title: Sulforaphane Ameliorates 3-Nitropropionic Acid-Induced Striatal Toxicity by Activating the Keap1-Nrf2-ARE Pathway and Inhibiting the MAPKs and NF-κB Pathways.
abstract: The potential neuroprotective value of sulforaphane (SFN) in Huntington's disease (HD) has not been established yet. We investigated whether SFN prevents and improves the neurological impairment and striatal cell death in a 3-nitropropionic acid (3-NP)-induced mouse model of HD. SFN (2.5 and 5.0 mg/kg/day, i.p.) was given daily 30 min before 3-NP treatment (pretreatment) and from onset/progression/peak points of the neurological scores. Pretreatment with SFN (5.0 mg/kg/day) produced the best neuroprotective effect with respect to the neurological scores and lethality among other conditions. The protective effects due to pretreatment with SFN were associated with the following: suppression of the formation of a lesion area, neuronal death, succinate dehydrogenase activity, apoptosis, microglial activation, and mRNA or protein expression of inflammatory mediators, including tumor necrosis factor-alpha, interleukin (IL)-1β, IL-6, inducible nitric oxide synthase, and cyclooxygenase-2 in the striatum after 3-NP treatment. Also, pretreatment with SFN activated the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway and inhibited the mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB) pathways in the striatum after 3-NP treatment. As expected, the pretreatment with activators (dimethyl fumarate and antioxidant response element inducer-3) of the Keap1-Nrf2-ARE pathway decreased the neurological impairment and lethality after 3-NP treatment. Our findings suggest that SFN may effectively attenuate 3-NP-induced striatal toxicity by activating the Keap1-Nrf2-ARE pathway and inhibiting the MAPKs and NF-κB pathways and that SFN has a wide therapeutic time-window for HD-like symptoms.
authors.affiliation: Department of Convergence Medical Science, College of Oriental Medicine, Kyung Hee University, Seoul, 130-701, Republic of Korea.|Department of Cancer Preventive Material Development, College of Oriental Medicine, Kyung Hee University, Seoul, 130-701, Republic of Korea.
authors.forename: Minhee
authors.initials: M
authors.lastname: Jang
authors.affiliation: Department of Convergence Medical Science, College of Oriental Medicine, Kyung Hee University, Seoul, 130-701, Republic of Korea. ihcho@khu.ac.kr.|Brain Korea 21 Plus Program, College of Oriental Medicine, Kyung Hee University, Seoul, 130-701, Republic of Korea. ihcho@khu.ac.kr.|Institute of Korean Medicine, College of Oriental Medicine, Kyung Hee University, Seoul, 130-701, Republic of Korea. ihcho@khu.ac.kr.
authors.forename: Ik-Hyun
authors.initials: IH
authors.lastname: Cho
mesh_terms: D000818:Animals; D061745:Antioxidant Response Elements / Q000235:genetics*; D001522:Behavior, Animal; D016923:Cell Death / Q000187:drug effects; D003342:Corpus Striatum / Q000473:pathology*; D015536:Down-Regulation / Q000187:drug effects; D018836:Inflammation Mediators / Q000378:metabolism; D017879:Isothiocyanates / Q000494:pharmacology*; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D009574:Nitro Compounds / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects; D011422:Propionates / Q000633:toxicity*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013385:Succinate Dehydrogenase / Q000378:metabolism; D013454:Sulfoxides
chemical_list: D018836:Inflammation Mediators; D017879:Isothiocyanates; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D009574:Nitro Compounds; D011422:Propionates; D012333:RNA, Messenger; D013454:Sulfoxides; D013385:Succinate Dehydrogenase; D020928:Mitogen-Activated Protein Kinases; C016766:sulforaphane; C015392:3-nitropropionic acid
keywords: 3-Nitropropionic acid; Huntington’s disease; Mitogen-activated protein kinases; Nuclear factor erythroid 2-related factor 2; Nuclear factor-kappa B; Sulforaphane