Abstract
BackgroundRecently, we have reported that LIM kinase 2 (LIMK2) involves programmed necrotic neuronal deaths induced by aberrant cyclin D1 expression following status epilepticus (SE). Up-regulation of LIMK2 expression induces neuronal necrosis by impairment of dynamin-related protein 1 (DRP1)-mediated mitochondrial fission. However, we could not elucidate the upstream effecter for LIMK2-mediated neuronal death. Thus, we investigated the role of endothelin-1 (ET-1) in LIMK2-mediated neuronal necrosis, since ET-1 involves neuronal death via various pathways.ResultsFollowing SE, ET-1 concentration and its mRNA were significantly increased in the hippocampus with up-regulation of ETB receptor expression. BQ788 (an ETB receptor antagonist) effectively attenuated SE-induced neuronal damage as well as reduction in LIMK2 mRNA/protein expression. In addition, BQ788 alleviated up-regulation of Rho kinase 1 (ROCK1) expression and impairment of DRP1-mediated mitochondrial fission in CA1 neurons following SE. BQ788 also attenuated neuronal death and up-regulation of LIMK2 expression induced by exogenous ET-1 injection.ConclusionThese findings suggest that ET-1 may be one of the upstream effectors for programmed neuronal necrosis through abnormal LIMK2 over-expression by ROCK1.
Highlights
We have reported that LIM kinase 2 (LIMK2) involves programmed necrotic neuronal deaths induced by aberrant cyclin D1 expression following status epilepticus (SE)
Three days after SE, ETB receptor expression was significantly reduced in CA1 neurons due to massive neuronal loss, while its expression was enhanced in astrocytes (Fig. 2f)
These findings indicate that SE may increase ET-1 synthesis and up-regulate ETB receptor expression in neurons as well as astrocytes
Summary
We have reported that LIM kinase 2 (LIMK2) involves programmed necrotic neuronal deaths induced by aberrant cyclin D1 expression following status epilepticus (SE). Up-regulation of LIMK2 expression induces neuronal necrosis by impairment of dynamin-related protein 1 (DRP1)-mediated mitochondrial fission. Some necrotic processes can be mediated by receptor interacting protein kinase 1 (RIP1), which is termed programmed necrosis or necroptosis [3,4,5,6]. ETB receptor activations elevate intracellular Ca2+ concentration in cultured neurons and hippocampal slices in an autocrine-signaling mode [9,10,11]. This intracellular mobilization of Ca2+ rapidly leads to Ca2+-dependent NO synthesis. NO reacts with superoxide anion to form peroxynitrite anion (ONOO−), which is a highly reactive oxidizing agent capable of causing tissue damage [12] and
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