Inhibition of mammalian target of rapamycin reduces epileptogenesis and blood-brain barrier leakage but not microglia activation
Summary Purpose: Previous studies have shown that inhibition of the mammalian target of rapamycin (mTOR) pathway with rapamycin prevents epileptogenesis after pharmacologically induced status epilepticus (SE) in rat models of temporal lobe epilepsy. Because rapamycin is also known for its immunosup...
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| Vydáno v: | Epilepsia (Copenhagen) Ročník 53; číslo 7; s. 1254 - 1263 |
|---|---|
| Hlavní autoři: | , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
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Oxford, UK
Blackwell Publishing Ltd
01.07.2012
Wiley-Blackwell Wiley Subscription Services, Inc |
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| ISSN: | 0013-9580, 1528-1167, 1528-1167 |
| On-line přístup: | Získat plný text |
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| Abstract | Summary
Purpose: Previous studies have shown that inhibition of the mammalian target of rapamycin (mTOR) pathway with rapamycin prevents epileptogenesis after pharmacologically induced status epilepticus (SE) in rat models of temporal lobe epilepsy. Because rapamycin is also known for its immunosuppressant properties we hypothesized that one of the mechanisms by which it exerts this effect could be via suppression of brain inflammation, a process that has been suggested to play a major role in the development and progression of epilepsy.
Methods: Rats were treated with rapamycin or vehicle once daily for 7 days (6 mg/kg/day, i.p.) starting 4 h after the induction of SE, which was evoked by electrical stimulation of the angular bundle. Hereafter rapamycin was administered every other day until rats were sacrificed, 6 weeks after SE. Video‐electroencephalography was used to monitor the occurrence of seizures. Neuronal death, synaptic reorganization, and microglia and astrocyte activation were assessed by immunohistologic staining. Fluorescein was administered to quantify blood–brain barrier leakage.
Key Findings: Rapamycin treatment did not alter SE severity and duration compared to vehicle treatment rats. Rapamycin‐treated rats developed hardly (n = 9) or no (n = 3) seizures during the 6‐week treatment, whereas vehicle‐treated rats showed a progressive increase of seizures starting 1 week after SE (mean 8 ± 2 seizures per day during the sixth week). Cell loss and sprouting that normally occur after SE were prominent but on average significantly less in rapamycin‐treated rats versus vehicle‐treated rats. Nevertheless, various inflammation markers (CD11b/c and CD68) were dramatically upregulated and not significantly different between post‐SE groups. Of interest, blood–brain barrier leakage was barely detected in the rapamycin‐treated group, whereas it was prominent in the vehicle‐treated group.
Significance: mTOR inhibition led to strong reduction of seizure development despite the presence of microglia activation, suggesting that effects of rapamycin on seizure development are not due to a control of inflammation. Whether the effects on blood–brain barrier leakage in rapamycin‐treated rats are a consequence of seizure suppressing properties of the drug, or contribute to a real antiepileptogenic effect still needs to be determined. |
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| AbstractList | Summary
Purpose: Previous studies have shown that inhibition of the mammalian target of rapamycin (mTOR) pathway with rapamycin prevents epileptogenesis after pharmacologically induced status epilepticus (SE) in rat models of temporal lobe epilepsy. Because rapamycin is also known for its immunosuppressant properties we hypothesized that one of the mechanisms by which it exerts this effect could be via suppression of brain inflammation, a process that has been suggested to play a major role in the development and progression of epilepsy.
Methods: Rats were treated with rapamycin or vehicle once daily for 7 days (6 mg/kg/day, i.p.) starting 4 h after the induction of SE, which was evoked by electrical stimulation of the angular bundle. Hereafter rapamycin was administered every other day until rats were sacrificed, 6 weeks after SE. Video‐electroencephalography was used to monitor the occurrence of seizures. Neuronal death, synaptic reorganization, and microglia and astrocyte activation were assessed by immunohistologic staining. Fluorescein was administered to quantify blood–brain barrier leakage.
Key Findings: Rapamycin treatment did not alter SE severity and duration compared to vehicle treatment rats. Rapamycin‐treated rats developed hardly (n = 9) or no (n = 3) seizures during the 6‐week treatment, whereas vehicle‐treated rats showed a progressive increase of seizures starting 1 week after SE (mean 8 ± 2 seizures per day during the sixth week). Cell loss and sprouting that normally occur after SE were prominent but on average significantly less in rapamycin‐treated rats versus vehicle‐treated rats. Nevertheless, various inflammation markers (CD11b/c and CD68) were dramatically upregulated and not significantly different between post‐SE groups. Of interest, blood–brain barrier leakage was barely detected in the rapamycin‐treated group, whereas it was prominent in the vehicle‐treated group.
