CDDO-Me Selectively Attenuates CA1 Neuronal Death Induced by Status Epilepticus via Facilitating Mitochondrial Fission Independent of LONP1

• Published in: Cells (Basel, Switzerland) Vol. 8; no. 8; p. 833
• Main Authors: Kim, Ji-Eun, Park, Hana, Choi, Seo-Hyeon, Kong, Min-Jeong, Kang, Tae-Cheon
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 05.08.2019; MDPI
• Subjects: 4-HNE; Animals; Antioxidants; ATP-Dependent Proteases - metabolism; c-Jun protein; CA1 Region, Hippocampal - cytology; CA1 Region, Hippocampal - drug effects; CA1 Region, Hippocampal - metabolism; Calcineurin; Cell cycle; Cell Death; Cell differentiation; Convulsions & seizures; Death; Degeneration; DRP1; Dynamin; Electrodes; Electroencephalography; Elongation; Epilepsy; ERK1/2; Extracellular signal-regulated kinase; Granule cells; hippocampus; Inflammation; Interneurons; JNK; JNK protein; Kinases; Lon protein; Male; Mitochondria; Mitochondrial Dynamics; Neurons; Neurons - drug effects; Neurons - metabolism; Neuroprotection; Neuroprotective Agents - pharmacology; Oleanolic acid; Oleanolic Acid - analogs & derivatives; Oleanolic Acid - pharmacology; Phosphorylation; PKA; Protein kinase A; protein phosphatases; Proteins; Rats; Rats, Sprague-Dawley; Recording sessions; Serine; siRNA; Status Epilepticus - metabolism; Surgery; Transcription factors; TUNEL; United States > US; South Korea; Germany; ERK1/2; TUNEL; 4-HNE; hippocampus; JNK; PKA; protein phosphatases; DRP1; mitochondrial dynamics
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells8080833

2-Cyano-3,12-dioxo-oleana-1,9(11)-dien-28-oic acid methyl ester (CDDO-Me) is a triterpenoid analogue of oleanolic acid that exhibits promising anti-cancer, anti-inflammatory, antioxidant and neuroprotective activities. In addition, CDDO-Me affects cellular differentiation and cell cycle arrest, and irreversibly inhibits Lon protease-1 (LONP1). In the present study, we evaluate the effects of CDDO-Me on mitochondrial dynamics and its downstream effectors in order to understand the underlying mechanism of the neuronal death following status epilepticus (SE, a prolonged seizure activity). CDDO-Me increased dynamin-related proteins 1 (DRP1)-serine 616 phosphorylation via activating extracellular-signal-regulated kinase 1/2 (ERK1/2) and c-Jun -terminal kinase (JNK), but not protein kinase A (PKA) or protein phosphatases (PPs). In addition, CDDO-Me facilitated DRP1-mediated mitochondrial fissions, which selectively attenuated SE-induced CA1 neuronal death. Unlike CDDO-Me, LONP1 knockdown led to SE-induced massive degeneration of dentate granule cells, CA1 neurons and hilus interneurons without altering the expression and phosphorylation of DRP1, ERK1/2, JNK and PP2B. LONP1 knockdown could not inhibit SE-induced mitochondrial elongation in CA1 neurons. Co-treatment of CDDO-Me with LONP1 siRNA ameliorated only CA1 neuronal death, concomitant with abrogation of mitochondrial elongation induced by SE. Thus, our findings suggest that CDDO-Me may selectively attenuate SE-induced CA1 neuronal death by rescuing the abnormal mitochondrial machinery, independent of LONP1 activity.