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Abstract

Dexmedetomidine is a highly selective α2-adrenoceptor agonist with sedation, anesthetic sparing, analgesia, sympatholytic, and neuroprotective properties. This study evaluated neuroprotective effects of dexmedetomidine on dopamine neurons correlated to histone acetylation via extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) pathway. Animals were randomly assigned to four groups and treatments were given as onetime doses: dimethyl sulfoxide (DMSO; n = 6), dexmedetomidine 1 mg/kg (n = 6), 10 mg/kg (n = 6), and 100 mg/kg (n = 6). Acetylation histone protein levels and ERK protein levels in rats dopamine neuron from striatum were determined by Western blotting after various doses of dexmedetomidine (1, 10, and 100 mg/kg) treatments. The messenger RNA expression related to signal transduction coupled to 5-hydroxytryptamine receptor (5-HTR) in striatum was assessed by quantitative real-time polymerase chain reaction (qRT-PCR) analysis. Dexmedetomidine administration increased expression of ERK1/2 phosphorylation and histones H3 acetylation. PD098059, an inhibitor of pERK1/2, almost completely blocked dexmedetomidine-induced histones H3 acetylation. In addition, bioinformatics analysis in combination with qRT-PCR demonstrated that dexmedetomidine could regulate the genes that are related to signal transduction coupled to 5-HTR via α2-adrenoceptor. Our results define dexmedetomidine as a modulator of histones H3 acetylation via ERK1/2 signaling pathway in dopamine neuron from striatum, which may provide clues for the mechanism underlying the neuroprotective effects of dexmedetomidine.

Keywords

Dexmedetomidine neuroprotection histone acetylation Htr signal

Introduction

Dexmedetomidine is a highly selective α2-adrenoceptor (α2-AR) agonist primarily used as an analgesic and sedative agent.¹ Dexmedetomidine can potentially reduce postoperative requirements for analgesics.² The combined analgesic and sedative effect of dexmedetomidine makes it a preferred drug for awake craniotomy.^3,4 Multiple evidences indicate that dexmedetomidine can improve treatment and prognosis in patients with severe brain trauma.^5,6 Besides, cell-protective effect on nervous tissue of dexmedetomidine under ischemic conditions has been reported.^7,8 Recently, evidence indicated that this neuroprotective effect was mediated by dexmedetomidine’s binding to imidazoline I1-receptors as well as dexmedetomidine’s α2-agonistic properties.⁹ The signal transduction cascade linked to these receptors was dependent on extracellular signal-regulated protein kinase 1 and 2 (ERK1/2),^9,10 which is also known to be an important regulator for cell survival and mediators of neuroprotective effects of various other agents.¹¹ The striatum harbors a population of dopamine neurons that play an important role in the initiation, selection, and reinforcement of motor actions and have been closely related to motor, cognitive, and addictive disorders.^12,13 Nevertheless, it has yet to be determined whether dexmedetomidine also activates ERK1/2 in dopamine neurons from striatum, which produces its neuroprotective effects.

Changes in histone acetylation, controlled by histone deacetylases (HDACs) and histone acetyltransferase (HAT), act on a target promoter and regulate gene transcription by altering chromatin structure.¹⁴ For example, the acetylation of histones H3 and histones H4 at gene promoters is in association with increased gene activity, while deacetylation is in association with suppression and silencing of gene activity. Previous studies have indicated that histone acetylation–deacetylation was regulated in adult neurons linked to learning and memory,¹¹ and in response to psychotropic drugs.¹⁵ In addition, HDAC inhibitors also have shown promise as Huntington’s disease¹⁶ and spinal muscular atrophy¹⁷ therapeutics in animal models. Above all, the acetylation of core histones may be a critical determinant of gene expression in brain. However, changes in histone acetylation of dopamine neurons after dexmedetomidine administration remain unexplored.

The aim of this study was to further explore the mechanism underlying the neuroprotective effects of dexmedetomidine in vivo using rat models. Herein, we explored the changes in ERK1/2 phosphorylation and histones H3 acetylation in dopamine neurons from striatum after acute dexmedetomidine treatment and found that dexmedetomidine increased expression of ERK1/2 phosphorylation and histones H3 acetylation. Subsequently, in order to investigate the correlation between ERK1/2 pathway and histones H3 acetylation, PD098059, an inhibitor of pERK1/2, was used to treat the rats, and the acetylation of their histones H3 was almost completely blocked, indicating that dexmedetomidine-induced histones H3 acetylation in dopamine neuron could be mediated by ERK1/2 signaling pathway. In addition, bioinformatics analysis of the previous reported Gene Expression data (accession number GSE6909),¹⁸ in combination with quantitative real-time polymerase chain reaction (qRT-PCR), demonstrated that dexmedetomidine could regulate the genes that are related to signal transduction coupled to human 5-hydroxytryptamine receptor (5-HTR) via α2-AR.

