Effect of Interaction between Adenosine and Nitric Oxide on Central Nervous System Oxygen Toxicity

  • Cheng-wei Xie
  • Wang Zhong-zhuang 
  • Ya-nan Zhang
  • Yu-liang Chen
  • Run-ping LiEmail author
  • Jun-dong ZhangEmail author
Original Article


The metabolism of adenosine (ADO) and nitric oxide (NO) in brain tissues is closely associated with the change of oxygen content. They have contrary effects in the onset of hyperbaric oxygen (HBO)-induced central nervous system oxygen toxicity (CNS OT): ADO can suppress the onset, while NO promotes it. We adopted the ADO-augmenting measure and NO-inhibiting measure in this study and found the combined use had a far superior preventive and therapeutic effect in protecting against CNS OT compared with the use of either measure alone. So we hypothesized that there is an interaction between ADO and NO which has an important impact on the onset of CNS OT. On this basis, we administered ADO-augmenting or ADO-inhibiting drugs to rats. After exposure to HBO, the onset of CNS OT was evaluated, followed by the measurement of NO content in brain tissues. In another experiment, rats were administered NO-augmenting or NO-inhibiting drugs. After exposure to HBO, the onset of CNS OT was evaluated, followed by measurement of the activities of ADO metabolism-related enzymes in brain tissues. The results showed that, following ADO augmentation, the content of NO and its metabolite was significantly reduced, and the onset of CNS OT significantly improved. After ADO inhibition, just the opposite was observed. NO promotion resulted in a decrease in the activity of ADO-producing enzyme, an increase in the activity of ADO-decomposing enzyme, and an aggravation in CNS OT. The above results were all reversed after an inhibition in NO content. Studies have shown that exposure to HBO has a significant impact on the content of ADO and NO in brain tissues as well as their biological effects, and ADO and NO might have an intense interaction, which might generate an important effect on the onset of CNS OT. The prophylaxis and treatment effects of CNS OT can be greatly enhanced by augmenting ADO and inhibiting NO.


Hyperbaric oxygen Seizure Convulsion Superoxide Peroxynitrite 


Funding Information

This work was supported by the National Natural Science Foundation of China (No. 81471813).

Compliance with Ethical Standards

All procedures were performed in accordance with the Second Military Medical University (SMMU) Guide for the care and use of laboratory animals, and approved by the ethics committee for Animal Experiments of SMMU.