Significance: mTOR inhibition led to strong reduction of seizure development despite the presence of microglia activation, suggesting that effects of rapamycin on seizure development are not due to a control of inflammation. Whether the effects on blood–brain barrier leakage in rapamycin‐treated rats are a consequence of seizure suppressing properties of the drug, or contribute to a real antiepileptogenic effect still needs to be determined. Previous studies have shown that inhibition of the mammalian target of rapamycin (mTOR) pathway with rapamycin prevents epileptogenesis after pharmacologically induced status epilepticus (SE) in rat models of temporal lobe epilepsy. Because rapamycin is also known for its immunosuppressant properties we hypothesized that one of the mechanisms by which it exerts this effect could be via suppression of brain inflammation, a process that has been suggested to play a major role in the development and progression of epilepsy. Rats were treated with rapamycin or vehicle once daily for 7 days (6 mg/kg/day, i.p.) starting 4 h after the induction of SE, which was evoked by electrical stimulation of the angular bundle. Hereafter rapamycin was administered every other day until rats were sacrificed, 6 weeks after SE. Video-electroencephalography was used to monitor the occurrence of seizures. Neuronal death, synaptic reorganization, and microglia and astrocyte activation were assessed by immunohistologic staining. Fluorescein was administered to quantify blood-brain barrier leakage. Rapamycin treatment did not alter SE severity and duration compared to vehicle treatment rats. Rapamycin-treated rats developed hardly (n = 9) or no (n = 3) seizures during the 6-week treatment, whereas vehicle-treated rats showed a progressive increase of seizures starting 1 week after SE (mean 8 ± 2 seizures per day during the sixth week). Cell loss and sprouting that normally occur after SE were prominent but on average significantly less in rapamycin-treated rats versus vehicle-treated rats. Nevertheless, various inflammation markers (CD11b/c and CD68) were dramatically upregulated and not significantly different between post-SE groups. Of interest, blood-brain barrier leakage was barely detected in the rapamycin-treated group, whereas it was prominent in the vehicle-treated group. mTOR inhibition led to strong reduction of seizure development despite the presence of microglia activation, suggesting that effects of rapamycin on seizure development are not due to a control of inflammation. Whether the effects on blood-brain barrier leakage in rapamycin-treated rats are a consequence of seizure suppressing properties of the drug, or contribute to a real antiepileptogenic effect still needs to be determined. Purpose: Previous studies have shown that inhibition of the mammalian target of rapamycin (mTOR) pathway with rapamycin prevents epileptogenesis after pharmacologically induced status epilepticus (SE) in rat models of temporal lobe epilepsy. Because rapamycin is also known for its immunosuppressant properties we hypothesized that one of the mechanisms by which it exerts this effect could be via suppression of brain inflammation, a process that has been suggested to play a major role in the development and progression of epilepsy. Methods: Rats were treated with rapamycin or vehicle once daily for 7 days (6 mg/kg/day, i.p.) starting 4 h after the induction of SE, which was evoked by electrical stimulation of the angular bundle. Hereafter rapamycin was administered every other day until rats were sacrificed, 6 weeks after SE. Video‐electroencephalography was used to monitor the occurrence of seizures. Neuronal death, synaptic reorganization, and microglia and astrocyte activation were assessed by immunohistologic staining. Fluorescein was administered to quantify blood–brain barrier leakage. Key Findings: Rapamycin treatment did not alter SE severity and duration compared to vehicle treatment rats. Rapamycin‐treated rats developed hardly (n = 9) or no (n = 3) seizures during the 6‐week treatment, whereas vehicle‐treated rats showed a progressive increase of seizures starting 1 week after SE (mean 8 ± 2 seizures per day during the sixth week). Cell loss and sprouting that normally occur after SE were prominent but on average significantly less in rapamycin‐treated rats versus vehicle‐treated rats. Nevertheless, various inflammation markers (CD11b/c and CD68) were dramatically upregulated and not significantly different between post‐SE groups. Of interest, blood–brain barrier leakage was barely detected in the rapamycin‐treated group, whereas it was prominent in the vehicle‐treated group. Significance: mTOR inhibition led to strong reduction of seizure development despite the presence of microglia activation, suggesting that effects of rapamycin on seizure development are not due to a control of inflammation. Whether the effects on blood–brain barrier leakage in rapamycin‐treated rats are a consequence of seizure suppressing properties of the drug, or contribute to a real antiepileptogenic effect still needs to be determined. Previous studies have shown that inhibition of the mammalian target of rapamycin (mTOR) pathway with rapamycin prevents epileptogenesis after pharmacologically induced status epilepticus (SE) in rat models of temporal lobe epilepsy. Because rapamycin is also known for its immunosuppressant properties we