Sauerstoffmangel im Gehirn: Perfusion und Verfügbarkeit von A₁-Adenosinrezeptoren

Zusammenfassung

In Nagern wurde beobachtet, dass der Neuromodulator Adenosin während Hypoxie im Gehirn freigesetzt wird und es vor Sauerstoffmangel und Überlastung schützt, indem Blutfluss, Stoffwechsel und elektrische Aktivität angepasst werden. An 10 Probanden wurde geprüft, ob durch Hypoxie – einem Sauerstoffpartialdruck auf 5500 m entsprechend – die Verfügbarkeit von A1-Adenosinrezeptoren (A₁AR) im menschlichen Gehirn entsprechend reduziert wird. Akute normobare Hypoxie führte im Gehirn zu einer Reduktion der A₁AR-Verfügbarkeit, während sich die Perfusion und die Herzfrequenz erhöhten und sich die Reaktionsgeschwindigkeit verringerte. Unseres Wissens sind wir die erste Studie, die beim Menschen eine Verringerung der A₁AR-Verfügbarkeit unter Hypoxie nachgewiesen hat. Die so reduzierte neuronale Aktivität bei gleichzeitig erhöhter Durchblutung wirken gemeinsam dem verringerten Sauerstoffangebot entgegen und könnte für zukünftige Gegenmaßnahmen eingesetzt werden.

Abstract

In animal studies, it has been observed that the neuromodulator adenosine is released into the interstitial space of the brain during hypoxia and protects the brain from oxygen deficiency and overexertion by adjusting cerebral blood flow, metabolism and electrical activity. This study exposed 10 subjects to an interval of 30-min hypoxia equivalent to the partial pressure of oxygen at about 5500 m. This resulted in a significant reduction in A1 adenosine receptor (A1AR) availability in the human brain, a significant increase in heart rate, and a significant slowing of reaction speed. This is to our knowledge the first demonstration in humans that acute hypoxia reduces A1AR availability in the brain. This result supports the hypothesis that hypoxia-induced adenosine release leads to increased occupancy of the A1AR and can thus pave the way for future countermeasures.

