Edaravone Attenuates the Proinflammatory Response in Amyloid-β-Treated Microglia by Inhibiting NLRP3 Inflammasome-Mediated IL-1β Secretion

Abstract

Background/Aims: Microglial activation is an important pathological feature in the brains of patients with Alzheimer's disease (AD), and amyloid-β (Aβ) peptides play a crucial role in microglial activation. In addition, edaravone (EDA) was recently shown to suppress oxidative stress and proinflammatory cytokine production in APPswePS1dE9 (APP/PS1) mice. However, the mechanism by which EDA inhibits the Aβ-induced proinflammatory response in microglia is poorly understood. Methods: The mitochondrial membrane potential (Dψm) was evaluated using JC-1 staining. Intracellular reactive oxygen species (ROS) and mitochondrial ROS levels were detected using CM-H2DCFDA and MitoSOX TM Red, respectively. The levels of CD11b, NLRP3, pro-caspase-1 and manganese superoxide dismutase (SOD-2) were observed by western blotting, and the levels of interleukin-1beta (IL-1β) in culture supernatants were quantified using an ELISA kit. Results: Aβ induced microglia activation and mitochondrial dysfunction. In addition, mitochondrial dysfunction was associated with ROS accumulation and activation of the NLRP3 inflammasome. Importantly, Aβ induced activation of the NLRP3 inflammasome, leading to caspase-1 activation and IL-1β release in microglia. Moreover, EDA obviously attenuated the depolarization of Δψm, reduced mitochondria-derived ROS production and increased SOD-2 activity, resulting in the suppression of NLRP3 inflammasomemediated IL-1β secretion in Aβ-treated microglia. Conclusion: EDA is a mitochondria-targeted antioxidant and exhibits anti-inflammatory effects on Aβ-treated microglia.

Protective Effect of Edaravone Against Oxidative Stress in C2C12 Myoblast and Impairment of Skeletal Muscle Regeneration Exposed to Ischemic Injury in Ob/ob Mice

“…However, several reports have demonstrated that administration of edaravone inhibited systemic or local inflammation associated with oxidative stress in various tissues. It suggested that edaravone indirectly suppresses inflammation by protecting against tissue damage via scavenging of free radicals (Zhang et al, 2005;Yoshida et al, 2006;Fujiwara et al, 2016;Wang et al, 2017). In this study, edaravone showed FIGURE 8 | The muscle ischemic-injured score showed that pretreatment with the edaravone significantly inhibited muscle injury at 7 days after ischemia in both control (Con) and obese (Ob) mice ( * compared to mice without administration of edaravone, p < 0.05).…”

Targeting NLRP3 Inflammasome in the Treatment of CNS Diseases

“…In the last few years, numerous studies have been conducted in the exploration of therapeutic pathways against neurodegenerative diseases through the inhibition of the NLRP3 inflammasome. For the studies of Alzheimer’s disease, it was recently reported that edaravone, a recently shown oxidative stress suppressor, functioned in attenuating the β-amyloid-induced proinflammatory response in microglia ( Wang et al, 2017 ). This effect was through the reduction of mitochondria-derived reactive oxygen species (ROS) production and increased manganese superoxide dismutase (SOD-2) activity, thus leading to the inhibition of the NLRP3 inflammasome-mediated proinflammatory secretion ( Wang et al, 2017 ).…”

“…For the studies of Alzheimer’s disease, it was recently reported that edaravone, a recently shown oxidative stress suppressor, functioned in attenuating the β-amyloid-induced proinflammatory response in microglia ( Wang et al, 2017 ). This effect was through the reduction of mitochondria-derived reactive oxygen species (ROS) production and increased manganese superoxide dismutase (SOD-2) activity, thus leading to the inhibition of the NLRP3 inflammasome-mediated proinflammatory secretion ( Wang et al, 2017 ). Furthermore, depeptidyl vinyl sulfone, a chemical agent, was demonstrated to suppress the high-mobility group box protein-1 (HMGB1)/NLRP3 inflammasome-related inflammation in β-amyloid-stimulated microglia, which was involved in the decrease of the two inflammation-related microRNA including microRNA-155 and microRNA-146a ( Falcao et al, 2017 ).…”

Dihydrolipoic acid protects against lipopolysaccharide-induced behavioral deficits and neuroinflammation via regulation of Nrf2/HO-1/ NLRP3 signaling in rat

“…The activation of NLRP3 inflammasome triggers the transformation of procaspase-1 to caspase-1 and catalyzes the exudation of mature IL-1β and IL-18 from pro-IL-1β and pro-IL-18, causing an inflammatory response [45,46]. Previous studies showed that ROS, especially from mitochondria, activated the NLRP3 inflammasome [47,48]. The current findings proposed that the expression of ROS, NLRP3, caspase-1, and IL-1β in the LPS group was increased as compared to that in the control groups; however, after the administration of DHLA, the level of NLRP3, caspase-1, and IL-1β decreased markedly.…”