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News from the American Epilepsy Society Annual Meeting
mTOR Signaling Pathway Found to Be Overactive in People with Treatment-Resistant Temporal Lobe Epilepsy, Suggesting New Therapeutic Targets

ARTICLE IN BRIEF

Researchers observed over-activity of the mechanistic target of rapamycin (mTOR) signaling pathway in brain tissue samples from patients preparing to undergo temporal lobe epilepsy surgery.

Researchers at the University of Pennsylvania have observed over-activity of the mechanistic target of rapamycin (mTOR) signaling pathway in brain tissue samples from patients with treatment-resistant temporal lobe epilepsy undergoing surgical resection, a finding previously observed in animal models.

The finding suggests that pharmacologically modulating the mTOR pathway could help reduce seizure activity in these patients, the researchers reported. Earlier research has shown that blocking the mTOR pathway with rapamycin in animal models of temporal lobe epilepsy results in decreased seizure activity.

mTOR is part of a complex cellular signaling network that plays a key role in cellular growth and survival via direct or indirect modulation of several hundred intracellular proteins. This pathway is activated by a variety of signals, including certain growth factors and nutrients, cellular energy levels, and stress signals, said Delia Talos, MD, an assistant professor of neurology at the University of Pennsylvania in Philadelphia, who presented the findings earlier this month at the annual meeting of the American Epilepsy Society (AES).

“Impaired functioning of the mTOR pathway has been implicated in the pathogenesis of a variety of cancers and neurodegenerative diseases and, more recently, in epilepsy,” Dr. Talos said.

STUDY METHODOLOGY, RESULTS

For the new study, Dr. Talos and her colleagues set out to determine whether the mTOR pathway might be involved in human forms of epilepsy. They obtained permission from patients preparing to undergo epilepsy surgery to collect tissue from the hippocampus and neocortex. They acquired eight samples of hippocampal tissue and 10 samples from the neocortex. In addition, they secured normal brain tissue samples from five age-matched deceased donors who did not have epilepsy through the University of Maryland Brain and Tissue Bank.

The 10 epilepsy patients, aged 20 to 56, had already undergone a comprehensive pre-surgical evaluation. Neuropathological studies confirmed the presence of mesial temporal sclerosis (MTS) in five of the cases. None of the patients had neuropathological evidence of cortical malformations.

The researchers conducted Western blots and immunohistochemistry on the samples to look for upstream and downstream markers of mTOR activity, specifically the phosphorylated forms of ribosomal protein S6 and the protein kinase Akt.

Compared with controls, mTOR pathway activity was significantly increased in all of the patient samples studied. Western blot and immunohistochemistry studies showed increased mTOR activity in the neocortex and hippocampus. There were no significant differences between temporal lobe epilepsy cases with MTS and epilepsy cases without MTS for any of these markers, the researchers reported.

“This is the first proof of up-regulation of the mTOR pathway in humans with temporal lobe epilepsy,” Dr. Talos said.

Whether the observed mTOR pathway abnormalities play a role in triggering seizures or are only a consequence of seizure activity remains to be seen.

The researchers are now looking downstream of the pathway to see if there are more specific targets that can be pharmacologically manipulated to achieve seizure freedom. “We are trying to find other ways to prevent seizures in patients resistant to traditional antiepileptic medications,” said Dr. Talos. “The results of our investigations in animal models of epilepsy led us to the mTOR pathway, and we believe this pathway is involved in some forms of epilepsy.”

Dr. Talos and others previously found up-regulation of the mTOR pathway in brain tissue taken from patients with tuberous sclerosis complex (TSC). In animal studies, treatment with rapamycin worked to regulate seizure activity, and these findings led to the first clinical trial testing rapamycin analogs in TSC patients. These clinical studies set out to investigate the effect of the therapy on seizures and cognition, as many TSC patients have both intractable seizures and cognitive impairments.

The concern with targeting the mTOR pathway, Dr. Talos said, “is that this pathway is involved in so many cellular processes. If we were to treat patients with rapamycin derivatives, we could inadvertently shut down processes that are critical for normal brain development and functioning. Therefore, we first need to understand what parts of the pathway we can target with minimal side effects.

“Having access to tissue from patients undergoing surgery has been a wonderful opportunity for us to try to understand what makes some seizures treatment-resistant,” she added. “We definitely need more data before we can think about using these medicines in temporal lobe epilepsy patients. We would like to find a more specific target so that we can avoid a complete mTOR pathway shutdown.”

She added that she and her colleagues have identified a few promising targets that they are now studying in depth.

EXPERTS COMMENT

“mTOR is a very important cell signaling protein in the central nervous system,” said Peter Crino, MD, PhD, professor and vice chair of neurology at Temple University School of Medicine in Philadelphia. A decade ago, his laboratory was among the first to identify mTOR's involvement in tuberous sclerosis complex. Since then, the genes that have been linked to brain malformations like TSC have been found to be part of the mTOR signaling cascade.

“The evidence in this abstract suggests that there may be activation of mTOR signaling cascade in temporal lobe epilepsy, but it would be a far cry to say that we can treat people with an mTOR inhibitor,” said Dr. Crino. “We just don't know that inhibiting mTOR would have an effect on controlling seizures. It is an intriguing preliminary finding, but we have to be cautious in interpreting it.”

Michael Wong, MD, PhD, the Allen P. and Josephine B. Green professor of pediatric neurology and a professor of neurology, pediatrics, and neurobiology at Washington University School of Medicine in St. Louis, said: “mTOR inhibitors, which have a completely different mechanism of action than current epilepsy drugs, have generated excitement as potential novel treatments for epilepsy in tuberous sclerosis complex. While animal models have suggested broader applications of mTOR inhibitors for epilepsy beyond tuberous sclerosis, the current study provides important evidence that mTOR could be involved in acquired epilepsy in people, and that mTOR inhibitors could be effective treatments for drug-resistant acquired epilepsy.”

Figure

DR. DELIA TALOS: “This is the first proof of up-regulation of the mTOR pathway in humans with temporal lobe epilepsy.”

However, a caveat to this study is that it is difficult to prove that abnormal mTOR signaling contributed to epilepsy in these patients. The abnormal signaling may be secondary to seizures or just an epiphenomenon, Dr. Wong said. “Seizures themselves have been shown to increase mTOR activity,” he added.

EXPERTS: ON AN OVERACTIVE mTOR SIGNALING PATHWAY IN TEMPORAL LOBE EPILEPSY

Figure

DR. PETER CRINO: “The evidence in this abstract suggests that there may be activation of mTOR signaling cascade in temporal lobe epilepsy, but it would be a far cry to say that we can treat people with an mTOR inhibitor. We just dont know that inhibiting mTOR would have an effect on controlling seizures. It is an intriguing preliminary finding, but we have to be cautious in interpreting it.”

Figure

DR. MICHAEL WONG: “While animal models have suggested broader applications of mTOR inhibitors for epilepsy beyond tuberous sclerosis, the current study provides important evidence that mTOR could be involved in acquired epilepsy in people, and that mTOR inhibitors could be effective treatments for drug-resistant acquired epilepsy.”

LINK UP FOR MORE INFORMATION:

•. Jacobs LM, Coto C, Sun T, et al.AESannual meeting abstract: Over-activation of mTOR signaling pathway in human therapy-resistant temporal lobe epilepsy: http://bit.ly/mTOR-AES