Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex

Zeng, Ling‐Hui; Xu, Lin; Gutmann, David H.; Wong, Michael

doi:10.1002/ana.21331

Cited by 575 publications

(608 citation statements)

References 32 publications

Supporting

Mentioning

552

Contrasting

Unclassified

Order By: Relevance

“…It was diluted in 5% Tween 80, 5% polyethyleneglycol 400 and 4% ethanol immediately before use 18. Rapamycin was injected intraperitoneal once a day at the dose of 3.0 mg/kg.…”

Section: Methodsmentioning

confidence: 99%

Rapamycin prevents cerebral stroke by modulating apoptosis and autophagy in penumbra in rats

Zhang

Kai

et al. 2017

Ann Clin Transl Neurol

Self Cite

View full text Add to dashboard Cite

ObjectiveWhether activation or inhibition of the mTOR pathway is beneficial to ischemic injury remains controversial. It may result from the different reaction of ischemic penumbra and core to modulation of mTOR pathway after cerebral ischemia–reperfusion injury in rats.MethodsLonga's middle cerebral artery occlusion (MCAO) method was conducted to induce the focal cerebral ischemia–reperfusion. Western blot analysis was used to examine the protein expression involving mTOR pathway, apoptosis, and autophagy‐related proteins. TTC staining and Fluoro‐Jade B staining was conducted to detect the infarct volume and cell apoptosis, respectively. Neurological function was measured by modified neurological severity score and left‐biased swing.Results mTOR signaling pathway was activated in ischemic penumbra and decreased in ischemic core after ischemia and ischemia–reperfusion. Ischemia–reperfusion injury induced the increase in cleaved caspase 9 and caspase 3 both in ischemic penumbra and in ischemic core, whereas the expression of phosphorylated ULK1, Beclin 1 and LC3‐II was decreased. Rapamycin pre or postadministration inhibited the overactivation of mTOR pathway in ischemic penumbra. Ameliorated neurological function and reduced infarct volume were observed after pre or postrapamycin treatment. Rapamycin markedly decreased the number of FJB‐positive cells and the expression of cleaved caspase‐3 and cleaved caspase‐9 proteins as well as increased the activation of autophagy reflected by ULK1, Beclin‐1 and LC3.Interpretation mTOR signaling pathway was activated in ischemic penumbra after cerebral ischemia–reperfusion injury in rats. mTOR inhibitor rapamycin significantly decreased the mTOR activation and infarct volume and subsequently improved neurological function. These results may relate to inhibition of neuron apoptosis and activation of autophagy.

show abstract

“…It was diluted in 5% Tween 80, 5% polyethyleneglycol 400 and 4% ethanol immediately before use 18. Rapamycin was injected intraperitoneal once a day at the dose of 3.0 mg/kg.…”

Section: Methodsmentioning

confidence: 99%

Rapamycin prevents cerebral stroke by modulating apoptosis and autophagy in penumbra in rats

Zhang

Kai

et al. 2017

Ann Clin Transl Neurol

Self Cite

View full text Add to dashboard Cite

show abstract

“…Rapamycin inhibits seizures and mTOR pathway activation in a mouse model of the TS complex [101,[103][104][105], And also improved cognitive outcome in a rat model of infantile spasms [104].…”

Section: New Optionsmentioning

confidence: 99%

“…These genes, known as tumour suppressors, are responsible for the inhibition of the mammalian target of rapamycin (mTOR) signalling pathways [100]. Mutations in these genes cause hyperactivation of the mTOR system and result in excessive cell growth and hamartomatous tumours in multiple organs [100,101]. Recently, novel treatment with mTOR inhibitors proved to be effective in the suppression of progressive proliferative growth of subependymal giant cell astrocytoma (SEGA) and renal angiomyolipomas [102].…”

Section: Tuberous Sclerosis (Ts)mentioning

confidence: 99%

Recent Advances in the Pharmacotherapy of Infantile Spasms

Riikonen

2014

CNS Drugs

View full text Add to dashboard Cite

Adrenocorticotrophic hormone (ACTH), oral corticosteroids and vigabatrin are now first-line treatments for infantile spasms in the US and Europe. There is now increased knowledge regarding the role of ACTH, corticosteroids and vigabatrin (e.g. efficacy, doses, side effects, treatment in specific aetiological subtypes of infantile spasms), and other antiepileptic drugs (i.e. topiramate, valproate, zonisamide, sulthiame, levetiracetam, lamotrigine, pyridoxine, ganaxolone), as well as adjunctive flunarizine and novel drugs not yet in clinical use for infantile spasms (i.e. pulse rapamycin and melanocortin receptor agonists). The existence of a latent period, weeks to months following a precipitating brain insult, raises the possibility of preventive interventions. Recent experimental data emerging from animal models of infantile spasms have provided optimism that new and innovative treatments can be developed, and knowledge that drug treatment can affect long-term cognitive outcome is increasing. The aim of this article is to review recent developments in the pharmacotherapy of infantile spasms and to highlight the practical implications of the latest research.

show abstract

“…Furthermore, Zeng et al [20] found that rapamycin exerted an anti-seizure effect in a mouse model of tuberous sclerosis-a disease in which there is strong evidence supporting a role for the hyperactivation of the mTOR pathway in the pathology of tuberous sclerosis. Unfortunately, the initial observations suggesting that rapamycin prevents SE-induced mossy fiber sprouting were contingent upon the continued exposure to rapamycin.…”

Section: Definitionsmentioning

confidence: 99%

Searching for the Ideal Antiepileptogenic Agent in Experimental Models: Single Treatment Versus Combinatorial Treatment Strategies

White

Löscher²

2014

Neurotherapeutics

View full text Add to dashboard Cite

A major unmet medical need is the lack of treatments to prevent (or modify) epilepsy in patients at risk, for example, after epileptogenic brain insults such as traumatic brain injury, stroke, or prolonged acute symptomatic seizures like complex febrile seizures or status epilepticus. Typically, following such brain insults there is a seizure-free interval ("latent period"), lasting months to years before the onset of spontaneous recurrent epileptic seizures. The latent period after a brain insult offers a window of opportunity in which an appropriate treatment may prevent or modify the epileptogenic process induced by a brain insult. A similar latent period occurs in patients with epileptogenic gene mutations. Studies using animal models of epilepsy have led to a greater understanding of the factors underlying epileptogenesis and have provided significant insight into potential targets by which the development of epilepsy may be prevented or modified. This review focuses largely on some of the most common animal models of epileptogenesis and their potential utility for evaluating proposed antiepileptogenic therapies and identifying useful biomarkers. The authors also describe some of the limitations of using animal models in the search for therapies that move beyond the symptomatic treatment of epilepsy. Promising results of previous studies designed to evaluate antiepileptogenesis and the role of monotherapy versus polytherapy approaches are also discussed. Recent data from both models of genetic and acquired epilepsies strongly indicate that it is possible to prevent or modify epileptogenesis, and, hopefully, such promising results can ultimately be translated into the clinic.

show abstract

Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex

Abstract: Rapamycin has strong efficacy for preventing seizures and prolonging survival in Tsc1(GFAP)CKO mice.

Cited by 575 publications

References 32 publications

Rapamycin prevents cerebral stroke by modulating apoptosis and autophagy in penumbra in rats

Rapamycin prevents cerebral stroke by modulating apoptosis and autophagy in penumbra in rats

Recent Advances in the Pharmacotherapy of Infantile Spasms

Searching for the Ideal Antiepileptogenic Agent in Experimental Models: Single Treatment Versus Combinatorial Treatment Strategies

Contact Info

Product

Resources

About