A unique modulator of endoplasmic reticulum stress‐signalling pathways: the novel pharmacological properties of amiloride in glial cells

Hosoi, Toru; Kume, Ayaka; Otani, Kayo; Oba, Tatsuya; Ozawa, Koichiro

doi:10.1111/j.1476-5381.2009.00544.x

Cited by 11 publications

(12 citation statements)

References 48 publications

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“…As a result, salubrinal enhances the PERK‐eIF2α signalling during ER stress and has been reported to protect a wide range of cells against ER stress‐induced apoptosis. (Boyce and Yuan, ; Hosoi et al ., ; Gong et al ., ; Ohri et al ., ). Under our experimental conditions, salubrinal prevented chemical hypoxia‐induced neuronal death, reinforcing the role of ER stress in chemical hypoxia‐induced delayed neuronal death.…”

Section: Discussionmentioning

confidence: 97%

The endoplasmic reticulum stress and the HIF‐1 signalling pathways are involved in the neuronal damage caused by chemical hypoxia

López-Hernández

Ceña

Posadas

2015

British J Pharmacology

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BACKGROUND AND PURPOSEHypoxia inducible factor-1 (HIF-1) promotes transitory neuronal survival suggesting that additional mechanisms such as the endoplasmic reticulum (ER) stress might be involved in determining neuronal survival or death. Here, we examined the involvement of ER stress in hypoxia-induced neuronal death and analysed the relationship between ER stress and the HIF-1 pathways. EXPERIMENTAL APPROACHCultures of rat cortical neurons were exposed to chemical hypoxia induced by 200 μM CoCl2, and its effect on neuronal viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and counting apoptotic nuclei. Protein levels were determined by Western blot analysis. RT-PCR was performed to analyse the content and the t1/2 of HIF-1α mRNA. KEY RESULTSChemical hypoxia induced neuronal apoptosis in a time-dependent manner and activated the ER stress PRK-like endoplasmic reticulum kinase (PERK)-dependent pathway. At later stages, chemical hypoxia increased the expression of the C/EBP homologous protein (CHOP) and caspase 12 activity. CoCl2 reduced HIF-1α mRNA t1/2 leading to a decrease in HIF-1α mRNA and protein content, simultaneously activating the ER stress PERK-dependent pathway. Salubrinal, a selective inhibitor of phospho-eIF2α phosphatase, protected neurons from chemical hypoxia by reducing CHOP levels and caspase 12 activity, and increasing the t1/2 of HIF-1α mRNA and the levels of HIF-1α protein. Knocking down HIF-1α blocked the neuroprotective effects of salubrinal. CONCLUSIONS AND IMPLICATIONSNeuronal apoptosis induced by chemical hypoxia is a process regulated by HIF-1α stabilization early on and by ER stress activation at later stages. Our data also suggested that HIF-1α levels were regulated by ER stress. AbbreviationsATF, activating transcription factor; CHOP, C/EBP homologous protein; ddH2O, double distillate water; DIV, days in vitro; eIF2α, initiation elongation factor 2α; EPO, erythropoietin; ER, endoplasmic reticulum; GLUT1, glucose transporter 1; GRP-78/Bip, glucose-regulated protein 78; HIF-1, hypoxia inducible factor-1; IRE1α, inositol-requiring 1 α; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; PERK, PRK-like endoplasmic reticulum kinase; TMRM, tetramethylrhodamine methyl ester BJP British Journal of Pharmacology

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Section: Discussionmentioning

confidence: 97%

The endoplasmic reticulum stress and the HIF‐1 signalling pathways are involved in the neuronal damage caused by chemical hypoxia

López-Hernández

Ceña

Posadas

2015

British J Pharmacology

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“…CB2 activation is also correlated with increasing anti-inflammatory gene expression in the dorsal horn and significant reductions in mechanical and thermal hypersensitivity (Luongo et al, 2010). Thus, the synergy observed between JWH015 and morphine is likely due to the activation of CB2 receptors on immune cells and subsequent inhibition of the inflammatory process (Hsieh et al, 2010; Kinsey et al, 2011; Yao et al, 2007) coupled with morphine’s well-characterized ability to inhibit nociceptive signaling (Fields, 2004; McCabe et al, 2014). These data strongly suggest that the combination of a MOR agonist along with a CB2 agonist may inhibit neuropathic pain at much lower doses than a MOR agonist alone, offering an effective therapeutic option for a difficult to manage pain state.…”