hypothesized that one of the mechanisms by which it exerts this effect could be via suppression of brain inflammation, a process that has been suggested to play a major role in the development and progression of epilepsy.PURPOSEPrevious studies have shown that inhibition of the mammalian target of rapamycin (mTOR) pathway with rapamycin prevents epileptogenesis after pharmacologically induced status epilepticus (SE) in rat models of temporal lobe epilepsy. Because rapamycin is also known for its immunosuppressant properties we hypothesized that one of the mechanisms by which it exerts this effect could be via suppression of brain inflammation, a process that has been suggested to play a major role in the development and progression of epilepsy.Rats were treated with rapamycin or vehicle once daily for 7 days (6 mg/kg/day, i.p.) starting 4 h after the induction of SE, which was evoked by electrical stimulation of the angular bundle. Hereafter rapamycin was administered every other day until rats were sacrificed, 6 weeks after SE. Video-electroencephalography was used to monitor the occurrence of seizures. Neuronal death, synaptic reorganization, and microglia and astrocyte activation were assessed by immunohistologic staining. Fluorescein was administered to quantify blood-brain barrier leakage.METHODSRats were treated with rapamycin or vehicle once daily for 7 days (6 mg/kg/day, i.p.) starting 4 h after the induction of SE, which was evoked by electrical stimulation of the angular bundle. Hereafter rapamycin was administered every other day until rats were sacrificed, 6 weeks after SE. Video-electroencephalography was used to monitor the occurrence of seizures. Neuronal death, synaptic reorganization, and microglia and astrocyte activation were assessed by immunohistologic staining. Fluorescein was administered to quantify blood-brain barrier leakage.Rapamycin treatment did not alter SE severity and duration compared to vehicle treatment rats. Rapamycin-treated rats developed hardly (n = 9) or no (n = 3) seizures during the 6-week treatment, whereas vehicle-treated rats showed a progressive increase of seizures starting 1 week after SE (mean 8 ± 2 seizures per day during the sixth week). Cell loss and sprouting that normally occur after SE were prominent but on average significantly less in rapamycin-treated rats versus vehicle-treated rats. Nevertheless, various inflammation markers (CD11b/c and CD68) were dramatically upregulated and not significantly different between post-SE groups. Of interest, blood-brain barrier leakage was barely detected in the rapamycin-treated group, whereas it was prominent in the vehicle-treated group.KEY FINDINGSRapamycin treatment did not alter SE severity and duration compared to vehicle treatment rats. Rapamycin-treated rats developed hardly (n = 9) or no (n = 3) seizures during the 6-week treatment, whereas vehicle-treated rats showed a progressive increase of seizures starting 1 week after SE (mean 8 ± 2 seizures per day during the sixth week). Cell loss and sprouting that normally occur after SE were prominent but on average significantly less in rapamycin-treated rats versus vehicle-treated rats. Nevertheless, various inflammation markers (CD11b/c and CD68) were dramatically upregulated and not significantly different between post-SE groups. Of interest, blood-brain barrier leakage was barely detected in the rapamycin-treated group, whereas it was prominent in the vehicle-treated group.mTOR inhibition led to strong reduction of seizure development despite the presence of microglia activation, suggesting that effects of rapamycin on seizure development are not due to a control of inflammation. Whether the effects on blood-brain barrier leakage in rapamycin-treated rats are a consequence of seizure suppressing properties of the drug, or contribute to a real antiepileptogenic effect still needs to be determined.SIGNIFICANCEmTOR inhibition led to strong reduction of seizure development despite the presence of microglia activation, suggesting that effects of rapamycin on seizure development are not due to a control of inflammation. Whether the effects on blood-brain barrier leakage in rapamycin-treated rats are a consequence of seizure suppressing properties of the drug, or contribute to a real antiepileptogenic effect still needs to be determined. Summary Purpose: Previous studies have shown that inhibition of the mammalian target of rapamycin (mTOR) pathway with rapamycin prevents epileptogenesis after pharmacologically induced status epilepticus (SE) in rat models of temporal lobe epilepsy. Because rapamycin is also known for its immunosuppressant properties we hypothesized that one of the mechanisms by which it exerts this effect could be via suppression of brain inflammation, a process that has been suggested to play a major role in the development and progression of epilepsy. Methods: Rats were treated with rapamycin or vehicle once daily for 7 days (6 mg/kg/day, i.p.) starting 4 h after the induction of SE, which was evoked by electrical stimulation of the angular bundle. Hereafter rapamycin was administered every other day until rats were sacrificed, 6 weeks after SE. Video-electroencephalography was used to monitor the occurrence of seizures. Neuronal death, synaptic reorganization, and microglia and astrocyte activation were assessed by immunohistologic staining. Fluorescein was administered