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 (Tsc1GFAPCKO 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 Tsc1GFAPCKO 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 Tsc1GFAPCKO mice before the onset of epilepsy in vivo, indicating that the inflammatory changes were not secondary to seizures. Epicathechin-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 Tsc1GFAPCKO mice. These findings suggest that mTOR-mediated inflammatory mechanisms may be involved in epileptogenesis in the genetic epilepsy, TSC.

The genomic landscape of tuberous sclerosis complex

“…Inflammation has been previously documented in TSC lesions, both in the brains of TSC animal models and in patient tissues59606162. Work from Zhang et al 62. suggested that this inflammation is directly related to hyperactive MTORC1 signalling and is not merely a result of seizure activity.…”

“…We used these molecular tools to detect neuroinflammation associated with TSC brain lesions. Inflammation has been previously documented in TSC lesions, both in the brains of TSC animal models and in patient tissues59606162. Work from Zhang et al 62.…”

Microglial activation during epileptogenesis in a mouse model of tuberous sclerosis complex

“…We have recently found evidence that inflammatory changes may contribute to epileptogenesis in a mouse model of TSC, Tsc1 GFAP CKO mice. Antiinflammatory treatments, which reduced cytokine and chemokine production, caused a moderate inhibition of seizure progression in this mouse model . Although astrocytes may play a central role in mediating inflammatory mechanisms and epileptogenesis in Tsc1 GFAP CKO mice, microglia may also be involved in reactive inflammatory changes in the brain.…”

“…Real‐time quantitative RT‐PCR was used to assay inflammatory cytokine and chemokine markers, C‐C motif chemokine ligand 2 (CCL2), Interleukin 1 beta (IL‐1 β) and C‐X‐C motif chemokine ligand 10 (CXCL10), as described previously . Total RNA was prepared from brains of 4‐week‐old Tsc1 GFAP CKO or control mice.…”

Os produtos dos genes Tsc1 e Tsc2 em processos neurodegenerativos

“…Por outro lado, camundongos com nocaute condicional de Tsc1 em células que expressam GFAP não apresentam crises convulsivas mas têm, na quarta semana pós-natal, um aumento da expressão de fatores envolvidos em processo inflamatório no cérebro (ZHANG et al, 2015). TSC1 e TSC2 são necessárias para uma resposta completa contra o estresse do retículo endoplasmático, o que sugere papel dessas proteínas na resposta a proteínas mal dobradas e sobrevivência celular (KANG et al, 2011).…”