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.

Schisantherin A Attenuates Neuroinflammation in Activated Microglia: Role of Nrf2 Activation Through ERK Phosphorylation

“…In response to various microenvironments, microglia can polarise into pro-and anti-inflammatory phenotypes [9,10]. Moreover, more remarkably, activation of Nrf2 pathways has been shown to promote microglial polarisation toward the anti- [27][28][29]. On the other hand, Nrf2-deficiency is reported to be more important in inflammatory models [10].…”

Proteostasis in Huntington’s Disease: Disease Mechanisms and Therapeutic Opportunities

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Stress Response of Dietary Phytochemicals in a Hormetic Manner for Health and Longevity

“…Sulforaphane showed protective effect against ethanol-induced oxidative stresses and apoptosis in neural crest cells by generating an antioxidant response with Nrf2 activation [106]. Sulforaphane activates the Nrf2/ARE pathway and inhibits 3-nitropropionic acidinduced toxicity in striatal cells by inhibiting MAPKs and NF-κB pathways [107]. In MSTO-211H cells administered with sulforaphane, Nrf2-mediated HO-1 expression was regulated by the PI3K/Akt pathway [108].…”