Abstract
Obstructive sleep apnea (OSA) is closely associated with central nervous system diseases and could lead to autonomic nerve dysfunction, which is often seen in neurodegenerative diseases. Previous studies have shown that metoprolol prevents several chronic OSA-induced cardiovascular diseases through inhibiting autonomic nerve hyperactivity. It remains unclear whether chronic OSA can lead to dendritic remodeling in the brain, and whether metoprolol affects the dendritic remodeling. In this study we investigated the effect of metoprolol on dendrite morphology in a canine model of chronic OSA, which was established in beagles through clamping and reopening the endotracheal tube for 4 h every other day for 12 weeks. OSA beagles were administered metoprolol (5 mg· kg−1· d−1). The dendritic number, length, crossings and spine density of neurons in hippocampi and prefrontal cortices were assessed by Golgi staining. And the protein levels of hypoxia-inducible factor-1α (HIF-1α) and brain-derived neurotrophic factor (BDNF) were measured by Western blotting. We showed that chronic OSA successfully induced significant brain hypoxia evidenced by increased HIF-1α levels in CA1 region and dentate gyrus of hippocampi, as well as in prefrontal cortex. Furthermore, OSA led to markedly decreased dendrite number, length and intersections, spine loss as well as reduced BDNF levels. Administration of metoprolol effectively prevented the dendritic remodeling and spine loss induced by chronic OSA. In addition, administration of metoprolol reversed the decreased BDNF, which might be associated with the metoprolol-induced neuronal protection. In conclusion, metoprolol protects against neuronal dendritic remodeling in hippocampi and prefrontal cortices induced by chronic OSA in canine.
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References
Young T, Skatrud J, Peppard PE. Risk factors for obstructive sleep apnea in adults. JAMA. 2004;291:2013–6.
Jordan AS, McSharry DG, Malhotra A. Adult obstructive sleep apnoea. Lancet. 2014;383:736–47.
Sarkar P, Mukherjee S, Chai-Coetzer CL, McEvoy RD. The epidemiology of obstructive sleep apnoea and cardiovascular disease. J Thorac Dis. 2018;10:S4189–200.
Torres G, Sanchez-de-la-Torre M, Barbe F. Relationship between OSA and hypertension. Chest. 2015;148:824–32.
Patel N, Donahue C, Shenoy A, Patel A, El-Sherif N. Obstructive sleep apnea and arrhythmia: a systemic review. Int J Cardiol. 2017;228:967–70.
Khattak HK, Hayat F, Pamboukian SV, Hahn HS, Schwartz BP, Stein PK. Obstructive sleep apnea in heart failure: review of prevalence, treatment with continuous positive airway pressure, and prognosis. Tex Heart Inst J. 2018;45:151–61.
Glantz H, Thunstrom E, Johansson MC, Wallentin Guron C, Uzel H, et al. Obstructive sleep apnea is independently associated with worse diastolic function in coronary artery disease. Sleep Med. 2015;16:160–7.
Ryan CM, Battisti-Charbonney A, Sobczyk O, Mikulis DJ, Duffin J, Fisher JA, et al. Evaluation of cerebrovascular reactivity in subjects with and without obstructive sleep apnea. J Stroke Cerebrovasc Dis. 2018;27:162–8.
Gagnon K, Baril AA, Montplaisir J, Carrier J, Chami S, Gauthier S, et al. Detection of mild cognitive impairment in middle-aged and older adults with obstructive sleep apnoea. Eur Respir J. 2018;52:1801137.
Liguori C, Mercuri NB, Izzi F, Romigi A, Cordella A, Sancesario G, et al. Obstructive sleep apnea is associated with early but possibly modifiable Alzheimer’s disease biomarkers changes. Sleep. 2017;40:zsx011. https://doi.org/10.1093/sleep/zsx011.
Quaranta VN, Carratu P, Damiani MF, Dragonieri S, Capozzolo A, Cassano A, et al. The prognostic role of obstructive sleep apnea at the onset of amyotrophic lateral sclerosis. Neurodegener Dis. 2017;17:14–21.
Saunamaki T, Jehkonen M. Depression and anxiety in obstructive sleep apnea syndrome: a review. Acta Neurol Scand. 2007;116:277–88.
Oyama F, Miyazaki H, Sakamoto N, Becquet C, Machida Y, Kaneko K, et al. Sodium channel beta4 subunit: down-regulation and possible involvement in neuritic degeneration in Huntington’s disease transgenic mice. J Neurochem. 2006;98:518–29.
Spires-Jones T, Knafo S. Spines, plasticity, and cognition in Alzheimer’s model mice. Neural Plast. 2012;2012:319836.
Fogarty MJ, Mu EW, Noakes PG, Lavidis NA, Bellingham MC. Marked changes in dendritic structure and spine density precede significant neuronal death in vulnerable cortical pyramidal neuron populations in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Acta Neuropathol Commun. 2016;4:77. https://doi.org/10.1186/s40478-016-0347-y.