to quantify blood-brain barrier leakage. Key Findings: Rapamycin treatment did not alter SE severity and duration compared to vehicle treatment rats. Rapamycin-treated rats developed hardly (n = 9) or no (n = 3) seizures during the 6-week treatment, whereas vehicle-treated rats showed a progressive increase of seizures starting 1 week after SE (mean 8 ± 2 seizures per day during the sixth week). Cell loss and sprouting that normally occur after SE were prominent but on average significantly less in rapamycin-treated rats versus vehicle-treated rats. Nevertheless, various inflammation markers (CD11b/c and CD68) were dramatically upregulated and not significantly different between post-SE groups. Of interest, blood-brain barrier leakage was barely detected in the rapamycin-treated group, whereas it was prominent in the vehicle-treated group. Significance: mTOR inhibition led to strong reduction of seizure development despite the presence of microglia activation, suggesting that effects of rapamycin on seizure development are not due to a control of inflammation. Whether the effects on blood-brain barrier leakage in rapamycin-treated rats are a consequence of seizure suppressing properties of the drug, or contribute to a real antiepileptogenic effect still needs to be determined. [PUBLICATION ABSTRACT] Purpose: Previous studies have shown that inhibition of the mammalian target of rapamycin (mTOR) pathway with rapamycin prevents epileptogenesis after pharmacologically induced status epilepticus (SE) in rat models of temporal lobe epilepsy. Because rapamycin is also known for its immunosuppressant properties we hypothesized that one of the mechanisms by which it exerts this effect could be via suppression of brain inflammation, a process that has been suggested to play a major role in the development and progression of epilepsy. Methods: Rats were treated with rapamycin or vehicle once daily for 7days (6mg/kg/day, i.p.) starting 4h after the induction of SE, which was evoked by electrical stimulation of the angular bundle. Hereafter rapamycin was administered every other day until rats were sacrificed, 6weeks after SE. Video-electroencephalography was used to monitor the occurrence of seizures. Neuronal death, synaptic reorganization, and microglia and astrocyte activation were assessed by immunohistologic staining. Fluorescein was administered to quantify blood-brain barrier leakage. Key Findings: Rapamycin treatment did not alter SE severity and duration compared to vehicle treatment rats. Rapamycin-treated rats developed hardly (n=9) or no (n=3) seizures during the 6-week treatment, whereas vehicle-treated rats showed a progressive increase of seizures starting 1week after SE (mean 8 plus or minus 2 seizures per day during the sixth week). Cell loss and sprouting that normally occur after SE were prominent but on average significantly less in rapamycin-treated rats versus vehicle-treated rats. Nevertheless, various inflammation markers (CD11b/c and CD68) were dramatically upregulated and not significantly different between post-SE groups. Of interest, blood-brain barrier leakage was barely detected in the rapamycin-treated group, whereas it was prominent in the vehicle-treated group. Significance: mTOR inhibition led to strong reduction of seizure development despite the presence of microglia activation, suggesting that effects of rapamycin on seizure development are not due to a control of inflammation. Whether the effects on blood-brain barrier leakage in rapamycin-treated rats are a consequence of seizure suppressing properties of the drug, or contribute to a real antiepileptogenic effect still needs to be determined. |
| Author | de Vries, Helga E. van Vliet, Erwin A. Sinjewel, Arno Forte, Grazia Holtman, Linda Aronica, Eleonora Gorter, Jan A. den Burger, Jeroen C. G. |
| Author_xml | – sequence: 1 givenname: Erwin A. surname: van Vliet fullname: van Vliet, Erwin A. organization: Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands – sequence: 2 givenname: Grazia surname: Forte fullname: Forte, Grazia organization: Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands – sequence: 3 givenname: Linda surname: Holtman fullname: Holtman, Linda organization: Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands – sequence: 4 givenname: Jeroen C. G. surname: den Burger fullname: den Burger, Jeroen C. G. organization: Department of Clinical Pharmacology and Pharmacy, VU University Medical Center, Amsterdam, The Netherlands – sequence: 5 givenname: Arno surname: Sinjewel fullname: Sinjewel, Arno organization: Department of Clinical Pharmacology and Pharmacy, VU University Medical Center, Amsterdam, The Netherlands – sequence: 6 givenname: Helga E. surname: de Vries fullname: de Vries, Helga E. organization: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands – sequence: 7 givenname: Eleonora surname: Aronica fullname: Aronica, Eleonora organization: Academic Medical Center, Department of (Neuro) Pathology, University of Amsterdam, Amsterdam, The Netherlands – sequence: 8 givenname: Jan A. surname: Gorter fullname: Gorter, Jan A. organization: Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands |
| BackLink | http://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26180557$$DView record in Pascal Francis https://www.ncbi.nlm.nih.gov/pubmed/22612226$$D View this record in MEDLINE/PubMed |
