Abstract
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 N-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.
Highlights
IntroductionOne of the most remarkable Status epilepticus (SE)-induced consequences is a massive neuronal death, which triggers long-term and profound alterations in the neuronal network that lead to the development of temporal lobe epilepsy (TLE) [2,3,4]
Status epilepticus (SE) is a condition which shows prolonged and uncontrolled seizure activity [1].One of the most remarkable SE-induced consequences is a massive neuronal death, which triggers long-term and profound alterations in the neuronal network that lead to the development of temporal lobe epilepsy (TLE) [2,3,4]
Unlike CDDO-Me, Lon protease-1 (LONP1) knockdown led to SE-induced massive degeneration of dentate granule cells, CA1 neurons and hilus interneurons without altering the expression and phosphorylation of dynamin-related proteins 1 (DRP1), extracellular-signal-regulated kinase 1/2 (ERK1/2), Jun N-terminal kinase (JNK) and PP2B
Summary
One of the most remarkable SE-induced consequences is a massive neuronal death, which triggers long-term and profound alterations in the neuronal network that lead to the development of temporal lobe epilepsy (TLE) [2,3,4]. The neuronal death pattern and susceptibility to SE shows the regional specific heterogeneity: Neurons in the hilus region of the dentate gyrus, such as mossy cells and hilus interneurons (in particular parvalbumin (PV) interneurons), are the most vulnerable to SE insults, while dentate granule cells are less vulnerable. SE induces programmed necrotic CA1 neuronal death, while it evokes apoptosis in the hilus region [5,6,7,8,9,10]. Mitochondria are dynamic organelles of eukaryotic cells responsible for generating ATP. Mitochondria participate in the synthesis of reactive oxygen species (ROS), cell homeostasis and
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