A Role for the Adenosine ADORA2B Receptor in Midazolam Induced Cognitive Dysfunction

Author(s): Jennifer Gile, Yoshimasa Oyama, Sydney Shuff, Tobias Eckle*

Journal Name: Current Pharmaceutical Design

Volume 26 , Issue 34 , 2020


Become EABM
Become Reviewer
Call for Editor

Abstract:

Background: We recently reported a role for the circadian rhythm protein Period 2 (PER2) in midazolam induced cognitive dysfunction. Based on previous studies showing a critical role for the adenosine A2B receptor (ADORA2B) in PER2 regulation, we hypothesized that hippocampal ADORA2B is crucial for cognitive function.

Methods: Midazolam treated C57BL/6J mice were analyzed for Adora2b hippocampal mRNA expression levels, and spontaneous T-maze alternation was determined in Adora2b-/- mice. Using the specific ADORA2B agonist BAY-60-6583 in midazolam treated C57BL/6J mice, we analyzed hippocampal Per2 mRNA expression levels and spontaneous T-maze alternation. Finally, Adora2b-/- mice were assessed for mRNA expression of markers for inflammation or cognitive function in the hippocampus.

Results: Midazolam treatment significantly downregulated Adora2b or Per2 mRNA in the hippocampus of C57BL/6J mice, and hippocampal PER2 protein expression or T-maze alternation was significantly reduced in Adora2b-/- mice. ADORA2B agonist BAY-60-6583 restored midazolam mediated reduction in spontaneous alternation in C57BL/6J mice. Analysis of hippocampal Tnf-α or Il-6 mRNA levels in Adora2b-/- mice did not reveal an inflammatory phenotype. However, C-fos, a critical component of hippocampus-dependent learning and memory, was significantly downregulated in the hippocampus of Adora2b-/- mice.

Conclusion: These results suggest a role of ADORA2B in midazolam induced cognitive dysfunction. Further, our data demonstrate that BAY-60-6583 treatment restores midazolam induced cognitive dysfunction, possibly via increases of Per2. Additional mechanistic studies hint towards C-FOS as another potential underlying mechanism of memory impairment in Adora2b-/- mice. These findings suggest the ADORA2B agonist as a potential therapy in patients with midazolam induced cognitive dysfunction.

Keywords: Adora2b, cognitive function, Per2, T maze, C-fos, Bdnf, delirium, BAY-60-6583.