Materials and methods

Ethical approval statement

Handling procedures according to the Guide for the Care and Use of Laboratory Animals (Huzhou Central Hospital) were followed. The experiments were performed upon approval from Institutional Animal Care and Use Committee. Male, adult Sprague-Dawley rats, initially weighing 250–300 g, were purchased from Shanghai Experimental Animal Center. The rats were housed in a temperature- and humidity-controlled room. All animals were on a 12-h light/12-h dark cycle, and had access to food and water ad libitum.

Drug administration

Intrastriatal stereotaxic drug administration was performed as described previously.¹⁹ Briefly, animals were randomly assigned to one of four groups and treatments were given as onetime doses: dimethyl sulfoxide (DMSO; n = 6), dexmedetomidine 1 mg/kg (n = 6), 10 mg/kg (n = 6), 100 mg/kg (n = 6). All treatment concentrations were calculated such that volumes administered across groups would be similar. The specific ERK-MAPK inhibitor, PD98059 (2 mg/kg), was given 30 min before the administration of dexmedetomidine.

Western blotting analysis

Western blotting analysis was performed as described previously.²⁰ Briefly, striatal tissues obtained from the treated rats were homogenized and then sonicated in a lysing buffer containing 0.1% sodium dodecyl sulfate (SDS), a protease inhibitor cocktail and DNase (Promega). Protein concentrations of samples were determined using a BCA protein assay kit (Pierce, Rockford, Illinois, USA) following the provided instructions. Equal amount of proteins (30 µg) were loaded and separated on 10% sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) gels and transferred to polyvinylidene difluoride membranes (Millipore, Bedford, Massachusetts, USA). Blots were blocked and then probed with primary antibodies, rabbit polyclonal anti-acH3 antibody (1:1500; Millipore), rabbit polyclonal H3 antibody (1:2500; Millipore), rabbit anti-phospho-ERK1/2 antibody (1:2000; Cell Signaling), rabbit anti-total-ERK1/2 antibody (1:2000; Cell Signaling), or rabbit anti-actin (1:5000; Santa Cruz, Dallas, Texas, USA), overnight at 4°C. After washing, the blots were incubated with horseradish peroxidase-conjugated secondary antibodies (1:5000; Santa Cruz). The immunoreactivity was detected with enhanced chemoluminescent autoradiography (ECL kit, Amersham, UK).

RNA extraction and qRT-PCR

Total messenger RNA (mRNA) was extracted from injected striatum using the Trizol solution (Invitrogen, Carlsbad, California, USA). RNA quality was determined with a Bioanalyzer instrument (Agilent Technologies, Palo Alto, California, USA). Then, the complementary DNA (cDNA) was reverse transcribed from isolated RNA using SuperScript III First-Strand Synthesis System (Invitrogen). According to the manual (TaKaRa Biotechnology, Japan), the RT-PCR was subsequently performed. Afterwards, qPCR amplification was analyzed using BioRad Connet RT-PCR platform (#CFX96, Bio-Rad Laboratories, Inc., Hercules, CA, USA), and performed using about 2 μg of cDNA as the following condition: 95°C for 1 min, 37 cycles of (95°C for 6 s, 60°C for 25 s), and read absorbance value at the extension stage. Actin was applied as the input reference.

Relative mRNA was determined by using the formula 2^−ΔΔCt (CT; cycle threshold) where ΔCT = CT (target gene) − CT (actin).

Gene expression analysis

The Gene Expression data were acquired from the Gene Expression Omnibus database at the National Center for Biotechnology Information (http://www.ncbi.nlm.nih.gov/geo; accession number GSE6909). The targeted deletion of the α2-AR genes in mice has been described previously.¹¹ Sample preparation and hybridization were performed according to the Affymetrix standard protocol (Eukaryotic Sample and Array Processing) using 5 μg of total RNA extracted from wild-type and α2-AR knockout individual placenta specimens. Comparative transcriptome analysis was performed using GeneChip Mouse Genome 430 2.0 Arrays (Affymetrix, Santa Clara, California, USA). In situ hybridization was performed as described.²¹ We used Significant Analysis of Microarray software (Stanford University, Stanford, California, USA) to identify significantly differentially expressed genes between wild-type mice and α2-AR knockout mice. A 1.5-fold cutoff was chosen to set a low bar for inclusion of potentially relevant genes. Genes with expression fold changes ≥1.5 or ≤0.66 were selected for further bioinformatics analyses of the protein–protein interaction (PPI) map and functional classification. The detailed description of the PPI procedure was performed as described previously.²²

