2-Cyano-3,12-dioxo-oleana-1,9(11)-dien-28-oic acid methyl ester (CDDO-Me) is a triterpenoid analogue of oleanolic acid. CDDO-Me shows anti-inflammatory and neuroprotective effects. Furthermore, CDDO-Me has antioxidant properties, since it activates nuclear factor-erythroid 2-related factor 2 (Nrf2), which is a key player of redox homeostasis. In the present study, we evaluated whether CDDO-Me affects astroglial responses to status epilepticus (SE, a prolonged seizure activity) in the rat hippocampus in order to understand the underlying mechanisms of reactive astrogliosis and astroglial apoptosis. Under physiological conditions, CDDO-Me increased Nrf2 expression in the hippocampus without altering activities (phosphorylations) of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), phosphatidylinositol-3-kinase (PI3K), and AKT. CDDO-Me did not affect seizure activity in response to pilocarpine. However, CDDO-Me ameliorated reduced astroglial Nrf2 expression in the CA1 region and the molecular layer of the dentate gyrus (ML), and attenuated reactive astrogliosis and ML astroglial apoptosis following SE. In CA1 astrocytes, CDDO-Me inhibited the PI3K/AKT pathway by activating PTEN. In contrast, CDDO-ME resulted in extracellular signal-related kinases 1/2 (ERK1/2)-mediated Nrf2 upregulation in ML astrocytes. Furthermore, CDDO-Me decreased nuclear factor-κB (NFκB) phosphorylation in both CA1 and ML astrocytes. Therefore, our findings suggest that CDDO-Me may attenuate SE-induced reactive astrogliosis and astroglial apoptosis via regulation of ERK1/2-Nrf2, PTEN-PI3K-AKT, and NFκB signaling pathways.
CDDO-Me Distinctly Regulates Regional Specific Astroglial Responses to Status Epilepticus via ERK1/2-Nrf2, PTEN-PI3K-AKT and NFκB Signaling Pathways
