Neuroprotective Effects of Dexmedetomidine against Thapsigargin-induced ER-stress via Activity of α<sub>2</sub>-adrenoceptors and Imidazoline Receptors
Dexmedetomidine is a potent and highly selective α<sub>2</sub>-adrenoceptor agonist with sedative, analgesic, and sympatholytic properties, though it also exhibits some affinity for imidazoline binding sites. In addition to its sedative effects, dexmedetomidine exerts neuroprotective eff...
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| Format: | Article |
| Language: | English |
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AIMS Press
2016-07-01
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| Series: | AIMS Neuroscience |
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| Online Access: | http://www.aimspress.com/neuroscience/article/860/fulltext.html |
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| author | Manami Inagaki Masayuki Somei Tatsunori Oguchi Ran Ono Sachie Fukutaka Ikumi Matsuoka Mayumi Tsuji Katsuji Oguchi |
| author_facet | Manami Inagaki Masayuki Somei Tatsunori Oguchi Ran Ono Sachie Fukutaka Ikumi Matsuoka Mayumi Tsuji Katsuji Oguchi |
| author_sort | Manami Inagaki |
| collection | DOAJ |
| description | Dexmedetomidine is a potent and highly selective α<sub>2</sub>-adrenoceptor agonist with sedative, analgesic, and sympatholytic properties, though it also exhibits some affinity for imidazoline binding sites. In addition to its sedative effects, dexmedetomidine exerts neuroprotective effects under ischemic conditions. Invasive incidents such as ischemia or hypoxia induce dysfunctions in energy production or depletion of ATP as well as accumulation and aggregation of abnormal proteins in the endoplasmic reticulum (ER), leading to an ER-stress response. In the present study, we examined whether dexmedetomidine exerts inhibitory effects on apoptosis mediated by thapsigargin-induced ER-stress in SH-SY5Y cells, and proposed a possible underlying mechanism for its neuroprotective effects. We used thapsigargin (TG) to generate an ER-stress response in SH-SY5Y cells. SH-SY5Y cells were pretreated with Dex (1–1000 nM) or receptor antagonists (atipamezole, efaroxan, BU99006, and 2’,5’-dideoxyadenosine) for 1 hour before co-treatment with 1 mM TG for 20 hours. Co-incubation with dexmedetomidine suppressed thapsigargin-induced increases in cytosolic Ca<sup>2+</sup>, caspase-4 and -3 activity, eIF2α phosphorylation, and expression of ER-stress biomarkers. Dexmedetomidine treatment also decreased cAMP levels. In the presence of atipamezole or efaroxan, but not BU99006, inhibition of eIF2α phosphorylation and CHOP expression significantly increased following treatment with dexmedetomidine in thapsigargin-treated cells. However, pretreatment with BU99006 enhanced the increase in mitochondrial membrane potential associated with dexmedetomidine treatment. The results of the present study demonstrate that dexmedetomidine at clinically relevant concentrations suppresses ER-stress-induced apoptosis in SH-SY5Y cells. Some neuroprotective effects of dexmedetomidine may be mediated by α<sub>2</sub>-adrenoceptor and I<sub>1</sub>- and I<sub>2</sub>-receptors. |
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| language | English |
| last_indexed | 2024-12-21T08:32:21Z |
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| spelling | doaj.art-c7b66ab38d974739bcddd85698df6d662022-12-21T19:10:10ZengAIMS PressAIMS Neuroscience2373-79722016-07-013223725210.3934/Neuroscience.2016.2.237Neurosci-03-00237Neuroprotective Effects of Dexmedetomidine against Thapsigargin-induced ER-stress via Activity of α<sub>2</sub>-adrenoceptors and Imidazoline ReceptorsManami Inagaki0Masayuki Somei1Tatsunori Oguchi2Ran Ono3Sachie Fukutaka4Ikumi Matsuoka5Mayumi Tsuji6Katsuji Oguchi7Department of Pharmacology, School of Medicine, Showa University, Tokyo, JapanDepartment of Pharmacology, School of Medicine, Showa University, Tokyo, JapanDepartment of Pharmacology, School of Medicine, Showa University, Tokyo, JapanDepartment of Pharmacology, School of Medicine, Showa University, Tokyo, JapanDepartment of