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| ContentType | Journal Article |
| Copyright | Wiley Periodicals, Inc. © 2012 International League Against Epilepsy 2015 INIST-CNRS Wiley Periodicals, Inc. © 2012 International League Against Epilepsy. |
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| Keywords | Antineoplastic agent Nervous system diseases Sirolimus Blood―brain barrier Neuroglia Central nervous system Complex partial epilepsy Lactone Inflammation Macrolide Blood brain barrier Encephalon Macrocycle Cerebral disorder Microglia Antibiotic Gliosis Subintrant crisis Central nervous system disease Temporal lobe epilepsy Protein synthesis inhibitor Immunosuppressive agent Status epilepticus |
| Language | English |
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| PublicationDate | July 2012 |
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| PublicationTitle | Epilepsia (Copenhagen) |
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| PublicationYear | 2012 |
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| References | Blamire AM, Anthony DC, Rajagopalan B, Sibson NR, Perry VH, Styles P. (2000) Interleukin-1beta -induced changes in blood-brain barrier permeability, apparent diffusion coefficient, and cerebral blood volume in the rat brain: a magnetic resonance study. J Neurosci 20:8153-8159. Seiffert E, Dreier JP, Ivens S, Bechmann I, Tomkins O, Heinemann U, Friedman A. (2004) Lasting blood-brain barrier disruption induces epileptic focus in the rat somatosensory cortex. J Neurosci 24:7829-7836. Daoud D, Scheld HH, Speckmann EJ, Gorji A. (2007) Rapamycin: brain excitability studied in vitro. Epilepsia 48:834-836. Martin-Martin N, Ryan G, McMorrow T, Ryan MP. (2010) Sirolimus and cyclosporine A alter barrier function in renal proximal tubular cells through stimulation of ERK1/2 signaling and claudin-1 expression. Am J Physiol Renal Physiol 298:F672-F682. Erlich S, Alexandrovich A, Shohami E, Pinkas-Kramarski R. (2007) Rapamycin is a neuroprotective treatment for traumatic brain injury. Neurobiol Dis 26:86-93. Dichter MA. (2009) Emerging concepts in the pathogenesis of epilepsy and epileptogenesis. Arch Neurol 66:443-447. Ruegg S, Baybis M, Juul H, Dichter M, Crino PB. (2007) Effects of rapamycin on gene expression, morphology, and electrophysiological properties of rat hippocampal neurons. Epilepsy Res 77:85-92. Ljungberg MC, Bhattacharjee MB, Lu Y, Armstrong DL, Yoshor D, Swann JW, Sheldon M, D'Arcangelo G. (2006) Activation of mammalian target of rapamycin in cytomegalic neurons of human cortical dysplasia. Ann Neurol 60:420-429. Marchi N, Tierney W, Alexopoulos AV, Puvenna V, Granata T, Janigro D. (2011b) The etiological role of blood-brain barrier dysfunction in seizure disorders. Cardiovasc Psychiatry Neurol 2011:482415. Zeng LH, Rensing NR, Wong M. (2009b) The mammalian target of rapamycin signaling pathway mediates epileptogenesis in a model of temporal lobe epilepsy. J Neurosci 29:6964-6972. Loscher W, Brandt C. (2010) Prevention or modification of epileptogenesis after brain insults: experimental approaches and translational research. Pharmacol Rev 62:668-700. Huang X, Zhang H, Yang J, Wu J, McMahon J, Lin Y, Cao Z, Gruenthal M, Huang Y. (2010) Pharmacological inhibition of the mammalian target of rapamycin pathway suppresses acquired epilepsy. Neurobiol Dis 40:193-199. Buckmaster PS, Ingram EA, Wen X. (2009) Inhibition of the mammalian target of rapamycin signaling pathway suppresses dentate granule cell axon sprouting in a rodent model of temporal lobe epilepsy. J Neurosci 29:8259-8269. Cornford EM, Oldendorf WH. (1986) Epilepsy and the blood-brain barrier. Adv Neurol 44:787-812. Vezzani A, French J, Bartfai T, Baram TZ. (2011) The role of inflammation in epilepsy. Nat Rev Neurol 7:31-40. Baulac M, Pitkanen A. (2009) Research priorities in epilepsy for the next decade-a representative view of the European scientific community. Epilepsia 50:571-578. Zucker DK, Wooten GF, Lothman EW. (1983) Blood-brain barrier changes with kainic acid-induced limbic seizures. Exp Neurol 79:422-433. Buckmaster PS, Lew FH. (2011) Rapamycin suppresses mossy fiber sprouting but not seizure frequency in a mouse model of temporal lobe epilepsy. J Neurosci 31:2337-2347. Marchi N, Angelov L, Masaryk T, Fazio V, Granata T, Hernandez N, Hallene K, Diglaw T, Franic L, Najm I, Janigro D. (2007) Seizure-promoting effect of blood-brain barrier disruption. Epilepsia 48:732-742. Zeng LH, Xu L, Gutmann DH, Wong M. (2008) Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Ann Neurol 63:444-453. Lorenzo AV, Shirahige I, Liang M, Barlow CF. (1972) Temporary alteration of cerebrovascular permeability to plasma protein during drug-induced seizures. Am J Physiol 223:268-277. van Vliet EA, da Costa Araujo S, Redeker S, van Schaik R, Aronica E, Gorter JA. (2007) Blood-brain barrier leakage may lead to progression of temporal lobe epilepsy. Brain 130:521-534. Chauhan A, Sharma U, Jagannathan NR, Reeta KH, Gupta YK. (2011) Rapamycin protects against middle cerebral artery occlusion induced focal cerebral ischemia in rats. Behav Brain Res 225:603-609. Kelley MS, Jacobs MP, Lowenstein DH. (2009) The NINDS epilepsy research benchmarks. Epilepsia 50:579-582. Shlosberg D, Benifla M, Kaufer D, Friedman A. (2010) Blood-brain barrier breakdown as a therapeutic target in traumatic brain injury. Nat Rev Neurol 6:393-403. Sliwa A, Plucinska G, Bednarczyk