Schlüsselwörter

Hypoxie - A₁AR - [¹⁸ F]CPFPX - PET - ASL

Key words

hypoxia - A₁AR - [¹⁸ F]CPFPX - PET - ASL

• Literatur

• 1 Lazarus M, Chen JF, Huang ZL. et al. Adenosine and Sleep. Handb Exp Pharmacol 2019; 253: 359-381
• 2 Dunwiddie TV, Masino SA. The role and regulation of adenosine in the central nervous system. Annu Rev Neurosci 2001; 24: 31-55
• 3 Fredholm BB, Chen JF, Cunha RA. et al. Adenosine and brain function. Int Rev Neurobiol 2005; 63: 191-270
• 4 Ribeiro JA, Sebastiao AM, de Mendonca A. Adenosine receptors in the nervous system: pathophysiological implications. Prog Neurobiol 2002; 68: 377-392
• 5 Zetterstrom T, Vernet L, Ungerstedt U. et al. Purine levels in the intact rat brain. Studies with an implanted perfused hollow fibre. Neurosci Lett 1982; 29: 111-115
• 6 Phillis JW, O’Regan MH, Perkins LM. Adenosine 5’-triphosphate release from the normoxic and hypoxic in vivo rat cerebral cortex. Neurosci Lett 1993; 151: 94-96
• 7 Chu S, Xiong W, Zhang D. et al. Regulation of adenosine levels during cerebral ischemia. Acta Pharmacol Sin 2013; 34: 60-66
• 8 Elmenhorst D, Garibotto V, Prescher A. et al. Adenosine A1 receptors in human brain and transfected CHO cells: Inhibition of [3 H]CPFPX binding by adenosine and caffeine. Neurosci Lett 2011; 487: 415-420
• 9 Joyce W, Wang T. Regulation of heart rate in vertebrates during hypoxia: A comparative overview. Acta Physiol (Oxf) 2022; 234: e13779
• 10 Benderoth S, Hörmann HJ, Schießl C. et al. Reliability and validity of a 3-min psychomotor vigilance task in assessing sensitivity to sleep loss and alcohol: fitness for duty in aviation and transportation. Sleep 2021; 44: zsab151
• 11 Mirna M, Bimpong-Buta NY, Hoffmann F. et al. Exposure to acute normobaric hypoxia results in adaptions of both the macro- and microcirculatory system. Sci Rep 2020; 10: 20938
• 12 Delso G, Furst S, Jakoby B. et al. Performance measurements of the Siemens mMR integrated whole-body PET/MR scanner. J Nucl Med 2011; 52: 1914-1922
• 13 Elmenhorst D, Elmenhorst EM, Hennecke E. et al. Recovery sleep after extended wakefulness restores elevated A(1) adenosine receptor availability in the human brain. Proc Natl Acad Sci U S A 2017; 114: 4243-4248
• 14 Elmenhorst EM, Elmenhorst D, Benderoth S. et al. Cognitive impairments by alcohol and sleep deprivation indicate trait characteristics and a potential role for adenosine A1 receptors. Proc Natl Acad Sci U S A 2018; 115: 8009-8014
• 15 Bauer A, Holschbach MH, Cremer M. et al. Evaluation of 18F-CPFPX, a novel adenosine A1 receptor ligand: in vitro autoradiography and high-resolution small animal PET. J Nucl Med 2003; 44: 1682-1689
• 16 Elmenhorst D, Meyer PT, Matusch A. et al. Caffeine occupancy of human cerebral A₁ adenosine receptors: in vivo quantification with 18F-CPFPX and PET. J Nucl Med 2012; 53: 1723-1729
• 17 Lassen NA, Iida H, Kanno I. Parametric imaging in nuclear medicine. Ann Nucl Med 1995; 9: 167-170
• 18 Cunningham VJ, Rabiner EA, Slifstein M. et al. Measuring drug occupancy in the absence of a reference region: the Lassen plot re-visited. J Cereb Blood Flow Metab 2010; 30: 46-50
• 19 Urry E, Landolt HP. Adenosine, caffeine, and performance: from cognitive neuroscience of sleep to sleep pharmacogenetics. Curr Top Behav Neurosci 2015; 25: 331-366
• 20 Leung K. 8-Cyclopentyl-3-(3-[(18)F]fluoropropyl)-1-propylxanthine. In: Molecular Imaging and Contrast Agent Database (MICAD). Bethesda (MD): National Center for Biotechnology Information (US); 2004
• 21 Lassen NA, Bartenstein PA, Lammertsma AA. et al. Benzodiazepine Receptor Quantification in vivo in Humans Using [11 C]Flumazenil and PET: Application of the Steady-State Principle. J Cereb Blood Flow Metab 1995; 15: 152-165
• 22 Calabresi P, Pisani A, Mercuri NB. et al. On the mechanisms underlying hypoxia-induced membrane depolarization in striatal neurons. Brain 1995; 118 Pt 4 1027-1038
• 23 Miguel PM, Silveira PP. Neonatal Hypoxia Ischemia and Individual Differences in Neurodevelopmental Outcomes. JAMA Pediatr 2020; 174: 803
• 24 Elmenhorst D, Meyer PT, Winz OH. et al. Sleep deprivation increases A₁ adenosine receptor binding in the human brain: a positron emission tomography study. J Neurosci 2007; 27: 2410-2415
• 25 Meyer PT, Elmenhorst D, Boy C. et al. Effect of aging on cerebral A₁ adenosine receptors: A [18 F]CPFPX PET study in humans. Neurobiol Aging 2007; 28: 1914-1924
• 26 Ribeiro JA, Sebastião AM. Caffeine and adenosine. J Alzheimers Dis 2010; 20 Suppl 1 S3-S15
