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Enhanced brain stem 5HT2A receptor function under neonatal hypoxic insult: role of glucose, oxygen, and epinephrine resuscitation

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Abstract

Molecular processes regulating brain stem serotonergic receptors play an important role in the control of respiration. We evaluated 5-HT2A receptor alterations in the brain stem of neonatal rats exposed to hypoxic insult and the effect of glucose, oxygen, and epinephrine resuscitation in ameliorating these alterations. Hypoxic stress increased the total 5-HT and 5-HT2A receptor number along with an up regulation of 5-HT Transporter and 5-HT2A receptor gene in the brain stem of neonates. These serotonergic alterations were reversed by glucose supplementation alone and along with oxygen to hypoxic neonates. The enhanced brain stem 5-HT2A receptors act as a modulator of ventilatory response to hypoxia, which can in turn result in pulmonary vasoconstriction and cognitive dysfunction. The adverse effects of 100% oxygenation and epinephrine administration to hypoxic neonates were also reported. This has immense clinical significance in neonatal care.

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References

  1. Semenza GL, Agani F, Feldser D, Iyer N, Kotch L, Laughner E, Yu A (2000) Hypoxia, HIF-1, and the pathophysiology of common human diseases. Adv Exp Med Biol 475:123–130

    Article  CAS  PubMed  Google Scholar 

  2. Johnston MV, Nakajima W, Hagberg H (2002) Mechanisms of hypoxic neurodegeneration in the developing brain. Neuroscientist 8(3):212–220

    CAS  PubMed  Google Scholar 

  3. Tryba AK, Pena F, Ramirez JM (2006) Gasping activity in vitro: a rhythm dependent on 5-HT2A receptors. J Neurosci 26:2623–2634

    Article  CAS  PubMed  Google Scholar 

  4. Justin EA, Frederic JS, Theodore A (2004) Slotkin developmental exposure to chlorpyrifos elicits sex-selective alterations of serotonergic synaptic function in adulthood: critical periods and regional selectivity for effects on the serotonin transporter, receptor subtypes, and cell signaling. Environ Health Perspect 112:148–155

    Google Scholar 

  5. Jackson J, Paulose CS (2000) Brain 5HT2A receptor regulation by tryptophan supplementation in streptozotocin diabetic rats. J Biochem Mole Biol Biophys 5:1–7

    Google Scholar 

  6. Eddahibi S, Raffestin B, Pham I, Launay JM, Aegerter P, Sitbon M, Adnot S (1997) Treatment with 5-HT potentiates development of pulmonary hypertension in chronically hypoxic rats. Am J Physiol 272:H1173–H1181

    CAS  PubMed  Google Scholar 

  7. Baker-Herman TL, Fuller DD, Bavis RW, Zabka AG, Golder FJ, Doperalski NJ, Johnson RA, Watters JJ, Mitchell GS (2004) BDNF is necessary and sufficient for spinal respiratory plasticity following intermittent hypoxia. Nat Neurosci 7(1):48–55

    Article  CAS  PubMed  Google Scholar 

  8. Serrano J, Encinas JM, Salas E, Fernández AP, Castro-Blanco S, Fernández-Vizarra P, Bentura ML, Rodrigo J (2003) Hypobaric hypoxia modifies constitutive nitric oxide synthase activity and protein nitration in the rat cerebellum. Brain Res 976:109–119

    Article  CAS  PubMed  Google Scholar 

  9. Varney AA, Schlenker EH (2007) Thyroid status affects 5-HT2A receptor modulation of breathing before, during, and following exposure of hamsters to acute intermittent hypoxia. Am J Physiol Regul Integr Comp Physiol 293(5):R2070–R2080

    Article  CAS  PubMed  Google Scholar 

  10. Abraham PM, Anju TR, Jayanarayanan S, Paulose CS (2010) Serotonergic receptor functional up regulation in cerebral cortex and down regulation in brain stem of Streptozotocin induced diabetic rats: antagonism by pyridoxine and insulin. Neurosci Lett 483:23–27

    Article  CAS  PubMed  Google Scholar 

  11. Reinebrant HE, Wixey JA, Gobe GC, Colditz PB, Buller KM (2010) Differential effects of neonatal hypoxic-ischemic brain injury on brainstem serotonergic raphe nuclei. Brain Res 1322:124–133

    Article  CAS  PubMed  Google Scholar 

  12. Richter DW, Manzke T, Wilken B, Ponimaskin E (2003) Serotonin receptors: guardians of stable breathing. Trends Mol Med 9:542–548

    Article  CAS  PubMed  Google Scholar 

  13. Launay JM, Callebert J, Bondoux D, Loric S, Maroteaux L (1994) Serotonin receptors and therapeutics. Cell Mol Biol 40(3):327–336

    CAS  PubMed  Google Scholar 

  14. Miller KJ, Hoffman BJ (1994) Adenosine A3 receptors regulate serotonin transport via nitric oxide and cGMP. J Biol Chem 269(44):27351–27356

