Traumatic brain injury (TBI) is a serious neuropathology that causes secondary injury mechanisms, including dynamic interplay between ischemic, inflammatory and cytotoxic processes. Fumaric acid esters (FAEs) showed beneficial effects in preclinical models of neuroinflammation and toxic oxidative stress, so the aim of the present work was to evaluate the potential beneficial effects of dimethyl fumarate (DMF), the most pharmacologically effective molecules among the FAEs, in a mouse model of TBI induced by controlled cortical impact (CCI). Mice were orally administered with DMF at the doses of 1, 10 and 30 mg/Kg, 1h and 4h after CCI. We performed histological, molecular, and immunohistochemistry analysis on the traumatic penumbral areas of the brain 24 hours after CCI. DMF treatment notably reduced histological damage and behavioral impairments, reducing neurodegeneration as evidenced by assessments of neuronal loss, Fluoro-jade C and TUNEL staining; also, treatment with DMF blocked apoptosis process increasing B-cell lymphoma 2 (Bcl-2) expression in injured cortex. Furthermore, DMF treatment up-regulated antioxidant Kelch-like ECH-associated protein 1/ Nuclear factor erythroid 2- related factor (Keap-1/Nrf-2) pathway, inducing activation of manganese superoxide dismutase (Mn-SOD) and heme-oxygenase-1 (HO-1) and reducing 4-hydroxy-2-nonenal (4-HNE) staining. Also, regulating NF-κB pathway, DMF treatment decreased the severity of inflammation through a modulation of neuronal nitrite oxide synthase (nNOS), interleukin 1 (Il-1β), tumor necrosis factor (TNF-α), cyclooxygenase 2 (COX-2) and myeloperoxidase (MPO) activity, reducing ionized calcium-binding adapter molecule 1 (Iba-1) and glial fibrillary acidic protein (GFAP) expression. Our results support the thesis that DMF may be an effective neuroprotectant after brain trauma and warrants further study.
Dimethyl fumarate attenuates neuroinflammation and neurobehavioral deficits induced by experimental traumatic brain injury
Casili, GiovannaPrimo
;Campolo, MichelaSecondo
;Paterniti, Irene;Lanza, Marika;Filippone, Alessia;Cuzzocrea, SalvatorePenultimo
;Esposito, Emanuela
Ultimo
2018-01-01
Abstract
Traumatic brain injury (TBI) is a serious neuropathology that causes secondary injury mechanisms, including dynamic interplay between ischemic, inflammatory and cytotoxic processes. Fumaric acid esters (FAEs) showed beneficial effects in preclinical models of neuroinflammation and toxic oxidative stress, so the aim of the present work was to evaluate the potential beneficial effects of dimethyl fumarate (DMF), the most pharmacologically effective molecules among the FAEs, in a mouse model of TBI induced by controlled cortical impact (CCI). Mice were orally administered with DMF at the doses of 1, 10 and 30 mg/Kg, 1h and 4h after CCI. We performed histological, molecular, and immunohistochemistry analysis on the traumatic penumbral areas of the brain 24 hours after CCI. DMF treatment notably reduced histological damage and behavioral impairments, reducing neurodegeneration as evidenced by assessments of neuronal loss, Fluoro-jade C and TUNEL staining; also, treatment with DMF blocked apoptosis process increasing B-cell lymphoma 2 (Bcl-2) expression in injured cortex. Furthermore, DMF treatment up-regulated antioxidant Kelch-like ECH-associated protein 1/ Nuclear factor erythroid 2- related factor (Keap-1/Nrf-2) pathway, inducing activation of manganese superoxide dismutase (Mn-SOD) and heme-oxygenase-1 (HO-1) and reducing 4-hydroxy-2-nonenal (4-HNE) staining. Also, regulating NF-κB pathway, DMF treatment decreased the severity of inflammation through a modulation of neuronal nitrite oxide synthase (nNOS), interleukin 1 (Il-1β), tumor necrosis factor (TNF-α), cyclooxygenase 2 (COX-2) and myeloperoxidase (MPO) activity, reducing ionized calcium-binding adapter molecule 1 (Iba-1) and glial fibrillary acidic protein (GFAP) expression. Our results support the thesis that DMF may be an effective neuroprotectant after brain trauma and warrants further study.File | Dimensione | Formato | |
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Descrizione: Dimethyl Fumarate Attenuates Neuroinflammation and Neurobehavioral Deficits lnduced by Experimental Traumatic Brain lnjury
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