Neuroprotective Effects of Dexmedetomidine against Thapsigargin-induced ER-stress via Activity of α<sub>2</sub>-adrenoceptors and Imidazoline Receptors

Manami Inagaki; Masayuki Somei; Tatsunori Oguchi; Ran Ono; Sachie Fukutaka; Ikumi Matsuoka; Mayumi Tsuji; Katsuji Oguchi; Manami Inagaki; Masayuki Somei; Tatsunori Oguchi; Ran Ono; Sachie Fukutaka; Ikumi Matsuoka; Mayumi Tsuji; Katsuji Oguchi

doi:10.3934/Neuroscience.2016.2.237

AIMS Neuroscience

2016, Volume 3, Issue 2: 237-252. doi: 10.3934/Neuroscience.2016.2.237

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Research article

Neuroprotective Effects of Dexmedetomidine against Thapsigargin-induced ER-stress via Activity of α₂-adrenoceptors and Imidazoline Receptors

1.
Department of Pharmacology, School of Medicine, Showa University, Tokyo, Japan
2.
Department of Pharmacology, School of Pharmacy, Showa University, Tokyo, Japan

Received: 26 May 2016 Accepted: 08 July 2016 Published: 26 May 2016

Dexmedetomidine is a potent and highly selective α₂-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 Ca²⁺, 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 α₂-adrenoceptor and I₁- and I₂-receptors.
- dexmedetomidine,
- α₂-agonist,
- imidazoline receptor,
- ER-stress-mediated apoptosis,
- ischemia,
- neurodegeneration
Citation: 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 α2-adrenoceptors and Imidazoline Receptors[J]. AIMS Neuroscience, 2016, 3(2): 237-252. doi: 10.3934/Neuroscience.2016.2.237

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Abstract

Dexmedetomidine is a potent and highly selective α₂-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 Ca²⁺, 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 α₂-adrenoceptor and I₁- and I₂-receptors.

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