[1]
Salluh JI, Wang H, Schneider EB, et al. Outcome of delirium in critically ill patients: systematic review and meta-analysis. BMJ 2015; 350: h2538.
[http://dx.doi.org/10.1136/bmj.h2538] [PMID: 26041151]
[2]
Gile J, Scott B, Eckle T. The period 2 enhancer nobiletin as novel therapy in murine models of circadian disruption resembling delirium. Crit Care Med 2018; 46(6): e600-8.
[http://dx.doi.org/10.1097/CCM.0000000000003077] [PMID: 29489460]
[3]
Scott B, Eckle T. The impact of sedation protocols on outcomes in critical illness. Ann Transl Med 2016; 4(2): 33.
[PMID: 26889486]
[4]
Bellapart J, Boots R. Potential use of melatonin in sleep and delirium in the critically ill. Br J Anaesth 2012; 108(4): 572-80.
[http://dx.doi.org/10.1093/bja/aes035] [PMID: 22419624]
[5]
Fitzgerald JM, Adamis D, Trzepacz PT, et al. Delirium: a disturbance of circadian integrity? Med Hypotheses 2013; 81(4): 568-76.
[http://dx.doi.org/10.1016/j.mehy.2013.06.032] [PMID: 23916192]
[6]
Hatta K, Kishi Y, Wada K, et al. DELIRIA-J Group Preventive effects of ramelteon on delirium: A randomized placebo-controlled trial. JAMA Psychiatry 2014; 71(4): 397-403.
[http://dx.doi.org/10.1001/jamapsychiatry.2013.3320] [PMID: 24554232]
[7]
Inouye SK, Westendorp RG, Saczynski JS. Delirium in elderly people. Lancet 2014; 383(9920): 911-22.
[http://dx.doi.org/10.1016/S0140-6736(13)60688-1] [PMID: 23992774]
[8]
Madrid-Navarro CJ, Sanchez-Galvez R, Martinez-Nicolas A, et al. Disruption of circadian rhythms and delirium, sleep impairment and sepsis in critically ill patients. potential therapeutic implications for increased light-dark contrast and melatonin therapy in an ICU environment. Curr Pharm Des 2015; 21(24): 3453-68.
[http://dx.doi.org/10.2174/1381612821666150706105602] [PMID: 26144941]
[9]
Yang J, Choi W, Ko YH, Joe SH, Han C, Kim YK. Bright light therapy as an adjunctive treatment with risperidone in patients with delirium: a randomized, open, parallel group study. Gen Hosp Psychiatry 2012; 34(5): 546-51.
[http://dx.doi.org/10.1016/j.genhosppsych.2012.05.003] [PMID: 22717090]
[10]
Scott BK. Disruption of circadian rhythms and sleep in critical illness and its impact on the development of delirium. Curr Pharm Des 2015; 21(24): 3443-52.
[http://dx.doi.org/10.2174/1381612821666150706110656] [PMID: 26144937]
[11]
Girard TD, Jackson JC, Pandharipande PP, et al. Delirium as a predictor of long-term cognitive impairment in survivors of critical illness. Crit Care Med 2010; 38(7): 1513-20.
[http://dx.doi.org/10.1097/CCM.0b013e3181e47be1] [PMID: 20473145]
[12]
Eckle T, Hartmann K, Bonney S, et al. Adora2b-elicited Per2 stabilization promotes a HIF-dependent metabolic switch crucial for myocardial adaptation to ischemia. Nat Med 2012; 18(5): 774-82.
[http://dx.doi.org/10.1038/nm.2728] [PMID: 22504483]
[13]
Fredholm BB, Chen JF, Cunha RA, Svenningsson P, Vaugeois JM. Adenosine and brain function. Int Rev Neurobiol 2005; 63: 191-270.
[http://dx.doi.org/10.1016/S0074-7742(05)63007-3] [PMID: 15797469]
[14]
Cunha RA, Agostinho PM. Chronic caffeine consumption prevents memory disturbance in different animal models of memory decline. J Alzheimers Dis 2010; 20(Suppl. 1): S95-116.
[http://dx.doi.org/10.3233/JAD-2010-1408] [PMID: 20182043]
[15]