J, Lukasiuk K. (2012) Post-treatment with rapamycin does not prevent epileptogenesis in the amygdala stimulation model of temporal lobe epilepsy. Neurosci Lett 509:105-109. Marchi N, Granata T, Freri E, Ciusani E, Ragona F, Puvenna V, Teng Q, Alexopolous A, Janigro D. (2011a) Efficacy of anti-inflammatory therapy in a model of acute seizures and in a population of pediatric drug resistant epileptics. PLoS ONE 6:e18200. Fabene PF, Navarro MG, Martinello M, Rossi B, Merigo F, Ottoboni L, Bach S, Angiari S, Benati D, Chakir A, Zanetti L, Schio F, Osculati A, Marzola P, Nicolato E, Homeister JW, Xia L, Lowe JB, McEver RP, Osculati F, Sbarbati A, Butcher EC, Constantin G. (2008) A role for leukocyte-endothelial adhesion mechanisms in epilepsy. Nat Med 14:1377-1383. Wong M. (2010) Mammalian target of rapamycin (mTOR) inhibition as a potential antiepileptogenic therapy: from tuberous sclerosis to common acquired epilepsies. Epilepsia 51:27-36. Lassmann H, Petsche U, Kitz K, Baran H, Sperk G, Seitelberger F, Hornykiewicz O. (1984) The role of brain edema in epileptic brain damage induced by systemic kainic acid injection. Neuroscience 13:691-704. Zeng LH, Rensing NR, Wong M. (2009a) Developing antiepileptogenic drugs for acquired epilepsy: targeting the mammalian target of rapamycin (mTOR) pathway. Mol Cell Pharmacol 1:124-129. Oby E, Janigro D. (2006) The blood-brain barrier and epilepsy. Epilepsia 47:1761-1774. Paxinos G, Watson C. (1998) The rat brain in stereotaxic coordinates. Academic press, San Diego, CA. Rigau V, Morin M, Rousset MC, de Bock F, Lebrun A, Coubes P, Picot MC, Baldy-Moulinier M, Bockaert J, Crespel A, Lerner-Natoli M. (2007) Angiogenesis is associated with blood-brain barrier permeability in temporal lobe epilepsy. Brain 130:1942-1956. Shorvon S, Ferlisi M. (2011) The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol. Brain 134:2802-2818. Gorter JA, Van Vliet EA, Aronica E, Lopes da Silva FH. (2001) Progression of spontaneous seizures after status epilepticus is associated with mossy fibre sprouting and extensive bilateral loss of hilar parvalbumin and somatostatin-immunoreactive neurons. Eur J Neurosci 13:657-669. 2009; 66 2009b; 29 2011a; 6 2009a; 1 2000; 20 2004; 24 2011; 31 2008; 14 1998 2012; 509 2007; 77 2011; 134 1983; 79 2010; 40 2010; 62 2011; 7 2009; 29 2011; 225 2006; 60 2009; 50 2011b; 2011 1986; 44 2006; 47 2007; 130 1984; 13 2010; 298 2008; 63 1972; 223 2001; 13 2010; 6 2010; 51 2007; 48 2007; 26 e_1_2_8_28_1 e_1_2_8_29_1 e_1_2_8_24_1 e_1_2_8_25_1 e_1_2_8_26_1 e_1_2_8_27_1 e_1_2_8_3_1 e_1_2_8_2_1 e_1_2_8_5_1 e_1_2_8_4_1 e_1_2_8_6_1 e_1_2_8_9_1 e_1_2_8_8_1 Cornford EM (e_1_2_8_7_1) 1986; 44 e_1_2_8_20_1 e_1_2_8_21_1 e_1_2_8_22_1 e_1_2_8_23_1 Lorenzo AV (e_1_2_8_17_1) 1972; 223 e_1_2_8_18_1 e_1_2_8_19_1 e_1_2_8_13_1 e_1_2_8_36_1 e_1_2_8_14_1 e_1_2_8_35_1 e_1_2_8_15_1 e_1_2_8_16_1 e_1_2_8_37_1 e_1_2_8_32_1 e_1_2_8_10_1 e_1_2_8_31_1 e_1_2_8_11_1 e_1_2_8_34_1 e_1_2_8_12_1 e_1_2_8_33_1 e_1_2_8_30_1 |
| References_xml | – reference: Ruegg S, Baybis M, Juul H, Dichter M, Crino PB. (2007) Effects of rapamycin on gene expression, morphology, and electrophysiological properties of rat hippocampal neurons. Epilepsy Res 77:85-92. – reference: Rigau V, Morin M, Rousset MC, de Bock F, Lebrun A, Coubes P, Picot MC, Baldy-Moulinier M, Bockaert J, Crespel A, Lerner-Natoli M. (2007) Angiogenesis is associated with blood-brain barrier permeability in temporal lobe epilepsy. Brain 130:1942-1956. – reference: Buckmaster PS, Lew FH. (2011) Rapamycin suppresses mossy fiber sprouting but not seizure frequency in a mouse model of temporal lobe epilepsy. J Neurosci 31:2337-2347. – reference: Seiffert E, Dreier JP, Ivens S, Bechmann I, Tomkins O, Heinemann U, Friedman A. (2004) Lasting blood-brain barrier disruption induces epileptic focus in the rat somatosensory cortex. J Neurosci 24:7829-7836. – reference: van Vliet EA, da Costa Araujo S, Redeker S, van Schaik R, Aronica E, Gorter JA. (2007) Blood-brain barrier leakage may lead to progression of temporal lobe epilepsy. Brain 130:521-534. – reference: Shorvon S, Ferlisi M. (2011) The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol. Brain 134:2802-2818. – reference: Marchi N, Granata T, Freri E, Ciusani E, Ragona F, Puvenna V, Teng Q, Alexopolous A, Janigro D. (2011a) Efficacy of anti-inflammatory therapy in a model of acute seizures and in a population of pediatric drug resistant epileptics. PLoS ONE 6:e18200. – reference: Huang X, Zhang H, Yang J, Wu J, McMahon J, Lin Y, Cao Z, Gruenthal M, Huang Y. (2010) Pharmacological inhibition of the mammalian target of rapamycin pathway suppresses acquired epilepsy. Neurobiol Dis 40:193-199. – reference: Ljungberg MC, Bhattacharjee MB, Lu Y, Armstrong DL, Yoshor D, Swann JW, Sheldon M, D'Arcangelo G. (2006) Activation of mammalian target of rapamycin in cytomegalic neurons of human cortical dysplasia. Ann Neurol 60:420-429. – reference: Lorenzo AV, Shirahige I, Liang M, Barlow CF. (1972) Temporary alteration of cerebrovascular permeability to plasma protein during drug-induced seizures. Am J Physiol 223:268-277. – reference: Oby E, Janigro D. (2006) The blood-brain barrier and epilepsy. Epilepsia 47:1761-1774. – reference: Dichter MA. (2009) Emerging concepts in the pathogenesis of epilepsy and epileptogenesis. Arch Neurol 66:443-447. – reference: Fabene PF, Navarro MG, Martinello M, Rossi B, Merigo F, Ottoboni L, Bach S, Angiari