Statistical analysis

Data were analyzed using GraphPad Prism software version 6.00 for Windows (GraphPad Prism Software, San Diego, California, USA). ImageJ software version 1.37 was used to perform the quantitative analysis of protein. Average values were presented as mean values ± standard error of the mean. Statistical significance between different groups was determined by repeated-measures analysis of variance test. A p value <0.05 was accepted as statistically significant.

Results

Dexmedetomidine increases acetylation level of histone in dopamine neuron from striatum

The acetylation of histones H3 at gene promoters is in association with increased gene activity, while deacetylation is in association with suppression and silencing of gene activity. Previous studies have indicated that histone acetylation–deacetylation is regulated in adult neurons linked to learning and memory,¹¹ and in response to psychotropic drugs.¹⁵ To better understand the molecular actions of dexmedetomidine, we studied H3 histone modifications in dopamine neuron from rat striatum after acute dexmedetomidine administration. Different doses of dexmedetomidine (1, 10, and 100 mg/kg) were administrated to rats and acetyl histone H3 expression in dopamine neuron from striatum was measured using Western blotting. As shown in Figure 1(a), we found that acute dexmedetomidine caused the robust induction of H3 acetylation in a dose-dependent manner after drug administration. As shown in Figure 1(b), the H3 acetylation level in high-dose (100 mg/kg) dexmedetomidine treatment group increased by about 3-fold compared to DMSO treatment group. The H3 acetylation level in the rats treated with medium-dose (10 mg/kg) dexmedetomidine also increased by approximately 2-fold compared to DMSO treatment rats. The findings of rapid and dramatic increase of acetylated histone in striatum in response to acute dexmedetomidine treatment suggested chromatin remodeling at specific gene promoters may be a regulatory mechanism underlying the neuroprotective effects of dexmedetomidine.

Figure 1.

Dexmedetomidine increases acetylation level of histone in dopamine neuron from striatum. (a) Acetylation H3 histone and total H3 histone protein levels were determined by Western blotting in dopamine neuron from striatum after various doses of dexmedetomidine (1, 10, and 100 mg/kg) treatment. DMSO was administrated as control group. (b) Results from six rats in each group were quantitatively analyzed with ImageJ software version 1.37 program and expressed as percent of DMSO-treatment control group. One-way analysis of variance followed by the Dunnett t-test was conducted for statistical analyses. Bar graphs represent the mean values from six experiments ± SEM. *p < 0.05 compared to DMSO group. AcH3/3 represents the ration between acetylation H3 histone and total H3 histone protein levels. DMSO: dimethyl sulfoxide; SEM: standard error of the mean.

Dexmedetomidine increases activation level of ERKs in dopamine neuron

Recent evidence suggested that the cell-protective effect of dexmedetomidine on nervous tissues was dependent on ERK1/2,^9,10 which is also known to be an important regulator for cell survival and mediator of neuroprotective effects of various other agents. Accordingly, we investigated effects of dexmedetomidine on ERK1/2 in dopamine neuron from rat striatum. As shown in Figure 2(a), dexmedetomidine produced a significant, concentration-related increase in pERK1/2 expression. However, dexmedetomidine didn’t affect basal levels of total ERK1/2. After acute administration of 10 mg/kg and 100 mg/kg dexmedetomidine, the magnitudes of the increase in pERK1/2 expression were 143.5% and 223.1%, respectively. In order to testify the link between ERK1/2 phosphorylation and H3 acetylation, we used PD098059, an inhibitor of pERK1/2, to block the activation of ERK1/2 before application of dexmedetomidine. The results showed that dexmedetomidine-induced increase in pERK1/2 expression was almost completely blocked by PD098059 (Figure 2(b)). The inhibition rate of PD098059 on H3 acetylation was 120.6% compared to dexmedetomidine treatment alone. These findings indicated that dexmedetomidine-induced H3 acetylation in dopamine neuron could be mediated by ERK1/2 signaling pathway.

Figure 2.