Shen HY, Canas PM, Garcia-Sanz P, et al. A AdenosineA receptors in striatal glutamatergic terminals and GABAergic neurons oppositely modulate psychostimulant action and DARPP-32 phosphorylation. PLoS One 2013; 8(11): e80902.
[http://dx.doi.org/10.1371/journal.pone.0080902] [PMID: 24312250]
[16]
Gonçalves FQ, Pires J, Pliassova A, et al. Adenosine A2b receptors control A1 receptor-mediated inhibition of synaptic transmission in the mouse hippocampus. Eur J Neurosci 2015; 41(7): 878-88.
[http://dx.doi.org/10.1111/ejn.12851] [PMID: 25704806]
[17]
Koeppen M, Harter PN, Bonney S, et al. Adora2b signaling on bone marrow derived cells dampens myocardial ischemia-reperfusion injury. Anesthesiology 2012; 116(6): 1245-57.
[http://dx.doi.org/10.1097/ALN.0b013e318255793c] [PMID: 22531331]
[18]
Eckle T, Krahn T, Grenz A, et al. Cardioprotection by ecto-5′-nucleotidase (CD73) and A2B adenosine receptors. Circulation 2007; 115(12): 1581-90.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.106.669697] [PMID: 17353435]
[19]
Eckle T, Faigle M, Grenz A, Laucher S, Thompson LF, Eltzschig HK. A2B adenosine receptor dampens hypoxia-induced vascular leak. Blood 2008; 111(4): 2024-35.
[http://dx.doi.org/10.1182/blood-2007-10-117044] [PMID: 18056839]
[20]
Eckle T, Grenz A, Laucher S, Eltzschig HK. A2B adenosine receptor signaling attenuates acute lung injury by enhancing alveolar fluid clearance in mice. J Clin Invest 2008; 118(10): 3301-15.
[http://dx.doi.org/10.1172/JCI34203] [PMID: 18787641]
[21]
Hart ML, Jacobi B, Schittenhelm J, Henn M, Eltzschig HK. Cutting Edge: A2B Adenosine receptor signaling provides potent protection during intestinal ischemia/reperfusion injury. J Immunol 2009; 182(7): 3965-8.
[http://dx.doi.org/10.4049/jimmunol.0802193] [PMID: 19299692]
[22]
Schingnitz U, Hartmann K, Macmanus CF, et al. Signaling through the A2B adenosine receptor dampens endotoxin-induced acute lung injury. J Immunol 2010; 184(9): 5271-9.
[http://dx.doi.org/10.4049/jimmunol.0903035] [PMID: 20348420]
[23]
Bonney S, Kominsky D, Brodsky K, Eltzschig H, Walker L, Eckle T. Cardiac Per2 functions as novel link between fatty acid metabolism and myocardial inflammation during ischemia and reperfusion injury of the heart. PLoS One 2013; 8(8): e71493.
[http://dx.doi.org/10.1371/journal.pone.0071493] [PMID: 23977055]
[24]
Seo SW, Koeppen M, Bonney S, et al. Differential tissue-specific function of Adora2b in cardioprotection. J Immunol 2015; 195(4): 1732-43.
[http://dx.doi.org/10.4049/jimmunol.1402288] [PMID: 26136425]
[25]
Oyama Y, Bartman CM, Bonney S, et al. Intense light-mediated circadian cardioprotection via transcriptional reprogramming of the endothelium. J Cell Rep 2019; 28: 1471-84.e11.
[http://dx.doi.org/10.1016/j.celrep.2019.07.020]
[26]
Oyama Y, Bartman CM, Gile J, Sehrt D, Eckle T. The circadian PER2 enhancer Nobiletin reverses the deleterious effects of midazolam in myocardial ischemia and reperfusion injury. Curr Pharm Des 2018; 24(28): 3376-83.
[http://dx.doi.org/10.2174/1381612824666180924102530] [PMID: 30246635]
[27]
Koeppen M, Lee JW, Seo SW, et al. Hypoxia-inducible factor 2-alpha-dependent induction of amphiregulin dampens myocardial ischemia-reperfusion injury. Nat Commun 2018; 9(1): 816.
[http://dx.doi.org/10.1038/s41467-018-03105-2] [PMID: 29483579]
[28]
