Article

Rapamycin Shows Promise for Treating Seizure Disorders


 

The drug reduced mossy fiber sprouting and decreased epileptiform activity in mouse studies, and may play a role in treating pretzel syndrome.


BOSTON—Treatment with rapamycin significantly reduced epileptiform activity in patients with tuberous sclerosis complex (TSC), and also may play a therapeutic role in treating pretzel syndrome, two separate studies reported at the 63rd Annual Meeting of the American Epilepsy Society.


Reduction in Mossy Fiber Sprouting
In one study, researchers at the Baylor College of Medicine and Rutgers University used video-EEG recordings, biochemical assays, and Timm staining to examine the effect of rapamycin on wild type and negative PI13-mTOR regulator PTEN (NS-PTEN) knockout mice. The investigators confirmed epileptic status of the knockout mice, all of which showed interictal spikes, repetitive spikes, and spike and wave discharge on the EEG videos.

By 6 weeks of age, these indicators of epilepsy were fully penetrant and grew more prevalent with age, the researchers noted. Mossy fiber sprouting, which has been linked to recurrent excitation in patients with temporal lobe epilepsy and in other animal models, was also evident by age 6 weeks.

C. Nicole Sunnen and colleagues treated the mice with 10 mg/kg daily intraperitoneal injections of rapamycin or vehicle for five days a week at ages 4 to 5 weeks and found that the rapamycin group displayed “decreased cortical pS6 levels, a downstream effector of mTORC1, indicating a successful inhibition of the PI3K-mTORC1 pathway.” The rapamycin group also showed a significant reduction in epileptiform activity immediately following treatment with rapamycin and for three weeks afterward. Rapamycin also significantly reduced mossy fiber sprouting.

“Our findings demonstrate that NS-PTEN knockout mice have epilepsy, and inhibition of the mTOR pathway not only attenuates epileptiform activity in this model, but also reduces aberrant mossy fiber sprouting,” reported Ms. Sunnen, a graduate student at the Baylor College of Medicine, and colleagues. “These results suggest that rapamycin may function as a novel treatment for some forms of epilepsy.”

Pretzel Syndrome
A second study suggested a potential therapeutic role of rapamycin in treating pretzel syndrome, an autosomal recessive disorder in Old Order Mennonite children. The syndrome is characterized by macrocephaly, severe cognitive disability, and intractable epilepsy.

Children with pretzel syndrome have a homozygous deletion in the STRADα gene (17q23.3), which encodes the pseudokinase STRADα (STE20 Related Adaptor alpha). Although the pathology of pretzel syndrome and the role of STRADα in corticogenesis remain unclear, STRADα is known to bind to and enhance the catalytic activity of the LKB1, which acts as an upstream kinase to many AMPK-related kinases. AMPK inhibits mTOR signaling by phosphorylating and activating tuberous sclerosis complex 2 (TSC2). LKB1 also may regulate neuronal migration during corticogenesis, according to recent research.

Investigators at the University of Pennsylvania analyzed postmortem brain tissue of subjects with pretzel syndrome to define the role of STRADα during corticogenesis and found neuronal cytomegaly and heterotopia in the subcortical white matter. “Immunohistochemical analysis demonstrated absent STRADα expression, enhanced phosphorylation of S6 protein suggestive of mTOR activation, and exclusively nuclear localization of LKB1,” reported Ksenia Orlova, a neuroscience graduate student, and colleagues at the Penn Epilepsy Center.

“STRADα regulates mTOR signaling in an AMPK- and rapamycin-dependent manner,” the investigators stated. “STRADα-depleted mNPCs exhibit nuclear LBK1 localization in contrast to control cells, which express LKB1 in the cytoplasmic compartment. STRADα knockdown in mNPCs resulted in cytomegaly that was prevented by treatment with the mTOR antagonist rapamycin.””

The researchers then analyzed the function of STRADα in vivo. At embryonic day 14 (E14), they noted aberrant cortical lamination.

“Specifically, STRADα-depleted cells remain in the ventricular/subventricular zones at E17 and E19 instead of assuming their appropriate laminar position,” the study authors reported. “This is of particular interest, since pretzel syndrome cortex contains abundant neuronal heterotopia in the subcortical white matter.”

The researchers pointed out that these studies are the first to delineate a functional role of STRADα during corticogenesis, and suggest a therapeutic role of rapamycin in treating pretzel syndrome.


—Rebecca K. Abma

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