Section: Discussionmentioning

confidence: 99%

Synergistic attenuation of chronic pain using mu opioid and cannabinoid receptor 2 agonists

et al. 2017

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The misuse of prescription opiates is on the rise with combination therapies (e.g. acetaminophen or NSAIDs) resulting in severe liver and kidney damage. In recent years, cannabinoid receptors have been identified as potential modulators of pain and rewarding behaviors associated with cocaine, nicotine and ethanol in preclinical models. Yet, few studies have identified whether mu opioid agonists and CB2 agonists act synergistically to inhibit chronic pain while reducing unwanted side effects including reward liability. We determined if analgesic synergy exists between the mu-opioid agonist morphine and the selective CB2 agonist, JWH015, in rodent models of acute and chronic inflammatory, post-operative, and neuropathic pain using isobolographic analysis. We also investigated if the MOR-CB2 agonist combination decreased morphine-induced conditioned place preference (CPP) and slowing of gastrointestinal transit. Co-administration of morphine with JWH015 synergistically inhibited preclinical inflammatory, post-operative and neuropathic-pain in a dose- and time-dependent manner; no synergy was observed for nociceptive pain. Opioid-induced side effects of impaired gastrointestinal transit and CPP were significantly reduced in the presence of JWH015. Here we show that MOR + CB2 agonism results in a significant synergistic inhibition of preclinical pain while significantly reducing opioid-induced unwanted side effects. The opioid sparing effect of CB2 receptor agonism strongly supports the advancement of a MOR-CB2 agonist combinatorial pain therapy for clinical trials.

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“…In fact, Hosoi et al . () reported that amiloride at 200 μ m , unlike the result at 20 μ m , resulted in an increase of tunicamycin‐induced apoptosis by inhibiting the IRE1/XBP1/GRP78 signaling pathway. Therefore, amiloride's effect on cell death seems be dependent on the dose used, but a careful in vivo examination of the dose–response relationship will be required.…”

Section: Discussionmentioning

confidence: 94%

“…The in vitro effects of amiloride were examined at a concentration of 20 μ m , based on the protocol of Hosoi et al . () in which suppression of apoptosis was observed. Our results showed that the addition of 20 μ m amiloride decreased CHOP expression in OPCs cultured under tunicamycin‐induced ER stress, confirming the cytoprotective effects of amiloride against ER stress.…”

Section: Discussionmentioning

confidence: 95%

“…Although the relationship between amiloride and ER stress has not been sufficiently investigated, Hosoi et al . () reported that 20 μ m amiloride modulated ER stress and significantly inhibited apoptosis in mouse primary cultured glial cells under tunicamycin‐induced ER stress. Amiloride increased eIF2α phosphorylation and, contrary to its normal behavior, decreased CHOP expression in a dose‐dependent manner.…”

Section: Discussionmentioning

confidence: 96%

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Effect of amiloride on endoplasmic reticulum stress response in the injured spinal cord of rats

Kuroiwa

Watanabe

Katoh

et al. 2014

Eur J of Neuroscience

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After traumatic spinal cord injury (SCI), endoplasmic reticulum (ER) stress exacerbates secondary injury, leading to expansion of demyelination and reduced remyelination due to oligodendrocyte precursor cell (OPC) apoptosis. Although recent studies have revealed that amiloride controls ER stress and leads to improvement in several neurological disorders including SCI, its mechanism is not completely understood. Here, we used a rat SCI model to assess the effects of amiloride on functional recovery, secondary damage expansion, ER stress-induced cell death and OPC survival. Hindlimb function in rats with spinal cord contusion significantly improved after amiloride administration. Amiloride significantly decreased the expression of the pro-apoptotic transcription factor CHOP in the injured spinal cord and significantly increased the expression of the ER chaperone GRP78, which protects cells against ER stress. In addition, amiloride treatment led to a significant decrease in ER stress-induced apoptosis and a significant increase of NG2-positive OPCs in the injured spinal cord. Furthermore, in vitro experiments performed to investigate the direct effect of amiloride on OPCs revealed that amiloride reduced CHOP expression in OPCs cultured under ER stress. These results suggest that amiloride controls ER stress in SCI and inhibits cellular apoptosis, contributing to OPC survival. The present study suggests that amiloride may be an effective treatment to reduce ER stress-induced cell death in the acute phase of SCI.

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A unique modulator of endoplasmic reticulum stress‐signalling pathways: the novel pharmacological properties of amiloride in glial cells

Cited by 11 publications

References 48 publications

The endoplasmic reticulum stress and the HIF‐1 signalling pathways are involved in the neuronal damage caused by chemical hypoxia

The endoplasmic reticulum stress and the HIF‐1 signalling pathways are involved in the neuronal damage caused by chemical hypoxia

Synergistic attenuation of chronic pain using mu opioid and cannabinoid receptor 2 agonists

Effect of amiloride on endoplasmic reticulum stress response in the injured spinal cord of rats

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