title: Inflammatory mechanisms contribute to the neurological manifestations of tuberous sclerosis complex.
abstract: Epilepsy and other neurological deficits are common, disabling manifestations of the genetic disorder, tuberous sclerosis complex (TSC). Brain inflammation has been implicated in contributing to epileptogenesis in acquired epilepsy due to brain injury, but the potential role of inflammatory mechanisms in genetic epilepsies is relatively unexplored. In this study, we investigated activation of inflammatory mediators and tested the effects of anti-inflammatory treatment on epilepsy in the Tsc1-GFAP conditional knock-out mouse model of TSC (Tsc1(GFAP)CKO mice). Real-time quantitative RT-PCR, immunohistochemistry, and Western blotting demonstrated increased expression of specific cytokines and chemokines, particularly IL-1β and CXCL10, in the neocortex and hippocampus of Tsc1(GFAP)CKO mice, which was reversed by treatment with a mammalian target of rapamycin complex 1 (mTORC1) inhibitor. Double-labeling immunohistochemical studies indicated that the increased IL-1β was localized primarily to astrocytes. Importantly, the increase in inflammatory markers was also observed in astrocyte culture in vitro and at 2 weeks of age in Tsc1(GFAP)CKO mice before the onset of epilepsy in vivo, indicating that the inflammatory changes were not secondary to seizures. Epicatechin-3-gallate, an inhibitor of IL-1β and CXCL10, at least partially reversed the elevated cytokine and chemokine levels, reduced seizure frequency, and prolonged survival of Tsc1(GFAP)CKO mice. These findings suggest that mTOR-mediated inflammatory mechanisms may be involved in epileptogenesis in the genetic epilepsy, TSC.
authors.affiliation: Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Zou
authors.affiliation: Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Rensing
authors.affiliation: Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Meihua
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: wong_m@wustl.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Wong
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D002392:Catechin / Q000008:administration & dosage / Q000031:analogs & derivatives; D004660:Encephalitis / Q000150:complications / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors; D019579:Neocortex / Q000187:drug effects / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D012640:Seizures / Q000209:etiology*; D020123:Sirolimus / Q000008:administration & dosage; D016019:Survival Analysis; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D014402:Tuberous Sclerosis / Q000150:complications* / Q000378:metabolism* / Q000473:pathology; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D000893:Anti-Inflammatory Agents; D018836:Inflammation Mediators; D046912:Multiprotein Complexes; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D002392:Catechin; C062669:epicatechin gallate; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Chemokine; Cytokine; Epilepsy; Inflammation; Interleukin; Mice; Seizure; Tuberous sclerosis