Dexmedetomidine increases activation level of ERKs in dopamine neuron. (a) Phosphorylation ERK1/2 and total ERK1/2 levels were determined by Western blotting in dopamine neuron from striatum after various doses of dexmedetomidine (1, 10, and 100 mg/kg) treatment. DMSO was administrated as control group. Results from six rats in each group were quantitatively analyzed with ImageJ program and expressed as percent of DMSO-treatment control group. *p < 0.05 compared to DMSO-group. (b) Acetylation H3 histone and total H3 histone protein levels were determined by Western blotting in dopamine neuron from striatum after the administration of 10 mg/kg dexmedetomidine. PD98059 (2 mg/kg) was given 30 min before the administration of dexmedetomidine. Results from six rats in each group were quantitatively analyzed with ImageJ program and expressed as percent of DMSO-treatment control group. One-way analysis if variance followed by the Dunnett t-test was conducted for statistical analyses. Bar graphs represent the mean values from six experiments ± SEM. *p < 0.05. AcH3/3 represents the ration between acetylation H3 histone and total H3 histone protein levels. ERKs: extracellular signal-regulated protein kinase; DMSO: dimethyl sulfoxide; SEM: standard error of the mean.

Dexmedetomidine regulates genes related to signal transduction coupled to 5-HTR

In order to investigate related genes regulated by dexmedetomidine, we firstly analyzed the Gene Expression data containing Microarray expression data of wild-type and α2-AR-deficient placentae. The Microarray analysis revealed that 179 genes were significantly up- or downregulated by >1.5-fold in α2-AR-deficient placentae.¹⁸ In this study, we used the Gene Expression data to make bioinformatics analyses of PPI map. As shown in Figure 3(a), we established a protein-interaction network associated with α2-AR. This network contains a total of 179 proteins and genes (nodes) and 19 PPIs (edges). Furthermore, gene ontology (GO) analysis was applied to analyze the main function of the differential expression genes. The categorization of GO biological process was analyzed using the GO project (http://www.geneontology.org).²³ As shown in Table 1, the main GO categories for differential expression genes were signal, secreted, glycoprotein, disulfide bond, cell membrane, hormone, and membrane. According to the Gene Expression data, Htra1, FCGR2b, GPR125, and GPR56 were significant differential expression genes in α2-AR-deficient placentae, indicating the potential relationship of them with α2-AR agonist dexmedetomidine. Therefore, we detected the mRNA levels of Htra1, FCGR2b, GPR125, and GPR56 after dexmedetomidine administration using qRT-PCR. As shown in Figure 3(b), the mRNA level of Htra1 was potently induced by dexmedetomidine in a dose-dependent manner. However, no change was observed in the mRNA levels of FCGR2b, GPR125, and GPR56 even at the maximum dose of dexmedetomidine (100 mg/kg). The results hinted that dexmedetomidine may regulate genes related to signal transduction coupled to 5-HTR.

Figure 3.

Dexmedetomidine regulates genes related to signal transduction coupled to 5-HTR. (a) Protein interaction network of α2-adrenoceptor-regulated genes. (b) Determination of mRNA expression of Htra1, FCGR2b, GPR125, and GPR56 in striatum by qRT-PCR analysis. Various doses of dexmedetomidine (1, 10, and 100 mg/kg) were given to rats, and DMSO was administrated as control group. Total mRNA was extracted from injected striatum. Values are expressed as 2^−ΔΔCt, relative to the levels of the controls, and corrected using β-actin expression. All the results were obtained from six rats in each treatment group. Bar graphs represent the mean ± SEM. *p < 0.05 compared to DMSO-group. ERKs: extracellular signal-regulated protein kinase; DMSO: dimethyl sulfoxide; SEM: standard error of the mean; qRT-PCR: quantitative real-time polymerase chain reaction; 5-HTR: 5-hydroxytryptamine receptor.

Table 1.

Functional classification of α2-AR-regulated genes.

Term	Genes	%	p value	Benjamini
Signal	38	4.5	3.10E−08	4.30E−06
Secreted	20	2.3	7.00E−05	4.90E−03
Glycoprotein	30	3.5	4.70E−03	2.00E−01
Disulfide bond	23	2.7	4.80E−03	1.60E−01
Cell membrane	17	2	1.10E−02	2.70E−01
Hormone	4	0.5	1.40E−02	2.80E−01
Membrane	37	4.3	4.00E−02	5.60E−01

