Anti-inflammatory effects of Edaravone and Scutellarin in activated microglia in experimentally induced ischemia injury in rats and in BV-2 microglia

Yun, Yuan; Zha, Hao; Rangarajan, Parakalan; Ling, Eng‐Ang; Wu, Cheng-Shong

doi:10.1186/s12868-014-0125-3

Cited by 104 publications

(77 citation statements)

References 47 publications

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“…With respect to multiple sclerosis, encouraging studies in the model of experimental allergic encephalomyelitis already exist42. It is of interest that edaravone rescues oligodendrocyte differentiation after prolonged ischemic damage in mice43, reduces white matter injury in a mouse model of hypoxic-ischemia44, and has anti-inflammatory effects in activated microglia45. The identification of two active analogs of edaravone and the purity analysis validated its biological and structural activity, allowing us to conclude that the remyelinating activity of edaravone is not a false positive.…”

Section: Discussionmentioning

confidence: 99%

A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials

Eleuteri

Olla

Veroni

et al. 2017

Sci Rep

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There is no treatment for the myelin loss in multiple sclerosis, ultimately resulting in the axonal degeneration that leads to the progressive phase of the disease. We established a multi-tiered platform for the sequential screening of drugs that could be repurposed as remyelinating agents. We screened a library of 2,000 compounds (mainly Food and Drug Administration (FDA)-approved compounds and natural products) for cellular metabolic activity on mouse oligodendrocyte precursors (OPC), identifying 42 molecules with significant stimulating effects. We then characterized the effects of these compounds on OPC proliferation and differentiation in mouse glial cultures, and on myelination and remyelination in organotypic cultures. Three molecules, edaravone, 5-methyl-7-methoxyisoflavone and lovastatin, gave positive results in all screening tiers. We validated the results by retesting independent stocks of the compounds, analyzing their purity, and performing dose-response curves. To identify the chemical features that may be modified to enhance the compounds’ activity, we tested chemical analogs and identified, for edaravone, the functional groups that may be essential for its activity. Among the selected remyelinating candidates, edaravone appears to be of strong interest, also considering that this drug has been approved as a neuroprotective agent for acute ischemic stroke and amyotrophic lateral sclerosis in Japan.

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Section: Discussionmentioning

confidence: 99%

A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials

Eleuteri

Olla

Veroni

et al. 2017

Sci Rep

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“…A recent study by Yuan et al [46] demonstrated anti-inflammatory effects of edaravone in stroke animals, focusing on inflammatory cytokines from activated microglia in the brain. Our current study may expand the previous finding from novel aspects.…”

Section: Discussionmentioning

confidence: 99%

A free radical scavenger edaravone suppresses systemic inflammatory responses in a rat transient focal ischemia model

Fujiwara

Som

Pham

et al. 2016

Neuroscience Letters

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A free radical scavenger edaravone is clinically used in Japan for acute stroke, and several basic researches have carefully examined the mechanisms of edaravone's protective effects. However, its actions on pro-inflammatory responses under stroke are still understudied. In this study, we subjected adult male Sprague-Dawley rats to 90-min middle cerebral artery (MCA) occlusion followed by reperfusion. Edaravone was treated twice via tail vein; after MCA occlusion and after reperfusion. As expected, edaravone-treated group showed less infarct volume and edema formation compared with control group at 24-hour after ischemic onset. Furthermore, edaravone reduced the levels of plasma interleukin (IL)-1β and matrix metalloproteinase-9 at 3-hour after ischemic onset. Several molecules besides IL-1β and MMP-9 are involved in inflammatory responses under stroke conditions. Therefore, we also examined whether edaravone treatment could decrease a wide range of pro-inflammatory cytokines/chemokines by testing rat plasma samples with a rat cytokine array. MCAO rats showed elevations in plasma levels of CINC-1, Fractalkine, IL-1α, IL-1ra, IL-6, IL-10, IP-10, MIG, MIP-1α, and MIP-3α, and all these increases were reduced by edaravone treatment. These data suggest that free radical scavengers may reduce systemic inflammatory responses under acute stroke conditions, and therefore, oxidative stress can be still a viable target for acute stroke therapy.

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“…In addition, EDA, a ROS scavenger, inhibits the release of proinflammatory cytokines from activated microglia [18]. Hence, we hypothesized that EDA inhibits mitochondrial depolarization and reduces ROS production in Aβ-treated microglia.…”

Section: Eda Reduces Mitochondrial Depolarization and Ros Levels In Amentioning

confidence: 99%

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

Wang

Zhang

Huang

et al. 2017

Cell Physiol Biochem

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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.

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Anti-inflammatory effects of Edaravone and Scutellarin in activated microglia in experimentally induced ischemia injury in rats and in BV-2 microglia

Cited by 104 publications

References 47 publications

A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials

A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials

A free radical scavenger edaravone suppresses systemic inflammatory responses in a rat transient focal ischemia model

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

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