S, Benati D, Chakir A, Zanetti L, Schio F, Osculati A, Marzola P, Nicolato E, Homeister JW, Xia L, Lowe JB, McEver RP, Osculati F, Sbarbati A, Butcher EC, Constantin G. (2008) A role for leukocyte-endothelial adhesion mechanisms in epilepsy. Nat Med 14:1377-1383. – reference: Baulac M, Pitkanen A. (2009) Research priorities in epilepsy for the next decade-a representative view of the European scientific community. Epilepsia 50:571-578. – reference: Chauhan A, Sharma U, Jagannathan NR, Reeta KH, Gupta YK. (2011) Rapamycin protects against middle cerebral artery occlusion induced focal cerebral ischemia in rats. Behav Brain Res 225:603-609. – reference: Vezzani A, French J, Bartfai T, Baram TZ. (2011) The role of inflammation in epilepsy. Nat Rev Neurol 7:31-40. – reference: Erlich S, Alexandrovich A, Shohami E, Pinkas-Kramarski R. (2007) Rapamycin is a neuroprotective treatment for traumatic brain injury. Neurobiol Dis 26:86-93. – reference: Gorter JA, Van Vliet EA, Aronica E, Lopes da Silva FH. (2001) Progression of spontaneous seizures after status epilepticus is associated with mossy fibre sprouting and extensive bilateral loss of hilar parvalbumin and somatostatin-immunoreactive neurons. Eur J Neurosci 13:657-669. – reference: Marchi N, Angelov L, Masaryk T, Fazio V, Granata T, Hernandez N, Hallene K, Diglaw T, Franic L, Najm I, Janigro D. (2007) Seizure-promoting effect of blood-brain barrier disruption. Epilepsia 48:732-742. – reference: Paxinos G, Watson C. (1998) The rat brain in stereotaxic coordinates. Academic press, San Diego, CA. – reference: Zeng LH, Rensing NR, Wong M. (2009b) The mammalian target of rapamycin signaling pathway mediates epileptogenesis in a model of temporal lobe epilepsy. J Neurosci 29:6964-6972. – reference: Marchi N, Tierney W, Alexopoulos AV, Puvenna V, Granata T, Janigro D. (2011b) The etiological role of blood-brain barrier dysfunction in seizure disorders. Cardiovasc Psychiatry Neurol 2011:482415. – reference: Sliwa A, Plucinska G, Bednarczyk J, Lukasiuk K. (2012) Post-treatment with rapamycin does not prevent epileptogenesis in the amygdala stimulation model of temporal lobe epilepsy. Neurosci Lett 509:105-109. – reference: Zeng LH, Rensing NR, Wong M. (2009a) Developing antiepileptogenic drugs for acquired epilepsy: targeting the mammalian target of rapamycin (mTOR) pathway. Mol Cell Pharmacol 1:124-129. – reference: Wong M. (2010) Mammalian target of rapamycin (mTOR) inhibition as a potential antiepileptogenic therapy: from tuberous sclerosis to common acquired epilepsies. Epilepsia 51:27-36. – reference: Zeng LH, Xu L, Gutmann DH, Wong M. (2008) Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Ann Neurol 63:444-453. – reference: Lassmann H, Petsche U, Kitz K, Baran H, Sperk G, Seitelberger F, Hornykiewicz O. (1984) The role of brain edema in epileptic brain damage induced by systemic kainic acid injection. Neuroscience 13:691-704. – reference: Loscher W, Brandt C. (2010) Prevention or modification of epileptogenesis after brain insults: experimental approaches and translational research. Pharmacol Rev 62:668-700. – reference: Shlosberg D, Benifla M, Kaufer D, Friedman A. (2010) Blood-brain barrier breakdown as a therapeutic target in traumatic brain injury. Nat Rev Neurol 6:393-403. – reference: Zucker DK, Wooten GF, Lothman EW. (1983) Blood-brain barrier changes with kainic acid-induced limbic seizures. Exp Neurol 79:422-433. – reference: Martin-Martin N, Ryan G, McMorrow T, Ryan MP. (2010) Sirolimus and cyclosporine A alter barrier function in renal proximal tubular cells through stimulation of ERK1/2 signaling and claudin-1 expression. Am J Physiol Renal Physiol 298:F672-F682. – reference: Buckmaster PS, Ingram EA, Wen X. (2009) Inhibition of the mammalian target of rapamycin signaling pathway suppresses dentate granule cell axon sprouting in a rodent model of temporal lobe epilepsy. J Neurosci 29:8259-8269. – reference: Daoud D, Scheld HH, Speckmann EJ, Gorji A. (2007) Rapamycin: brain excitability studied in vitro. Epilepsia 48:834-836. – reference: Blamire AM, Anthony DC, Rajagopalan B, Sibson NR, Perry VH, Styles P. (2000) Interleukin-1beta -induced changes in blood-brain barrier permeability, apparent diffusion coefficient, and cerebral blood volume in the rat brain: a magnetic resonance study. J Neurosci 20:8153-8159. – reference: Cornford EM, Oldendorf WH. (1986) Epilepsy and the blood-brain barrier. Adv Neurol 44:787-812. – reference: Kelley MS, Jacobs MP, Lowenstein DH. (2009) The NINDS epilepsy research benchmarks. Epilepsia 50:579-582. – volume: 14 start-page: 1377 year: 2008 end-page: 1383 article-title: A role for leukocyte‐endothelial adhesion mechanisms in epilepsy publication-title: Nat Med – volume: 130 start-page: 521 year: 2007 end-page: 534 article-title: Blood brain barrier leakage may lead to progression of temporal lobe epilepsy publication-title: Brain – volume: 20 start-page: 8153 year: 2000 end-page: 8159 article-title: Interleukin‐1beta ‐induced changes in blood–brain barrier permeability, apparent diffusion coefficient, and cerebral blood volume in the rat brain: a magnetic resonance study publication-title: J Neurosci – volume: 509 start-page: 105 year: 2012 end-page: 109 article-title: Post‐treatment with rapamycin does not prevent epileptogenesis in the amygdala stimulation model of temporal lobe epilepsy publication-title: Neurosci Lett – volume: 