CDDO-Me Inhibits Microglial Activation and Monocyte Infiltration by Abrogating NFκB- and p38 MAPK-Mediated Signaling Pathways Following Status Epilepticus

Abstract

Following status epilepticus (SE, a prolonged seizure activity), microglial activation, and monocyte infiltration result in the inflammatory responses in the brain that is involved in the epileptogenesis. Therefore, the regulation of microglia/monocyte-mediated neuroinflammation is one of the therapeutic strategies for avoidance of secondary brain injury induced by SE. 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid methyl ester (CDDO-Me; RTA 402) is an activator of nuclear factor-erythroid 2-related factor 2 (Nrf2), which regulates intracellular redox homeostasis. In addition, CDDO-Me has anti-inflammatory properties that suppress microglial proliferation and its activation, although the underlying mechanisms have not been clarified. In the present study, CDDO-Me ameliorated monocyte infiltration without vasogenic edema formation in the frontoparietal cortex (FPC) following SE, accompanied by abrogating monocyte chemotactic protein-1 (MCP-1)/tumor necrosis factor-α (TNF-α) expressions and p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation. Furthermore, CDDO-Me inhibited nuclear factor-κB (NFκB)-S276 phosphorylation and microglial transformation, independent of Nrf2 expression. Similar to CDDO-Me, SN50 (an NFκB inhibitor) mitigated monocyte infiltration by reducing MCP-1 and p38 MAPK phosphorylation in the FPC following SE. Therefore, these findings suggest, for the first time, that CDDO-Me may attenuate microglia/monocyte-mediated neuroinflammation via modulating NFκB- and p38 MAPK-MCP-1 signaling pathways following SE.

Dual Effect of Soloxolone Methyl on LPS-Induced Inflammation In Vitro and In Vivo

“…The ability of CETs to modulate macrophage migration, as far as we know, has not yet been published. Only Kim et al [ 119 ] showed the inhibitory activity of CDDO-Me on monocyte infiltration in the inflamed frontoparietal cortex in mice; however, this effect was more associated with the CDDO-Me-induced alteration in the chemokine profile than its influence on the motility of cells.…”

The Function of NF-Kappa B During Epilepsy, a Potential Therapeutic Target

“…On the other hand, Kim and his group found an increase in phosphorylated NF-κB at the threonine 435 site in microglia after SE ( Kim et al, 2019 ). Similarly, NF-κB serine 276 phosphorylation was found to be increased in microglia in the frontoparietal cortex ( Kim et al, 2020 ) or piriform cortex ( Lee et al, 2014 ). The elevated high mobility group protein B1 after epilepsy must activate microglia through the toll-like receptor 4 (TLR4)/receptor for advanced glycation endproducts for late glycation end products of the NF-κB pathway to disrupt the function of neurons ( Shi et al, 2018 ; Massey et al, 2019 ; Rosciszewski et al, 2019 ).…”

“…Microglia activation plays a key role in regulating inflammation and immune response and can have a pro-inflammatory or anti-inflammatory effect depending on the M1/M2 polarization phenotype ( Zhao et al, 2019 ). The phosphorylation of p65-Ser276 can convert microglia from the resting state to the activated state ( Kim et al, 2020 ). The increase of p65 in microglia can promote the transition to the M1 phenotype of microglia ( Zhang et al, 2019 ).…”

Crosstalk between peripheral and the brain-resident immune components in epilepsy

“…Additionally, it has been revealed that there is an apparent decrease in monocyte infiltration into the brain following SE while CCR2 is suppressed, further demonstrating the importance of the CCL2-CCR2 axis [41,42]. It is worth noting that 2-cyano-3,12dioxolane-1,9-dien-28-oic acid methyl ester (CDDO-Me) reduces both SE-induced monocyte infiltration in the fron-toparietal cortex (FPC) and microglial activation, by suppressing CCL2 expression and p38 mitogen-activated protein kinase (p38 MAPK) signaling, independent of the activity of nuclear factor-erythroid 2-related factor 2 (Nrf2) [46].…”