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. Akar F, Mutlu O, Komsuoglu Celikyurt I, Bektas E, Tanyeri P, Ulak G, Erden F (2014) Effects of 7-NI and ODQ on memory in the passive avoidance, novel object recognition, and social transmission of food preference tests in mice. Med Sci Monitor Basic Res 20:27–35. CrossRefGoogle Scholar
  2. Akula KK, Dhir A, Kulkarni SK (2008) Nitric oxide signaling pathway in the anti-convulsant effect of adenosine against pentylenetetrazol-induced seizure threshold in mice. Eur J Pharmacol 587:129–134. CrossRefGoogle Scholar
  3. Allen BW, Demchenko IT, Piantadosi CA (2009) Two faces of nitric oxide: implications for cellular mechanisms of oxygen toxicity. J Appl Physiol (1985) 106:662–667. CrossRefGoogle Scholar
  4. Aronica E, Sandau US, Iyer A, Boison D (2013) Glial adenosine kinase—a neuropathological marker of the epileptic brain. Neurochem Int 63:688–695. CrossRefGoogle Scholar
  5. Bitterman N, Bitterman H (1998) L-arginine-NO pathway and CNS oxygen toxicity. J Appl Physiol (1985) 84:1633–1638. CrossRefGoogle Scholar
  6. Boison D (2011) Modulators of nucleoside metabolism in the therapy of brain diseases. Curr Top Med Chem 11:1068–1086CrossRefGoogle Scholar
  7. Boison D (2013a) Adenosine and seizure termination: endogenous mechanisms. Epilepsy Curr 13:35–U70. CrossRefGoogle Scholar
  8. Boison D (2013b) Adenosine kinase: exploitation for therapeutic gain. Pharmacol Rev 65:906–943. CrossRefGoogle Scholar
  9. Boison D (2016a) Adenosinergic signaling in epilepsy. Neuropharmacology 104:131–139. CrossRefGoogle Scholar
  10. Boison D (2016b) The biochemistry and epigenetics of epilepsy: focus on adenosine and glycine. Front Mol Neurosci 9:26. CrossRefGoogle Scholar
  11. Boison D, Sandau US, Ruskin DN, Kawamura M, Masino SA (2013) Homeostatic control of brain function - new approaches to understand epileptogenesis. Front Cell Neurosci 7:Artn 109. CrossRefGoogle Scholar
  12. Brozickova C, Mikulecka A, Otahal J (2014) Effect of 7-nitroindazole, a neuronal nitric oxide synthase inhibitor, on behavioral and physiological parameters. Physiol Res 63:637–648Google Scholar
  13. Chavko M, Auker CR, McCarron RM (2003) Relationship between protein nitration and oxidation and development of hyperoxic seizures. Nitric Oxide Biol Chem 9:18–23CrossRefGoogle Scholar
  14. Chen YL, Zhang YN, Wang ZZ, Xu WG, Li RP, Zhang JD (2016) Effects of adenosine metabolism in astrocytes on central nervous system oxygen toxicity. Brain Res 1635:180–189. CrossRefGoogle Scholar
  15. Demchenko IT, Boso AE, Whorton AR, Piantadosi CA (2001) Nitric oxide production is enhanced in rat brain before oxygen-induced convulsions. Brain Res 917:253–261CrossRefGoogle Scholar
  16. Demchenko IT, Atochin DN, Boso AE, Astern J, Huang PL, Piantadosi CA (2003) Oxygen seizure latency and peroxynitrite formation in mice lacking neuronal or endothelial nitric oxide synthases. Neurosci Lett 344:53–56CrossRefGoogle Scholar
  17. Demchenko IT, Atochin DN, Gutsaeva DR, Godfrey RR, Huang PL, Piantadosi CA, Allen BW (2008) Contributions of nitric oxide synthase isoforms to pulmonary oxygen toxicity, local vs. mediated effects. Am J Physiol Lung C 294:L984–L990. CrossRefGoogle Scholar
  18. Demchenko IT, Zhilyaev SY, Moskvin AN, Piantadosi CA, Allen BW (2011) Autonomic activation links CNS oxygen toxicity to acute cardiogenic pulmonary injury. Am J Physiol Lung C 300:L102–L111. CrossRefGoogle Scholar
  19. Demchenko IT, Moskvin AN, Krivchenko AI, Piantadosi CA, Allen BW (2012) Nitric oxide-mediated central sympathetic excitation promotes CNS and pulmonary O(2) toxicity. J Appl Physiol (1985) 112:1814–1823. CrossRefGoogle Scholar
  20. Echeverry MB, Salgado ML, Ferreira FR, da-Silva CA, Del Bel EA (2007) Intracerebroventricular administration of nitric oxide-sensitive guanylyl cyclase inhibitors induces catalepsy in mice. Psychopharmacology 194:271–278. CrossRefGoogle Scholar