Csabai D, Wiborg O, Czeh B. Reduced synapse and axon numbers in the prefrontal cortex of rats subjected to a chronic stress model for depression. Front Cell Neurosci. 2018;12:24. https://doi.org/10.3389/fncel.2018.00024.
Davis EM, O’Donnell CP. Rodent models of sleep apnea. Respir Physiol Neurobiol. 2013;188:355–61.
Kheirandish L, Gozal D, Pequignot JM, Pequignot J, Row BW. Intermittent hypoxia during development induces long-term alterations in spatial working memory, monoamines, and dendritic branching in rat frontal cortex. Pediatr Res. 2005;58:594–9.
Xu LH, Xie H, Shi ZH, Du LD, Wing YK, Li AM, et al. Critical role of endoplasmic reticulum stress in chronic intermittent hypoxia-induced deficits in synaptic plasticity and long-term memory. Antioxid Redox Signal. 2015;23:695–710.
Toth LA, Bhargava P. Animal models of sleep disorders. Comp Med. 2013;63:91–104.
Kimoff RJ, Makino H, Horner RL, Kozar LF, Lue F, Slutsky AS, et al. Canine model of obstructive sleep apnea: model description and preliminary application. J Appl Physiol (1985). 1994;76:1810–7.
Tobaldini E, Costantino G, Solbiati M, Cogliati C, Kara T, Nobili L, et al. Sleep, sleep deprivation, autonomic nervous system and cardiovascular diseases. Neurosci Biobehav Rev. 2017;74:321–9.
Zhao J, Xu W, Yun F, Zhao H, Li W, Gong Y, et al. Chronic obstructive sleep apnea causes atrial remodeling in canines: mechanisms and implications. Basic Res Cardiol. 2014;109:427.
Haj Kheder S, Heller J, Bar JK, Wutzler A, Menge BA, Juckel G. Autonomic dysfunction of gastric motility in major depression. J Affect Disord. 2018;226:196–202.
Femminella GD, Rengo G, Komici K, Iacotucci P, Petraglia L, Pagano G, et al. Autonomic dysfunction in Alzheimer’s disease: tools for assessment and review of the literature. J Alzheimers Dis. 2014;42:369–77.
Palma JA, Kaufmann H. Autonomic disorders predicting Parkinson’s disease. Parkinsonism Relat Disord. 2014;20(Suppl 1):S94–8.
Sun L, Yan S, Wang X, Zhao S, Li H, Wang Y, et al. Metoprolol prevents chronic obstructive sleep apnea-induced atrial fibrillation by inhibiting structural, sympathetic nervous and metabolic remodeling of the atria. Sci Rep. 2017;7:14941.
Li W, Yan S, Zhao J, Ding X, Zhang S, Wang D, et al. Metoprolol inhibits cardiac apoptosis and fibrosis in a canine model of chronic obstructive sleep apnea. Cell Physiol Biochem. 2015;36:1131–41.
Dai H, Yuan Y, Yin S, Zhang Y, Han Y, Sun L, et al. Metoprolol inhibits profibrotic remodeling of epicardial adipose tissue in a canine model of chronic obstructive sleep apnea. J Am Heart Assoc. 2019;8:e011155.
Coenen VA, Gielen FL, Castro-Prado F, Abdel Rahman A, Honey CR. Noradrenergic modulation of subthalamic nucleus activity in human: metoprolol reduces spiking activity in microelectrode recordings during deep brain stimulation surgery for Parkinson’s disease. Acta Neurochir (Wien). 2008;150:757–62. discussion 762.
Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm. 2016;7:27–31.
Ke Q, Costa M. Hypoxia-inducible factor-1 (HIF-1). Mol Pharmacol. 2006;70:1469–80.
Hausser M, Spruston N, Stuart GJ. Diversity and dynamics of dendritic signaling. Science. 2000;290:739–44.
Chen X, Jiang XM, Zhao LJ, Sun LL, Yan ML, Tian Y, et al. MicroRNA-195 prevents dendritic degeneration and neuron death in rats following chronic brain hypoperfusion. Cell Death Dis. 2017;8:e2850.
Jiang X, Chai GS, Wang ZH, Hu Y, Li XG, Ma ZW, et al. CaMKII-dependent dendrite ramification and spine generation promote spatial training-induced memory improvement in a rat model of sporadic Alzheimer’s disease. Neurobiol Aging. 2015;36:867–76.
Wu YK, Fujishima K, Kengaku M. Differentiation of apical and basal dendrites in pyramidal cells and granule cells in dissociated hippocampal cultures. PLoS One. 2015;10:e0118482.
Linz D, Schotten U, Neuberger HR, Bohm M, Wirth K. Negative tracheal pressure during obstructive respiratory events promotes atrial fibrillation by vagal activation. Heart Rhythm. 2011;8:1436–43.
Shi J, Yuan Y, Deng X, Pan Y, He M, Liu G, et al. Metoprolol has a similar therapeutic effect as amlodipine on BP lowering in hypertensive patients with obstructive sleep apnea. Sleep Breath 2019;23:227–33.
Alkadhi KA. Cellular and molecular differences between area CA1 and the dentate gyrus of the hippocampus. Mol Neurobiol. 2019;56:6566–80.