Bartman CM, Oyama Y, Brodsky K, et al. Intense light-elicited upregulation of miR-21 facilitates glycolysis and cardioprotection through Per2-dependent mechanisms. PLoS One 2017; 12(4): e0176243.
[http://dx.doi.org/10.1371/journal.pone.0176243] [PMID: 28448534]
[29]
Eckle T, Kewley EM, Brodsky KS, et al. Identification of hypoxia-inducible factor HIF-1A as transcriptional regulator of the A2B adenosine receptor during acute lung injury. J Immunol 2014; 192(3): 1249-56.
[http://dx.doi.org/10.4049/jimmunol.1100593] [PMID: 24391213]
[30]
Eckle T, Hughes K, Ehrentraut H, et al. Crosstalk between the equilibrative nucleoside transporter ENT2 and alveolar Adora2b adenosine receptors dampens acute lung injury. FASEB J 2013; 27(8): 3078-89.
[http://dx.doi.org/10.1096/fj.13-228551] [PMID: 23603835]
[31]
Eckle T, Brodsky K, Bonney M, et al. HIF1A reduces acute lung injury by optimizing carbohydrate metabolism in the alveolar epithelium. PLoS Biol 2013; 11(9): e1001665.
[http://dx.doi.org/10.1371/journal.pbio.1001665] [PMID: 24086109]
[32]
Frank A, Bonney M, Bonney S, Weitzel L, Koeppen M, Eckle T. Myocardial ischemia reperfusion injury: From basic science to clinical bedside. Semin Cardiothorac Vasc Anesth 2012; 16(3): 123-32.
[http://dx.doi.org/10.1177/1089253211436350] [PMID: 22368166]
[33]
Deacon RM, Rawlins JN. T-maze alternation in the rodent. Nat Protoc 2006; 1(1): 7-12.
[http://dx.doi.org/10.1038/nprot.2006.2] [PMID: 17406205]
[34]
Griffin EW, Skelly DT, Murray CL, Cunningham C. Cyclooxygenase-1-dependent prostaglandins mediate susceptibility to systemic inflammation-induced acute cognitive dysfunction. J Neurosci 2013; 33(38): 15248-58.
[http://dx.doi.org/10.1523/JNEUROSCI.6361-11.2013] [PMID: 24048854]
[35]
LeSauter J, Lambert CM, Robotham MR, Model Z, Silver R, Weaver DR. Antibodies for assessing circadian clock proteins in the rodent suprachiasmatic nucleus. PLoS One 2012; 7(4): e35938.
[http://dx.doi.org/10.1371/journal.pone.0035938] [PMID: 22558277]
[36]
Yang D, Zhang Y, Nguyen HG, et al. The A2B adenosine receptor protects against inflammation and excessive vascular adhesion. J Clin Invest 2006; 116(7): 1913-23.
[http://dx.doi.org/10.1172/JCI27933] [PMID: 16823489]
[37]
Aherne CM, Kewley EM, Eltzschig HK. The resurgence of A2B adenosine receptor signaling. Biochim Biophys Acta 2011; 1808(5): 1329-39.
[http://dx.doi.org/10.1016/j.bbamem.2010.05.016] [PMID: 20546702]
[38]
Eltzschig HK, Bonney SK, Eckle T. Attenuating myocardial ischemia by targeting A2B adenosine receptors. Trends Mol Med 2013; 19(6): 345-54.
[http://dx.doi.org/10.1016/j.molmed.2013.02.005] [PMID: 23540714]
[39]
Gile J, Eckle T. ADORA2b Signaling in Cardioprotection. J Nat Sci 2016; 2(10): 2.
[PMID: 27747290]
[40]
Grenz A, Osswald H, Eckle T, et al. The reno-vascular A2B adenosine receptor protects the kidney from ischemia. PLoS Med 2008; 5(6): e137.
[http://dx.doi.org/10.1371/journal.pmed.0050137] [PMID: 18578565]
[41]
Koeppen M, Eckle T, Eltzschig HK. Interplay of hypoxia and A2B adenosine receptors in tissue protection. Adv Pharmacol 2011; 61: 145-86.
[http://dx.doi.org/10.1016/B978-0-12-385526-8.00006-0] [PMID: 21586359]
[42]
O’Neill JS, Maywood ES, Chesham JE, Takahashi JS, Hastings MH. cAMP-dependent signaling as a core component of the mammalian circadian pacemaker. Science 2008; 320(5878): 949-53.
[http://dx.doi.org/10.1126/science.1152506] [PMID: 18487196]
[43]