    CAS  PubMed  Google Scholar 

  15. Yura A, Kiuchi Y, Uchikawa T, Uchida J, Yamazaki K, Oguchi K (1996) Possible involvement of calmodulin-dependent kinases in Ca(2+)-dependent enhancement of [3H]5-hydroxytryptamine uptake in rat cortex. Brain Res 738(1):96–102

    Article  CAS  PubMed  Google Scholar 

  16. Eddahibi S, Hanoun N, Lanfumey L, Lesch KP, Raffestin B, Hamon M, Adnot S (2000) Attenuated hypoxic pulmonary hypertension in mice lacking the 5-hydroxytryptamine transporter gene. J Clin Invest 105:1555–1562

    Article  CAS  PubMed  Google Scholar 

  17. Paul SA, Simons JW, Mabjeesh NJ (2004) HIF at the crossroads between ischemia and carcinogenesis. J Cell Physiol 200:20–30

    Article  CAS  PubMed  Google Scholar 

  18. Wang GB, Wang XQ, Luo GX, He WF, Chen XW, Wu J, Bian XW (2007) Design of a multifunction medical experiment platform and its temperature regulation in cell in vitro culture. J Third Mil Med Univ 29:1289–1292

    Google Scholar 

  19. Glowinski J, Iversen LL (1966) Regional studies of catecholamines in the rat brain: the disposition of [3H] Norepinephrine, [3H] DOPA in various regions of the brain. J Neurochem 13:655–669

    Article  CAS  PubMed  Google Scholar 

  20. Uzbekov MN, Murphy S, Rose SPR (1979) Ontogenesis of serotonin ‘receptors’ in different regions of rat brain. Brain Res 168:195–199

    Article  CAS  PubMed  Google Scholar 

  21. Leysen JE, Neimegeers CJE, Van Nueten JM, Laduron PM (1982) [3H] Ketanserin, a selective ligand for serotonin2 receptor binding sites. Mol Pharmacol 21:301–314

    CAS  PubMed  Google Scholar 

  22. Lowry OH, Rosenbrough NH, Farr AL, Randall RJ (1951) Protein measurement with folin phenol reagent. J Biol Chem 193:265–275

    CAS  PubMed  Google Scholar 

  23. Scatchard G (1949) The attractions of proteins for small molecules and ions. Ann N Y Acad Sci 51:660–672

    Article  CAS  Google Scholar 

  24. Tagliaferro P, Ramos AJ, López-Costa JJ, López EM, Saavedra JP, Brusco A (2001) Increased nitric oxide synthase activity in a model of serotonin depletion. Brain Res Bull 54:199–205

    Article  CAS  PubMed  Google Scholar 

  25. Henley WN, Bellush LL, Notestine MA (1992) Hypoxic attenuation of brain stem serotonin does not influence sodium-induced hypertension. Clin Exp Hypertens A 14:413–433

    Article  CAS  PubMed  Google Scholar 

  26. Richter DW, Schmidt-Garcon P, Pierrefiche O, Bischoff AM, Lalley PM (1999) Neurotransmitters and neuromodulators controlling the hypoxic respiratory responses in anaesthesized cats. J Physiol 514:567–578

    Article  CAS  PubMed  Google Scholar 

  27. Taylor AH, Nattie EE (2005) Medullary serotonergic neurones modulate the ventilatory response to hypercapnia, but not hypoxia in conscious rats. J Physiol 566:543–557

    Article  CAS  PubMed  Google Scholar 

  28. Pena F, Ramirez JM (2002) Endogenous activation of serotonin-2A receptors is required for respiratory rhythm generation in vitro. J Neurosci 22:11055–11064

    CAS  PubMed  Google Scholar 

  29. Davis JN, Carlsson A (1973) Effect of hypoxia on tyrosine and tryptophan hydroxylation in unanaesthetized rat brain. J Neurochem 20:913–915

    Article  CAS  PubMed  Google Scholar 

  30. Poncet L, Denoroy L, Dalmaz Y, Pequignot JM (1997) Activity of tryptophan hydroxylase and content of indolamines in discrete brain regions after a long-term hypoxic exposure in the rat. Brain Res 765:122–128

    Article  CAS  PubMed  Google Scholar 

  31. Steiner AA, Branco LGS (2003) Fever and anapyrexia in systemic inflammation: intracellular signaling by cyclic nucleotides. Front Biosci 8:1398–1408

    Article  Google Scholar 

  32. Gargaglioni LH, Steiner AA, Branco LGS (2005) Involvement of serotoninergic receptors in the anteroventral preoptic region on hypoxia-induced hypothermia. Brain Res 1044:16–24

    Article  CAS  PubMed  Google Scholar 

  33. Shartau RB, Tam R, Patrick S, Goldberg JI (2010) Serotonin prolongs survival of encapsulated pond snail embryos exposed to long-term anoxia. J Exp Biol 213:1529–1535

    Article  CAS  PubMed  Google Scholar 

  34. Yamada J, Sugimoto Y, Horisaka K (1995) Serotonin2 (5-HT2) receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) inhibits chlorpromazine- and haloperidol-induced hypothermia in mice. Biol Pharm Bull 18(11):1580–1583

