. This binding
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like behavior and epilepsy. For traumatic brain injury, allosterically alters the mTOR active site, inhibiting mTORC
assembly, disrupting its interaction with substrates, and
Guo et al. reported that rapamycin did not prevent thereby suppressing kinase activity. 57-59 Rapamycin exhibits
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acute symptomatic seizures following controlled cortical a differential sensitivity toward mTORC, being highly
impact injury in rats, but it significantly reduced the rate selective for mTORC1, whereas mTORC2 is relatively
of developing post-traumatic epilepsy. On the other hand, insensitive to rapamycin. mTORC2’s stronger interaction
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rapamycin has been shown to have little or no effects on with phosphatidic acid compared to mTORC1 renders its
acutely induced seizures. 20,49,50
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stability against rapamycin, resulting in the need for much
Wong postulated that the anti-seizure and anti- higher concentration and longer exposure to rapamycin to
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epileptogenic effects of mTOR inhibition may depend on suppress mTORC2 assembly and activity. 58,60,61
timing, duration, age, pathology, and the specific model Rapamycin was first approved by the U.S. FDA in 1999
used. Overall, early and long-term treatment with mTOR as an immunosuppressant for rejection prophylaxis in
inhibitors may be crucial to achieving maximal anti- renal transplant patients. In the context of neurological
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epileptogenic effects in both genetic and acquired models disorders, the clinical response to rapamycin in patients
of mTOR hyperactive conditions. 20 with tuberous sclerosis complex was first reported in 2006.
6. mTOR inhibitors and clinical studies Significant volume reduction of subependymal giant cell
astrocytomas (SEGAs) was observed in five tuberous
Targeting mTOR signaling is emerging as a promising sclerosis complex patients treated with rapamycin
approach for treating epilepsy, given that mTOR signaling (Table 2). When rapamycin was administered to six
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networks play a crucial role in epilepsy development by tuberous sclerosis complex patients with refractory epilepsy,
influencing processes such as neuronal growth, synaptic all but one experienced a 50% or greater reduction in
changes, neurotransmitter release, energy metabolism, seizures with sirolimus. In the study, the initial sirolimus
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and autophagy. mTOR inhibitors are considered rational dosage was 1.0 mg/m /d, with a target sirolimus level of
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candidates as potential anti-epileptogenic or disease- 4 – 10 ng/mL. The initial sirolimus dosage of 1.0 mg/m /d is
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modifying agents, with the ability to prevent epilepsy or the recommended dosage for other established indications
slow disease progression rather than merely controlling in patients weighing less than 40 kg. However, the safety of

Volume 3 Issue 3 (2024) 6 doi: 10.36922/an.3568