Ripperger JA, Albrecht U. The circadian clock component PERIOD2: from molecular to cerebral functions Prog Brain Res 2012; 199: 233-45.
[http://dx.doi.org/10.1016/B978-0-444-59427-3.00014-9] [PMID: 22877669]
[44]
Wang LM, Dragich JM, Kudo T, et al. Expression of the circadian clock gene period2 in the hippocampus: Possible implications for synaptic plasticity and learned behaviour. ASN Neuro 2009; 1(3): 1.
[http://dx.doi.org/10.1042/AN20090020] [PMID: 19570032]
[45]
Maldonado JR. Pathoetiological model of delirium: a comprehensive understanding of the neurobiology of delirium and an evidence-based approach to prevention and treatment Crit Care Clin 2008; 24(4): 789-856, ix.
[http://dx.doi.org/10.1016/j.ccc.2008.06.004] [PMID: 18929943]
[46]
Xu Y, Toh KL, Jones CR, Shin JY, Fu YH, Ptácek LJ. Modeling of a human circadian mutation yields insights into clock regulation by PER2. Cell 2007; 128(1): 59-70.
[http://dx.doi.org/10.1016/j.cell.2006.11.043] [PMID: 17218255]
[47]
Kamdar BB, Needham DM, Collop NA. Sleep deprivation in critical illness: Its role in physical and psychological recovery. J Intensive Care Med 2012; 27(2): 97-111.
[http://dx.doi.org/10.1177/0885066610394322] [PMID: 21220271]
[48]
Fujioka A, Fujioka T, Tsuruta R, Izumi T, Kasaoka S, Maekawa T. Effects of a constant light environment on hippocampal neurogenesis and memory in mice. Neurosci Lett 2011; 488(1): 41-4.
[http://dx.doi.org/10.1016/j.neulet.2010.11.001] [PMID: 21056622]
[49]
Ralph MR, Menaker M. GABA regulation of circadian responses to light. I. Involvement of GABAA-benzodiazepine and GABAB receptors. J Neurosci 1989; 9(8): 2858-65.
[http://dx.doi.org/10.1523/JNEUROSCI.09-08-02858.1989] [PMID: 2549220]
[50]
Kim M, de la Peña JB, Cheong JH, Kim HJ. Neurobiological Functions of the Period Circadian Clock 2 Gene, Per2. Biomol Ther (Seoul) 2018; 26(4): 358-67.
[http://dx.doi.org/10.4062/biomolther.2017.131] [PMID: 29223143]
[51]
Ehlen JC, Novak CM, Karom MC, Gamble KL, Paul KN, Albers HE. GABAA receptor activation suppresses Period 1 mRNA and Period 2 mRNA in the suprachiasmatic nucleus during the mid-subjective day. Eur J Neurosci 2006; 23(12): 3328-36.
[http://dx.doi.org/10.1111/j.1460-9568.2006.04857.x] [PMID: 16820022]
[52]
Matsuo I, Iijima N, Takumi K, et al. Characterization of sevoflurane effects on Per2 expression using ex vivo bioluminescence imaging of the suprachiasmatic nucleus in transgenic rats. Neurosci Res 2016; 107: 30-7.
[http://dx.doi.org/10.1016/j.neures.2015.11.010] [PMID: 26696094]
[53]
Novak CM, Ehlen JC, Paul KN, Fukuhara C, Albers HE. Light and GABA)(A) receptor activation alter period mRNA levels in the SCN of diurnal Nile grass rats. Eur J Neurosci 2006; 24(10): 2843-52.
[http://dx.doi.org/10.1111/j.1460-9568.2006.05166.x] [PMID: 17156208]
[54]
Aton SJ, Huettner JE, Straume M, Herzog ED. GABA and Gi/o differentially control circadian rhythms and synchrony in clock neurons. Proc Natl Acad Sci USA 2006; 103(50): 19188-93.
[http://dx.doi.org/10.1073/pnas.0607466103] [PMID: 17138670]
[55]
Brainard J, Gobel M, Scott B, Koeppen M, Eckle T. Health implications of disrupted circadian rhythms and the potential for daylight as therapy. Anesthesiology 2015; 122(5): 1170-5.
[http://dx.doi.org/10.1097/ALN.0000000000000596] [PMID: 25635592]
[56]
