A pulse rapamycin therapy for infantile spasms and associated cognitive decline

Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx NY 10461, USA.
Neurobiology of Disease (Impact Factor: 5.08). 08/2011; 43(2):322-9. DOI: 10.1016/j.nbd.2011.03.021
Source: PubMed


Infantile spasms are seizures manifesting within a spectrum of epileptic encephalopathies of infancy that often lead to cognitive impairment. Their current therapies, including adrenocorticotropic hormone (ACTH), high dose steroids, or vigabatrin, are not always effective and may be associated with serious side effects. Overactivation of the TORC1 complex of the mTOR pathway is implicated in the pathogenesis of certain genetic and acquired disorders that are linked with infantile spasms, like tuberous sclerosis. Here, we tested the therapeutic potential of rapamycin, a TORC1 inhibitor, as a potential treatment for infantile spasms in the multiple-hit rat model of ACTH-refractory symptomatic infantile spasms, which is not linked to tuberous sclerosis. Rapamycin or vehicle was given after spasms appeared. Their effects on spasms, other seizures, performance in Barnes maze, and expression of the phosphorylated S6 ribosomal protein (pS6: a TORC1 target) in the cortex, using immunofluorescence, were compared. Rapamycin suppressed spasms dose-dependently and improved visuospatial learning, although it did not reduce the frequency of other emerging seizures. High-dose pulse rapamycin effected acute and sustained suppression of spasms and improved cognitive outcome, without significant side effects. Therapeutically effective rapamycin doses normalized the pS6 expression, which was increased in perilesional cortical regions of pups with spasms. These findings support that pathological overactivation of TORC1 may be implicated in the pathogenesis of infantile spasms, including those that are not linked to tuberous sclerosis. Furthermore, a high-dose, pulse rapamycin treatment is a promising, well tolerated and disease-modifying new therapy for infantile spasms, including those refractory to ACTH.

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    • "IS'li çocuklarda nöroprotektif olduğu belirtil- miştir.[93]ACTH'a dirençli olgularda " pulse " rapamisin tedavisi tüberoskleroz sıçan modellerinde IS'lerin durdurulmasında etkin olmuştur.[94]Ketojenik diyet de infantil spazm tedavisinde denenmiş ve refrakter epilepsilerin bir kısmında olduğu gibi bazı olgularda (%20) etkili olmuştur.[95]Spazmların "

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    • "Dysregulation of mTOR activity is observed in cortical dysplasias and malformations often associated with symptomatic West syndrome. Pulse application of rapamycin, an mTOR inhibitor, suppressed spasms and improved the cognitive outcomes suggesting of contributing role of ongoing spasm in the expression of the encephalopathy (Raffo et al., 2011 "
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    ABSTRACT: The application of metabolic imaging and genetic analysis, and now the development of appropriate animal models, has generated critical insights into the pathogenesis of epileptic encephalopathies. In this article we present ideas intended to move from the lesions associated with epileptic encephalopathies toward understanding the effects of these lesions on the functioning of the brain, specifically of the cortex. We argue that the effects of focal lesions may be magnified through the interaction between cortical and subcortical structures, and that disruption of subcortical arousal centers that regulate cortex early in life may lead to alterations of intracortical synapses that affect a critical period of cognitive development. Impairment of interneuronal function globally through the action of a genetic lesion similarly causes widespread cortical dysfunction manifesting as increased delta slow waves on electroencephalography (EEG) and as developmental delay or arrest clinically. Finally, prolonged focal epileptic activity during sleep (as occurring in the syndrome of continuous spike-wave in slow sleep, or CSWSS) might interfere with local slow wave activity at the site of the epileptic focus, thereby impairing the neural processes and, possibly, the local plastic changes associated with learning and other cognitive functions. Seizures may certainly add to these pathologic processes, but they are likely not necessary for the development of the cognitive pathology. Nevertheless, although seizures may be either a consequence or symptom of the underlying lesion, their effective treatment can improve outcomes as both clinical and experimental studies may suggest. Understanding their substrates may lead to novel, effective treatments for all aspects of the epileptic encephalopathy phenotype.
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    • "Animal models showed that mTOR inhibitors proved to have antiepileptic and even antiepileptogenic effect, decreasing seizures when started after epilepsy onset of seizures, or preventing the development of epilepsy when initiated prior to the onset of seizures [10]. There is some evidence showing that rapamycin might be a disease modifier agent in epileptic spasms, even not specifically related to TSC, but it doesn’t seem to have the same efficacy on other seizure types [11]. Different models show that beneficial effects on seizures are lost when treatment is withdrawn, suggesting that mTOR inhibitors are “epileptostatic” in only stalling epilepsy progression during treatment [12]. "
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    ABSTRACT: Tuberous sclerosis complex (TSC) is a genetic multisystem disorder characterized by the development of hamartomas in several organs. Mutations in the TSC1 and TSC2 tumor suppressor genes determin overactivation of the mammalian target of rapamycin (mTOR) signaling pathway and subsequent abnormalities in numerous cell processes. As a result, mTOR inhibitors such as sirolimus and everolimus have the potential to provide targeted therapy for TSC patients. Everolimus has been recently approved as a pharmacotherapy option for TSC patients with subependymal giant-cell astrocytomas (SEGAs) or renal angiomyolipomas (AMLs). However, clinical evidence suggests that this treatment can benefit other TSC-associated disease manifestations, such as skin manifestations, pulmonary lymphangioleiomyomatosis, cardiac rhabdomyomas, and epilepsy. Therefore, the positive effects that mTOR inhibition have on a wide variety of TSC disease manifestations make this a potential systemic treatment option for this genetic multifaceted disorder.
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