Kubota Y, Karube F, Nomura M, Kawaguchi Y. The diversity of cortical inhibitory synapses. Front Neural Circuits. 2016;10:27. https://doi.org/10.3389/fncir.2016.00027.
Brown SM, Henning S, Wellman CL. Mild, short-term stress alters dendritic morphology in rat medial prefrontal cortex. Cereb Cortex. 2005;15:1714–22.
Liston C, Miller MM, Goldwater DS, Radley JJ, Rocher AB, Hof PR, et al. Stress-induced alterations in prefrontal cortical dendritic morphology predict selective impairments in perceptual attentional set-shifting. J Neurosci. 2006;26:7870–4.
Radley JJ, Rocher AB, Miller M, Janssen WG, Liston C, Hof PR, et al. Repeated stress induces dendritic spine loss in the rat medial prefrontal cortex. Cereb Cortex. 2006;16:313–20.
Li WY, Chang YC, Lee LJ, Lee LJ. Prenatal infection affects the neuronal architecture and cognitive function in adult mice. Dev Neurosci. 2014;36:359–70.
Berry KP, Nedivi E. Spine dynamics: are they all the same? Neuron. 2017;96:43–55.
Leal G, Afonso PM, Salazar IL, Duarte CB. Regulation of hippocampal synaptic plasticity by BDNF. Brain Res. 2015;1621:82–101.
Chan JP, Cordeira J, Calderon GA, Iyer LK, Rios M. Depletion of central BDNF in mice impedes terminal differentiation of new granule neurons in the adult hippocampus. Mol Cell Neurosci. 2008;39:372–83.
Miranda M, Morici JF, Zanoni MB, Bekinschtein P. Brain-derived neurotrophic factor: a key molecule for memory in the healthy and the pathological brain. Front Cell Neurosci. 2019;13:363.
Sidorova YA, Volcho KP, Salakhutdinov NF. Neuroregeneration in Parkinson’s disease: from proteins to small molecules. Curr Neuropharmacol. 2019;17:268–87.
Lam CS, Li JJ, Tipoe GL, Youdim MBH, Fung ML. Monoamine oxidase A upregulated by chronic intermittent hypoxia activates indoleamine 2,3-dioxygenase and neurodegeneration. PLoS One. 2017;12:e0177940.
Raman L, Hamilton KL, Gewirtz JC, Rao R. Effects of chronic hypoxia in developing rats on dendritic morphology of the CA1 subarea of the hippocampus and on fear-potentiated startle. Brain Res. 2008;1190:167–74.
Wallace MG, Hartle KD, Snow WM, Ward NL, Ivanco TL. Effect of hypoxia on the morphology of mouse striatal neurons. Neuroscience. 2007;147:90–6.
Yu L, Li X, Huang B, Zhou X, Wang M, Zhou L, et al. Atrial fibrillation in acute obstructive sleep apnea: autonomic nervous mechanism and modulation. J Am Heart Assoc. 2017;6:e006264.
Tavosanis G. Dendritic structural plasticity. Dev Neurobiol. 2012;72:73–86.
Charych EI, Akum BF, Goldberg JS, Jornsten RJ, Rongo C, Zheng JQ, et al. Activity-independent regulation of dendrite patterning by postsynaptic density protein PSD-95. J Neurosci. 2006;26:10164–76.
von Bohlen Und Halbach O, von Bohlen Und Halbach V. BDNF effects on dendritic spine morphology and hippocampal function. Cell Tissue Res. 2018;373:729–41.
Ying X, Tu W, Li S, Wu Q, Chen X, Zhou Y, et al. Hyperbaric oxygen therapy reduces apoptosis and dendritic/synaptic degeneration via the BDNF/TrkB signaling pathways in SCI rats. Life Sci. 2019;229:187–99.
Lin TW, Shih YH, Chen SJ, Lien CH, Chang CY, Huang TY, et al. Running exercise delays neurodegeneration in amygdala and hippocampus of Alzheimer’s disease (APP/PS1) transgenic mice. Neurobiol Learn Mem. 2015;118:189–97.
Baloyannis SJ, Mavroudis I, Mitilineos D, Baloyannis IS, Costa VG. The hypothalamus in Alzheimer’s disease: a Golgi and electron microscope study. Am J Alzheimers Dis Other Demen. 2015;30:478–87.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (81870849 and 81671052) and the Key project of the Natural Science Foundation of Heilongjiang province (ZD2018004) to J.A.
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JA and YL designed the study. LY, JZ, YQ, QS, TTL, LMY, JMD, XKL, RYW, YSH and SZ performed experiments and analyzed the data. LY wrote the manuscript. All authors discussed the results.
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Yang, L., Zhao, J., Qu, Y. et al. Metoprolol prevents neuronal dendrite remodeling in a canine model of chronic obstructive sleep apnea. Acta Pharmacol Sin 41, 620–628 (2020). https://doi.org/10.1038/s41401-019-0323-8
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DOI: https://doi.org/10.1038/s41401-019-0323-8