  21. El-Gowelli HM, El-Gowilly SM, Elsalakawy LK, El-Mas MM (2013) Nitric oxide synthase/K+ channel cascade triggers the adenosine A(2B) receptor-sensitive renal vasodilation in female rats. Eur J Pharmacol 702:116–125. CrossRefGoogle Scholar
  22. Fragata IR, Ribeiro JA, Sebastiao AM (2006) Nitric oxide mediates interactions between GABAA receptors and adenosine A1 receptors in the rat hippocampus. Eur J Pharmacol 543:32–39. CrossRefGoogle Scholar
  23. Gasier HG, Demchenko IT, Tatro LG, Piantadosi CA (2017) S-nitrosylation of GAD65 is implicated in decreased GAD activity and oxygen-induced seizures. Neurosci Lett 653:283–287. CrossRefGoogle Scholar
  24. Giuntini J, Giusti L, Lucacchini A, Mazzoni MR (2004) Modulation of A1 adenosine receptor signaling by peroxynitrite. Biochem Pharmacol 67:375–383CrossRefGoogle Scholar
  25. Guttinger M, Padrun V, Pralong WF, Boison D (2005) Seizure suppression and lack of adenosine A1 receptor desensitization after focal long-term delivery of adenosine by encapsulated myoblasts. Exp Neurol 193:53–64. CrossRefGoogle Scholar
  26. Hagioka S, Takeda Y, Zhang S, Sato T, Morita K (2005) Effects of 7-nitroindazole and N-nitro-l-arginine methyl ester on changes in cerebral blood flow and nitric oxide production preceding development of hyperbaric oxygen-induced seizures in rats. Neurosci Lett 382:206–210. CrossRefGoogle Scholar
  27. Janigro D, Wender R, Ransom G, Tinklepaugh DL, Winn HR (1996) Adenosine-induced release of nitric oxide from cortical astrocytes. Neuroreport 7:1640–1644CrossRefGoogle Scholar
  28. Lamb IR, Murrant CL (2015) Potassium inhibits nitric oxide and adenosine arteriolar vasodilatation via K(IR) and Na(+)/K(+) ATPase: implications for redundancy in active hyperaemia. J Physiol 593:5111–5126. CrossRefGoogle Scholar
  29. Moskvin AN, Zhilyaev SY, Sharapov OI, Platonova TF, Gutsaeva DR, Kostkin VB, Demchenko IT (2003) Brain blood flow modulates the neurotoxic action of hyperbaric oxygen via neuronal and endothelial nitric oxide. Neurosci Behav Physiol 33:883–888CrossRefGoogle Scholar
  30. Mutlu O, Akar F, Celikyurt IK, Tanyeri P, Ulak G, Erden F (2015) 7-NI and ODQ disturbs memory in the elevated plus maze, Morris water maze, and radial arm maze tests in mice. Drug Target Insights 9:1–8. CrossRefGoogle Scholar
  31. Persson AE, Lai EY, Gao X, Carlstrom M, Patzak A (2013) Interactions between adenosine, angiotensin II and nitric oxide on the afferent arteriole influence sensitivity of the tubuloglomerular feedback. Front Physiol 4:187. CrossRefGoogle Scholar
  32. Singh L, Kulshrestha R, Singh N, Jaggi AS (2018) Mechanisms involved in adenosine pharmacological preconditioning-induced cardioprotection. Korean J Physiol Pharmacol 22:225–234. CrossRefGoogle Scholar
  33. Van Dycke A, Raedt R, Vonck K, Boon P (2011) Local delivery strategies in epilepsy: a focus on adenosine. Seizure 20:376–382. CrossRefGoogle Scholar
  34. Williams-Karnesky RL, Sandau US, Lusardi TA, Lytle NK, Farrell JM, Pritchard EM, Kaplan DL, Boison D (2013) Epigenetic changes induced by adenosine augmentation therapy prevent epileptogenesis. J Clin Invest 123:3552–3563. CrossRefGoogle Scholar
  35. Wingelaar TT, van Ooij PAM, van Hulst RA (2017) Oxygen toxicity and special operations forces diving: hidden and dangerous. Front Psychol 8:1263. CrossRefGoogle Scholar
  36. Yildirim M, Marangoz AH, Ayyildiz M, Ankarali S, Marangoz C (2011) The interactions of nitric oxide and adenosine on penicillin-induced epileptiform activity in rats. Acta Neurobiol Exp 71:208–219Google Scholar
  37. Zhu H, Traore K, Santo A, Trush MA, Li YR (2016) Oxygen and oxygen toxicity: the birth of concepts. React Oxyg Species (Apex) 1:1–8. Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Diving Medicine, Faculty of Naval MedicineSecond Military Medical UniversityShanghaiChina
  2. 2.Department of Pharmacy, Changhai HospitalSecond Military Medical UniversityShanghaiChina
  3. 3.Nautical and Aviation Medicine CenterNavy General Hospital of PLABeijingChina
  4. 4.Tenth People’s Hospital of Tongji UniversityShanghaiChina

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