Discussion

The aim of this study was to investigate the underlying mechanism of the α2-AR agonist dexmedetomidine’s neuroprotective effects in vivo rat model. Dexmedetomidine shows neuroprotective effects in several settings of neuronal injury. Multiple evidences have indicated that dexmedetomidine can improve treatment and prognosis in patients with severe brain trauma.^5,6 Besides, cell-protective effect on nervous tissue of dexmedetomidine under ischemic conditions also has been reported.^7,8 Dexmedetomidine attenuates isoflurane-induced injury in the developing brain and shows neurocognitive protection in vivo.²⁴ The neuroprotective effect of dexmedetomidine is mediated both by imidazoline I1-receptor and α2-AR.⁹ It has been reported that the signal transduction cascade linked to these receptors was dependent on ERK1/2,^9,10 which is also known to be an important regulator for cell survival and mediator of neuroprotective effects of various other agents.¹¹ Here, we found that dexmedetomidine administration significantly increased expression of ERK1/2 phosphorylation in dopamine neuron from striatum in a dose-dependent manner, with a dose of 100 mg/kg showing the strongest effect. This finding is consistent with the results from previous studies. Combined with previous research reports, increased ERK1/2 phosphorylation in dopamine neuron, at least in part, participated in neuroprotective effect of dexmedetomidine in striatum. As we know, the striatum is a subcortical part of the forebrain, which integrates inputs from cortex, hippocampus, thalamus, amygdala, and ventral tegmental area/substantia nigra pars compacta to instruct the selection of appropriate motor actions. Furthermore, the striatum also harbors a population of dopamine neurons that play an important role in the initiation, selection, and reinforcement of motor actions and have been closely related to motor, cognitive, and addictive disorders.^12,13 Therefore, our findings will help to provide clues for the underlying mechanism of neuroprotective effects of dexmedetomidine in several settings of neuronal injury such as ischemic stroke and severe brain trauma.

HDACs and HAT control histone acetylation and regulate gene transcription by altering chromatin structure.¹⁴ Multiple studies have indicated that histone acetylation–deacetylation is regulated in adult neurons linked to learning and memory,¹¹ and in response to psychotropic drugs.¹⁵ Besides, HDAC inhibitors also have shown promise as Huntington’s disease¹⁶ and spinal muscular atrophy¹⁷ therapeutics in animal models. Apparently, the acetylation of core histones plays a critical role in gene expression in brain. Our study found that dexmedetomidine increased expression of histones H3 acetylation for the first time. Moreover, using PD098059, the inhibitor of pERK1/2, the acetylation of histones H3 was almost completely blocked, proving that dexmedetomidine-induced histones H3 acetylation in dopamine neuron could be mediated by ERK1/2 signaling pathway. The results of our experiments also indicated that acetylation of histones H3 may be an important factor in the protection of dopamine neuron from striatum by dexmedetomidine.

α2-ARs are crucial presynaptic regulators of norepinephrine release from sympathetic nerves.²⁵ Previous study reported that deletion of the three α2-AR subtypes in the mouse (α2ABC−/−) caused embryonic lethality associated with a severe defect in the development of the extraembryonic vasculature and reduced activity of ERK1/2 in the placenta and yolk sac at embryonic day (E) 10.5.²⁶ Firstly, we used the Gene Expression data to make bioinformatics analyses of PPI map, showing the protein-interaction network associated with α2-AR. Further analysis of the data found that the main GO categories for differential expression genes were signal, secreted, glycoprotein, disulfide bond, cell membrane, hormone, and membrane. Moreover, after dexmedetomidine administration, we verified the mRNA levels of Htra1, FCGR2b, GPR125, and GPR56, the expression of which significantly changed in α2-AR-deficient placentae. No difference was found in the mRNA levels of FCGR2b, GPR125, and GPR56 after various doses of dexmedetomidine administration. Interestingly, the mRNA level of Htra1 was potently induced by dexmedetomidine in a dose-dependent manner. 5-HTRs are neuromodulator or neurotransmitter receptors whose active state can trigger a signal transduction cascade within cells resulting in cell–cell communication. Among 5-HTRs, the Htra1 subtype is best studied and is involved in psychiatric disorders such as anxiety and depression.²⁷ Hence, our results hinted that dexmedetomidine could regulate genes related to signal transduction coupled to 5-HTR.

In conclusion, it is the first report to define dexmedetomidine as a modulator of histones H3 acetylation via ERK1/2 signaling pathway in dopamine neuron from striatum. Furthermore, dexmedetomidine could regulate genes related to signal transduction coupled to 5-HTR. Our report may provide clues for the underlying mechanism of the neuroprotective effects of dexmedetomidine.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Science and Technology Plan Project of Huzhou (2013GYB13).

Supplemental material

The online [appendices] are available at .

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Dexmedetomidine increases acetylation level of histone through ERK1/2 pathway in dopamine neuron