Pharmacology, School of Pharmacy, Showa University, Tokyo, JapanDepartment of Pharmacology, School of Pharmacy, Showa University, Tokyo, JapanDepartment of Pharmacology, School of Medicine, Showa University, Tokyo, JapanDepartment of Pharmacology, School of Medicine, Showa University, Tokyo, JapanDexmedetomidine is a potent and highly selective α<sub>2</sub>-adrenoceptor agonist with sedative, analgesic, and sympatholytic properties, though it also exhibits some affinity for imidazoline binding sites. In addition to its sedative effects, dexmedetomidine exerts neuroprotective effects under ischemic conditions. Invasive incidents such as ischemia or hypoxia induce dysfunctions in energy production or depletion of ATP as well as accumulation and aggregation of abnormal proteins in the endoplasmic reticulum (ER), leading to an ER-stress response. In the present study, we examined whether dexmedetomidine exerts inhibitory effects on apoptosis mediated by thapsigargin-induced ER-stress in SH-SY5Y cells, and proposed a possible underlying mechanism for its neuroprotective effects. We used thapsigargin (TG) to generate an ER-stress response in SH-SY5Y cells. SH-SY5Y cells were pretreated with Dex (1–1000 nM) or receptor antagonists (atipamezole, efaroxan, BU99006, and 2’,5’-dideoxyadenosine) for 1 hour before co-treatment with 1 mM TG for 20 hours. Co-incubation with dexmedetomidine suppressed thapsigargin-induced increases in cytosolic Ca<sup>2+</sup>, caspase-4 and -3 activity, eIF2α phosphorylation, and expression of ER-stress biomarkers. Dexmedetomidine treatment also decreased cAMP levels. In the presence of atipamezole or efaroxan, but not BU99006, inhibition of eIF2α phosphorylation and CHOP expression significantly increased following treatment with dexmedetomidine in thapsigargin-treated cells. However, pretreatment with BU99006 enhanced the increase in mitochondrial membrane potential associated with dexmedetomidine treatment. The results of the present study demonstrate that dexmedetomidine at clinically relevant concentrations suppresses ER-stress-induced apoptosis in SH-SY5Y cells. Some neuroprotective effects of dexmedetomidine may be mediated by α<sub>2</sub>-adrenoceptor and I<sub>1</sub>- and I<sub>2</sub>-receptors.http://www.aimspress.com/neuroscience/article/860/fulltext.htmldexmedetomidineα<sub>2</sub>-agonistimidazoline receptorER-stress-mediated apoptosisischemianeurodegeneration |
| spellingShingle | Manami Inagaki Masayuki Somei Tatsunori Oguchi Ran Ono Sachie Fukutaka Ikumi Matsuoka Mayumi Tsuji Katsuji Oguchi Neuroprotective Effects of Dexmedetomidine against Thapsigargin-induced ER-stress via Activity of α<sub>2</sub>-adrenoceptors and Imidazoline Receptors AIMS Neuroscience dexmedetomidine α<sub>2</sub>-agonist imidazoline receptor ER-stress-mediated apoptosis ischemia neurodegeneration |
| title | Neuroprotective Effects of Dexmedetomidine against Thapsigargin-induced ER-stress via Activity of α<sub>2</sub>-adrenoceptors and Imidazoline Receptors |
| title_full | Neuroprotective Effects of Dexmedetomidine against Thapsigargin-induced ER-stress via Activity of α<sub>2</sub>-adrenoceptors and Imidazoline Receptors |
| title_fullStr | Neuroprotective Effects of Dexmedetomidine against Thapsigargin-induced ER-stress via Activity of α<sub>2</sub>-adrenoceptors and Imidazoline Receptors |
| title_full_unstemmed | Neuroprotective Effects of Dexmedetomidine against Thapsigargin-induced ER-stress via Activity of α<sub>2</sub>-adrenoceptors and Imidazoline Receptors |
| title_short | Neuroprotective Effects of Dexmedetomidine against Thapsigargin-induced ER-stress via Activity of α<sub>2</sub>-adrenoceptors and Imidazoline Receptors |
| title_sort | neuroprotective effects of dexmedetomidine against thapsigargin induced er stress via activity of α sub 2 sub adrenoceptors and imidazoline receptors |
| topic | dexmedetomidine α<sub>2</sub>-agonist imidazoline receptor ER-stress-mediated apoptosis ischemia neurodegeneration |
| url | http://www.aimspress.com/neuroscience/article/860/fulltext.html |
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