Humanin Attenuates NMDA-Induced Excitotoxicity by Inhibiting ROS-dependent JNK/p38 MAPK Pathway

Yang, Xiaorong; Zhang, Hongmei; Wu, Jinzi; Yin, Litian; Yan, Liang; Zhang, Ce

doi:10.3390/ijms19102982

Cited by 33 publications

(19 citation statements)

References 48 publications

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“…HN has been shown to protect cultured rat cortical neurons from NMDA-induced neurotoxicity, an effect that seems to be time- and concentration-dependent (Cui et al, 2014, 2017; Yang et al, 2018). In this study, we aimed at studying HN effects on structural synaptic plasticity in glutamate-induced dendritic atrophy and synapse alterations (Podestá et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Humanin, a Mitochondrial-Derived Peptide Released by Astrocytes, Prevents Synapse Loss in Hippocampal Neurons

Zárate

Traetta

Codagnone

et al. 2019

Front. Aging Neurosci.

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Astroglial cells are crucial for central nervous system (CNS) homeostasis. They undergo complex morpho-functional changes during aging and in response to hormonal milieu. Ovarian hormones positively affect different astroglia parameters, including regulation of cell morphology and release of neurotrophic and neuroprotective factors. Thus, ovarian hormone loss during menopause has profound impact in astroglial pathophysilogy and has been widely associated to the process of brain aging. Humanin (HN) is a secreted mitochondrial-encoded peptide with neuroprotective effects. It is localized in several tissues with high metabolic rate and its expression decreases with age. In the brain, humanin has been found in glial cells in physiological conditions. We previously reported that surgical menopause induces hippocampal mitochondrial dysfunction that mimics an aging phenotype. However, the effect of ovarian hormone deprivation on humanin expression in this area has not been studied. Also, whether astrocytes express and release humanin and the regulation of such processes by ovarian hormones remain elusive. Although humanin has also proven to be beneficial in ameliorating cognitive impairment induced by different insults, its putative actions on structural synaptic plasticity have not been fully addressed. In a model of surgical menopause in rats, we studied hippocampal humanin expression and localization by real-time quantitative polymerase chain reaction (RT-qPCR) and double immunohistochemistry, respectively. Humanin production and release and ovarian hormone regulation of such processes were studied in cultured astrocytes by flow cytometry and ELISA, respectively. Humanin effects on glutamate-induced structural synaptic alterations were determined in primary cultures of hippocampal neurons by immunocytochemistry. Humanin expression was lower in the hippocampus of ovariectomized rats and its immunoreactivity colocalized with astroglial markers. Chronic ovariectomy also promoted the presence of less complex astrocytes in this area. Ovarian hormones increased humanin intracellular content and release by cultured astrocytes. Humanin prevented glutamate-induced dendritic atrophy and reduction in puncta number and total puncta area for pre-synaptic marker synaptophysin in cultured hippocampal neurons. In conclusion, astroglial functional and morphological alterations induced by chronic ovariectomy resemble an aging phenotype and could affect astroglial support to neuronal function by altering synaptic connectivity and functionality. Reduced astroglial-derived humanin may represent an underlying mechanism for synaptic dysfunction and cognitive decline after menopause.

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Section: Discussionmentioning

confidence: 99%

Humanin, a Mitochondrial-Derived Peptide Released by Astrocytes, Prevents Synapse Loss in Hippocampal Neurons

Zárate

Traetta

Codagnone

et al. 2019

Front. Aging Neurosci.

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“…Studies have shown in both cellular and animal models that oxidative stress upregulates the expression and activity of BACE1 through the activation of the c-Jun N-terminal kinase/activator protein1 pathway [58,59,60,61]. Kim et al reported that treating SK-N-MC cells with palmitic acid conjugated with bovine serum albumin (PA-BSA) results in an increased expression of BACE1 and Aβ production through the G protein-coupled receptor 40 (GPCR40) [62].…”

Section: Discussionmentioning

confidence: 99%

MST1 Regulates Neuronal Cell Death via JNK/Casp3 Signaling Pathway in HFD Mouse Brain and HT22 Cells