Smith HAB, Gangopadhyay M, Goben CM, et al. Delirium and benzodiazepines associated with prolonged ICU stay in critically ill infants and young children. Crit Care Med 2017; 45(9): 1427-35.
[http://dx.doi.org/10.1097/CCM.0000000000002515] [PMID: 28594681]
[57]
Valero J, Mastrella G, Neiva I, Sánchez S, Malva JO. Long-term effects of an acute and systemic administration of LPS on adult neurogenesis and spatial memory. Front Neurosci 2014; 8: 83.
[http://dx.doi.org/10.3389/fnins.2014.00083] [PMID: 24795557]
[58]
Hoogland IC, Houbolt C, van Westerloo DJ, van Gool WA, van de Beek D. Systemic inflammation and microglial activation: systematic review of animal experiments. J Neuroinflammation 2015; 12: 114.
[http://dx.doi.org/10.1186/s12974-015-0332-6] [PMID: 26048578]
[59]
Ming Z, Sawicki G, Bekar LK. Acute systemic LPS-mediated inflammation induces lasting changes in mouse cortical neuromodulation and behavior. Neurosci Lett 2015; 590: 96-100.
[http://dx.doi.org/10.1016/j.neulet.2015.01.081] [PMID: 25650524]
[60]
Alonso M, Vianna MR, Depino AM, et al. BDNF-triggered events in the rat hippocampus are required for both short- and long-term memory formation. Hippocampus 2002; 12(4): 551-60.
[http://dx.doi.org/10.1002/hipo.10035] [PMID: 12201640]
[61]
Leal G, Bramham CR, Duarte CB. BDNF and hippocampal synaptic plasticity. Vitam Horm 2017; 104: 153-95.
[http://dx.doi.org/10.1016/bs.vh.2016.10.004] [PMID: 28215294]
[62]
Fleischmann A, Hvalby O, Jensen V, et al. Impaired long-term memory and NR2A-type NMDA receptor-dependent synaptic plasticity in mice lacking c-Fos in the CNS. J Neurosci 2003; 23(27): 9116-22.
[http://dx.doi.org/10.1523/JNEUROSCI.23-27-09116.2003] [PMID: 14534245]
[63]
An JJ, Gharami K, Liao GY, et al. Distinct role of long 3′ UTR BDNF mRNA in spine morphology and synaptic plasticity in hippocampal neurons. Cell 2008; 134(1): 175-87.
[http://dx.doi.org/10.1016/j.cell.2008.05.045] [PMID: 18614020]
[64]
Vann SD, Brown MW, Erichsen JT, Aggleton JP. Fos imaging reveals differential patterns of hippocampal and parahippocampal subfield activation in rats in response to different spatial memory tests. J Neurosci 2000; 20(7): 2711-8.
[http://dx.doi.org/10.1523/JNEUROSCI.20-07-02711.2000] [PMID: 10729352]
[65]
He J, Yamada K, Nabeshima T. A role of Fos expression in the CA3 region of the hippocampus in spatial memory formation in rats. Neuropsychopharmacology 2002; 26(2): 259-68.
[http://dx.doi.org/10.1016/S0893-133X(01)00332-3] [PMID: 11790521]
[66]
Gandolfi D, Cerri S, Mapelli J, et al. Activation of the CREB/c-Fos pathway during long-term synaptic plasticity in the cerebellum granular layer. Front Cell Neurosci 2017; 11: 184.
[http://dx.doi.org/10.3389/fncel.2017.00184] [PMID: 28701927]
[67]
Porterfield VM, Piontkivska H, Mintz EM. Identification of novel light-induced genes in the suprachiasmatic nucleus. BMC Neurosci 2007; 8: 98.
[http://dx.doi.org/10.1186/1471-2202-8-98] [PMID: 18021443]
[68]
Shearman LP, Weaver DR. Photic induction of Period gene expression is reduced in Clock mutant mice. Neuroreport 1999; 10(3): 613-8.
[http://dx.doi.org/10.1097/00001756-199902250-00031] [PMID: 10208599]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 26
ISSUE: 34
Year: 2020
Published on: 12 October, 2020
Page: [4330 - 4337]
Pages: 8
DOI: 10.2174/1381612826666200415171622
Price: $65

Article Metrics

PDF: 18
HTML: 2