Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038220 (status epilepticus)
 7,272 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transient receptor potential canonical channel-6 (TRPC6) is one of Ca2+-permeable non-selective cation channels. In the rat hippocampus, TRPC6 expression is predominantly observed in dentate granule cells (DGC) rather than other hippocampal components. Interestingly, TRPC6 knockdown results in the massive DGC degeneration following status epilepticus (SE), although DGC is one of the resistant neuronal populations to various harmful stresses. However, the molecular events underlying the DGC degeneration induced by TRPC6 knockdown are still unclear. In the present study, TRPC6 knockdown resulted in mitochondrial elongation accompanied by reduction in dynamin-related proteins 1 (DRP1)-S616 phosphorylation. Furthermore, TRPC6 knockdown selectively decreased extracellular-signal-regulated kinase 1/2 (ERK1/2) phosphorylation. Similar to TRPC6 knockdown, ERK1/2 inhibition by U0126 evoked mitochondrial elongation with diminished DRP1-S616 phosphorylation, and facilitated SE-induced DGC degeneration independent of seizure severity. These findings indicate that TRPC6 may regulate mitochondrial dynamics via ERK1/2-mediaed DRP1 activation, which would be involved in DGC invulnerability to SE. Therefore, TRPC6 will be an interesting and important therapeutic target for neurological diseases related to impaired mitochondrial dynamics.
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PMID:TRPC6-mediated ERK1/2 phosphorylation prevents dentate granule cell degeneration via inhibiting mitochondrial elongation. 2847 96

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.
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PMID:CDDO-Me Selectively Attenuates CA1 Neuronal Death Induced by Status Epilepticus via Facilitating Mitochondrial Fission Independent of LONP1. 3138 95