Khan

Rutten

Kim

2019

IJMS

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Oxidative stress has been considered as the main mediator in neurodegenerative diseases. A high-fat diet (HFD) and metabolic diseases result in oxidative stress generation, leading to various neurodegenerative diseases via molecular mechanisms that remain largely unknown. Protein kinases play an important role in the homeostasis between cell survival and cell apoptosis. The mammalian sterile 20-like kinase-1 (MST1) protein kinase plays an important role in cellular apoptosis in different organ systems, including the central nervous system. In this study, we evaluated the MST1/c-Jun N-terminal kinase (JNK) dependent oxidative damage mediated cognitive dysfunction in HFD-fed mice and stress-induced hippocampal HT22 (mice hippocampal) cells. Our Western blot and immunofluorescence results indicate that HFD and stress-induced hippocampal HT22 cells activate MST1/JNK/Caspase-3 (Casp-3) signaling, which regulates neuronal cell apoptosis and beta-amyloid-cleaving enzyme (BACE1) expression and leads to impaired cognition. Moreover, MST1 expression inhibition by shRNA significantly reduced JNK/Casp-3 signaling. Our in vivo and in vitro experiments mimicking metabolic stress, such as a high-fat diet, hyperglycemia, and an inflammatory response, determined that MST1 plays a key regulatory role in neuronal cell death and cognition, suggesting that MST1 could be a potential therapeutic target for numerous neurodegenerative diseases.

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“…It has depicted that ROS-mediated oxidative stress can activate the pathway of MAPKs including ERK, JNK, and p38 in neurons (Samanta et al, 1998; Kamata et al, 2005; Yang et al, 2018). The prevention of ROS accumulation by a ROS scavenger, namely, NAC, abrogates JNK and p38 MAPK activation and subsequently promotes neuronal survival under NMDA-induced excitotoxic conditions (Yang et al, 2018), indicating the critical role of ROS-mediated JNK and p38 MAPKs activation in neuronal apoptosis. Although the mechanism for ROS-mediated activations of JNK and p38 MAPK is not well understood, it implicates that JNK and p38 serve as the potential targets for modulating neuronal apoptosis during seizures and/or epileptogenesis.…”

Section: Oxidative Stress Signaling and Neuronal Apoptosismentioning

confidence: 99%

Redox-Related Neuronal Death and Crosstalk as Drug Targets: Focus on Epilepsy

2019

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Cell death has a vital role in embryonic development and organismal homeostasis. Biochemical, pharmacological, behavioral, and electrophysiological evidences support the idea that dysregulation of cell death programs are involved in neuropathological conditions like epilepsy. The brain is particularly vulnerable to oxidative damage due to higher oxygen consumption and lower endogenous antioxidant defense than other bodily organ. Thus, in this review, we focused on the comprehensive summarization of evidence for redox-associated cell death pathways including apoptosis, autophagy, necroptosis, and pyroptosis in epilepsy and the oxidative stress-related signaling in this process. We specially proposed that the molecular crosstalk of various redox-linked neuronal cell death modalities might occur in seizure onset and/or epileptic conditions according to the published data. Additionally, abundance of polyunsaturated fatty acids in neuronal membrane makes the brain susceptible to lipid peroxidation. This presumption was then formalized in the proposal that ferroptosis, a novel type of lipid reactive oxygen species (ROS)-dependent regulatory cell death, is likely to be a critical mechanism for the emergence of epileptic phenotype. Targeting ferroptosis process or combination treatment with multiple cell death pathway inhibitors may shed new light on the therapy of epilepsy.

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Humanin Attenuates NMDA-Induced Excitotoxicity by Inhibiting ROS-dependent JNK/p38 MAPK Pathway

Cited by 33 publications

References 48 publications

Humanin, a Mitochondrial-Derived Peptide Released by Astrocytes, Prevents Synapse Loss in Hippocampal Neurons

Humanin, a Mitochondrial-Derived Peptide Released by Astrocytes, Prevents Synapse Loss in Hippocampal Neurons

MST1 Regulates Neuronal Cell Death via JNK/Casp3 Signaling Pathway in HFD Mouse Brain and HT22 Cells

Redox-Related Neuronal Death and Crosstalk as Drug Targets: Focus on Epilepsy

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