47 start-page: 1761 year: 2006 end-page: 1774 article-title: The blood brain barrier and epilepsy publication-title: Epilepsia – volume: 26 start-page: 86 year: 2007 end-page: 93 article-title: Rapamycin is a neuroprotective treatment for traumatic brain injury publication-title: Neurobiol Dis – volume: 134 start-page: 2802 year: 2011 end-page: 2818 article-title: The treatment of super‐refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol publication-title: Brain – volume: 31 start-page: 2337 year: 2011 end-page: 2347 article-title: Rapamycin suppresses mossy fiber sprouting but not seizure frequency in a mouse model of temporal lobe epilepsy publication-title: J Neurosci – volume: 13 start-page: 657 year: 2001 end-page: 669 article-title: Progression of spontaneous seizures after status epilepticus is associated with mossy fibre sprouting and extensive bilateral loss of hilar parvalbumin and somatostatin‐immunoreactive neurons publication-title: Eur J Neurosci – volume: 50 start-page: 579 year: 2009 end-page: 582 article-title: The NINDS epilepsy research 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7829 year: 2004 end-page: 7836 article-title: Lasting blood brain barrier disruption induces epileptic focus in the rat somatosensory cortex publication-title: J Neurosci – volume: 79 start-page: 422 year: 1983 end-page: 433 article-title: Blood brain barrier changes with kainic acid‐induced limbic seizures publication-title: Exp Neurol – volume: 223 start-page: 268 year: 1972 end-page: 277 article-title: Temporary alteration of cerebrovascular permeability to plasma protein during drug‐induced seizures publication-title: Am J Physiol – volume: 77 start-page: 85 year: 2007 end-page: 92 article-title: Effects of rapamycin on gene expression, morphology, and electrophysiological properties of rat hippocampal neurons publication-title: Epilepsy Res – volume: 40 start-page: 193 year: 2010 end-page: 199 article-title: Pharmacological inhibition of the mammalian target of rapamycin pathway suppresses acquired epilepsy publication-title: Neurobiol Dis – volume: 7 start-page: 31 year: 2011 end-page: 40 article-title: The role of inflammation in epilepsy publication-title: Nat Rev Neurol – volume: 2011 start-page: 482415 year: 2011b article-title: The etiological role of blood brain barrier dysfunction in seizure disorders publication-title: Cardiovasc Psychiatry Neurol – volume: 44 start-page: 787 year: 1986 end-page: 812 article-title: Epilepsy and the blood brain barrier publication-title: Adv Neurol – volume: 60 start-page: 420 year: 2006 end-page: 429 article-title: Activation of mammalian target of rapamycin in cytomegalic neurons of human cortical dysplasia publication-title: Ann Neurol – volume: 48 start-page: 834 year: 2007 end-page: 836 article-title: Rapamycin: brain excitability studied in vitro publication-title: Epilepsia – volume: 50 start-page: 571 year: 2009 end-page: 578 article-title: Research priorities in epilepsy for the next decade‐a representative view of the European scientific community publication-title: Epilepsia – volume: 51 start-page: 27 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Purpose: Previous studies have shown that inhibition of the mammalian target of rapamycin (mTOR) pathway with rapamycin prevents epileptogenesis after... Purpose: Previous studies have shown that inhibition of the mammalian target of rapamycin (mTOR) pathway with rapamycin prevents epileptogenesis after... Previous studies have shown that inhibition of the mammalian target of rapamycin (mTOR) pathway with rapamycin prevents epileptogenesis after pharmacologically... Summary Purpose: Previous studies have shown that inhibition of the mammalian target of rapamycin (mTOR) pathway with rapamycin prevents epileptogenesis after... Purpose: Previous studies have shown that inhibition of the mammalian target of rapamycin (mTOR) pathway with rapamycin prevents epileptogenesis after... |
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| SubjectTerms | Animals Anticonvulsants. Antiepileptics. Antiparkinson agents Antigens, CD - metabolism Antigens, Differentiation, Myelomonocytic - metabolism Biological and medical sciences Blood-brain barrier Blood-Brain Barrier - drug effects CD11b Antigen - metabolism Cytokines - blood Disease Models, Animal Drug Administration Schedule Electric Stimulation - adverse effects Electroencephalography Gliosis Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy Immunosuppressive Agents - therapeutic use Inflammation Male Medical sciences Microglia - drug effects Microglia - metabolism Monocytes - drug effects Monocytes - metabolism Nervous system (semeiology, syndromes) Neurology Neuropharmacology Pharmacology. Drug treatments Phosphopyruvate Hydratase - metabolism Rats Rats, Sprague-Dawley Seizures - drug therapy Seizures - etiology Signal Transduction - drug effects Sirolimus - blood Sirolimus - therapeutic use Statistics as Topic Statistics, Nonparametric Status epilepticus Status Epilepticus - blood Status Epilepticus - drug therapy Status Epilepticus - etiology Status Epilepticus - pathology Temporal lobe epilepsy Time Factors TOR Serine-Threonine Kinases - metabolism Vimentin - metabolism |
| Title | Inhibition of mammalian target of rapamycin reduces epileptogenesis and blood-brain barrier leakage but not microglia activation |
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