• 27 Juliano LM, Griffiths RR. A critical review of caffeine withdrawal: empirical validation of symptoms and signs, incidence, severity, and associated features. Psychopharmacology (Berl) 2004; 176: 1-29
• 28 Sander CY, Mandeville JB, Wey HY. et al. Effects of flow changes on radiotracer binding: Simultaneous measurement of neuroreceptor binding and cerebral blood flow modulation. J Cereb Blood Flow Metab 2019; 39: 131-146
• 29 Buono M, Rostomily K. Acute normobaric hypoxia does not increase blood or plasma viscosity. Clin Hemorheol Microcirc 2021; 78: 461-464
• 30 Anglada-Huguet M, Endepols H, Sydow A. et al. Reversal of Tau-Dependent Cognitive Decay by Blocking Adenosine A1 Receptors: Comparison of Transgenic Mouse Models with Different Levels of Tauopathy. Int J Mol Sci 2023; 24: 9260
• 31 Hackett PH. Caffeine at high altitude: java at base cAMP. High Alt Med Biol 2010; 11: 13-17
• 32 Sparks K, Wehling RR, Acharya S. et al. 0106 The Effects of Caffeine on Blood Pressure and Cognitive Performance in Hypoxic Conditions on the Slopes of Mt. Everest. Sleep 2020; 43 Suppl 1 A42
• 33 Smirmaul BP, de Moraes AC, Angius L. et al. Effects of caffeine on neuromuscular fatigue and performance during high-intensity cycling exercise in moderate hypoxia. Eur J Appl Physiol 2017; 117: 27-38
• 34 Leinonen A, Varis N, Kokki H. et al. Normobaric hypoxia training in military aviation and subsequent hypoxia symptom recognition. Ergonomics 2021; 64: 545-552
• 35 Pérez Regalado S, León J, Feriche B. Therapeutic approach for digestive system cancers and potential implications of exercise under hypoxia condition: what little is known? a narrative review. J Cancer Res Clin Oncol 2022; 148: 1107-1121
• 36 Timon R, González-Custodio A, Vasquez-Bonilla A. et al. Intermittent Hypoxia as a Therapeutic Tool to Improve Health Parameters in Older Adults. Int J Environ Res Public Health 2022; 19: 5339
• 37 Timon R, Olcina G, Padial P. et al. Effects of Resistance Training in Hypobaric vs. Normobaric Hypoxia on Circulating Ions and Hormones. Int J Environ Res Public Health 2022; 19: 3436
• 38 Richalet JP, Letournel M, Souberbielle JC. Effects of high-altitude hypoxia on the hormonal response to hypothalamic factors. Am J Physiol Regul Integr Comp Physiol 2010; 299: R1685-R1692
• 39 Virani SS, Alonso A, Benjamin EJ. et al. Heart Disease and Stroke Statistics-2020 Update: A Report From the American Heart Association. Circulation 2020; 141: e139-e596
• 40 Martire A, Lambertucci C, Pepponi R. et al. Neuroprotective potential of adenosine A1 receptor partial agonists in experimental models of cerebral ischemia. J Neurochem 2019; 149: 211-230
• 41 Joya A, Ardaya M, Montilla A. et al. In vivo multimodal imaging of adenosine A1 receptors in neuroinflammation after experimental stroke. Theranostics 2021; 11: 410-425
• 42 Luengo-Fernandez R, Violato M, Candio P. et al. Economic burden of stroke across Europe: A population-based cost analysis. Eur Stroke J 2020; 5: 17-25
• 43 Wafa HA, Wolfe CDA, Emmett E. et al. Burden of Stroke in Europe: Thirty-Year Projections of Incidence, Prevalence, Deaths, and Disability-Adjusted Life Years. Stroke 2020; 51: 2418-2427
• 44 Camici M, Micheli V, Ipata PL. et al. Pediatric neurological syndromes and inborn errors of purine metabolism. Neurochem Int 2010; 56: 367-378
• 45 Harris AD, Murphy K, Diaz CM. et al. Cerebral blood flow response to acute hypoxic hypoxia. NMR Biomed 2013; 26: 1844-1852
• 46 Rogan M, Friend AT, Rossetti GM. et al. Hypoxia alters posterior cingulate cortex metabolism during a memory task: A (1)H fMRS study. Neuroimage 2022; 260: 119397
• 47 Alsop DC, Detre JA, Golay X. et al. Recommended implementation of arterial spin-labeled perfusion MRI for clinical applications: A consensus of the ISMRM perfusion study group and the European consortium for ASL in dementia. Magn Reson Med 2015; 73: 102-116
• 48 Elmenhorst D, Elmenhorst EM, Luks N. et al. Performance impairment during four days partial sleep deprivation compared with the acute effects of alcohol and hypoxia. Sleep Med 2009; 10: 189-197
• 49 Chroboczek M, Kujach S, Luszczyk M. et al. Acute Normobaric Hypoxia Lowers Executive Functions among Young Men despite Increase of BDNF Concentration. Int J Environ Res Public Health 2022; 19: 10802
• 50 Michno M, Schmitz J, Foerges AL. et al. Effect of Acute Hypoxia Exposure on the Availability of A₁ adenosine Receptors and Perfusion in the Human Brain. J Nucl Med 2025; 66: 142-149