    CAS  PubMed  Google Scholar 

  35. Hommer D, Andreasen P, Rio D, Williams W, Ruttimann U, Momenan R, Zametkin A, Rawlings R, Linnoila M (1997) Effects of m-chlorophenylpiperazine on regional brain glucose utilization: a positron emission tomographic comparison of alcoholic and control subjects. J Neurosci 17(8):2796–2806

    CAS  PubMed  Google Scholar 

  36. Choi DW (1988) Glutamate neurotoxicity and diseases of the nervous system. Neuron 1:623–634

    Article  CAS  PubMed  Google Scholar 

  37. Coyle JT, Puttfarcken P (1993) Oxidative stress, glutamate, and neurodegenerative disorders. Science 262:689–695

    Article  CAS  PubMed  Google Scholar 

  38. Li Y, Powers C, Jiang N, Chopp M (1998) Intact, injured, necrotic, and apoptotic cells after focal cerebral ischemia in the rat. J Neurol Sci 156:119–132

    Article  CAS  PubMed  Google Scholar 

  39. Wrona MZ, Dryhurst G (1991) Interactions of 5-hydroxytryptamine with oxidative enzymes. Biochem Pharmacol 41:1145–1162

    Article  CAS  PubMed  Google Scholar 

  40. Ikeda Y, Anderson JH, Long DM (1989) Oxygen free radicals in the genesis of traumatic and peritumoral brain edema. Neurosyrgery 24:679–685

    Article  CAS  Google Scholar 

  41. Sakamoto A, Ohnishi ST, Ohnishi T, Ogawa R (1991) Relationship between free radical production and lipid peroxidation during ischemia-reperfusion injury in the rat brain. Brain Res 554:186–192

    Article  CAS  PubMed  Google Scholar 

  42. Karacaoglu E, Bayram I, Celiköz B, Zienowicz RJ (2007) Does sustained epinephrine release trigger a hypoxia-neovascularization cascade. Plast Reconstr Surg 119:858–864

    Article  CAS  PubMed  Google Scholar 

  43. Jensen A, Künzel W, Kastendieck E (2009) Epinephrine and norepinephrine release in the fetus after repeated hypoxia. J Perinat Med 10:109–110

    Article  Google Scholar 

  44. Shah BH, Siddiqui A, Qureshi KA, Khan M, Rafi S, Ujan VA, Yakoob MY, Rasheed H, Saeed SA (1999) Co-activation of Gi and Gq proteins exerts synergistic effect on human platelet. Exp Mol Med 31:42–46

    CAS  PubMed  Google Scholar 

  45. Semenza GL (1999) Perspectives on oxygen sensing. Cell 98:281–284

    Article  CAS  PubMed  Google Scholar 

  46. Bruick RK (2000) Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia. Proc Natl Acad Sci USA 97:9082–9087

    Article  CAS  PubMed  Google Scholar 

  47. Sowter HM, Ratcliffe PJ, Watson P, Greenberg AH, Harris AL (2001) HIF-1-dependent regulation of hypoxic induction of the cell death factors BNIP3 and NIX in human tumors. Cancer Res 61:6669–6673

    CAS  PubMed  Google Scholar 

  48. Li Y, Zhou C, Calvert JW, Colohan AR, Zhang JH (2005) Multiple effects of hyperbaric oxygen on the expression of HIF-1 alpha and apoptotic genes in a global ischemia-hypotension rat model. Exp Neurol 191:198–210

    Article  CAS  PubMed  Google Scholar 

  49. Halterman MW, Federoff HJ (1999) HIF-1alpha and p53 promote hypoxia-induced delayed neuronal death in models of CNS ischemia. Exp Neurol 159:65–72

    Article  CAS  PubMed  Google Scholar 

  50. Aminova LR, Chavez JC, Lee J, Ryu H, Kung A, Lamanna JC, Ratan RR (2005) Prosurvival and prodeath effects of hypoxia-inducible factor-1alpha stabilization in a murine hippocampal cell line. J Biol Chem 280:3996–4003

    Article  CAS  PubMed  Google Scholar 

  51. Vangeison G, Carr D, Federoff HJ, Rempe DA (2008) The good, the bad, and the cell type-specific roles of hypoxia inducible factor-1 alpha in neurons and astrocytes. J Neurosci 28:1988–1993

    Article  CAS  PubMed  Google Scholar 

  52. Del Duca D, Wong G, Trieu P, Rodaros D, Kouremenos A, Tadevosyan A, Vaniotis G, Villeneuve LR, Tchervenkov CI, Nattel S, Allen BG, Hébert TE, Rohlicek CV (2009) Association of neonatal hypoxia with lasting changes in left ventricular gene expression: an animal model. J Thorac Cardiovasc Surg 138(3):538–546

    Article  PubMed  Google Scholar 

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Acknowledgments

This study was supported by the research grants from DBT, DST, ICMR, Govt. of India and KSCSTE, Govt. of Kerala to Dr. C. S. Paulose. Anju T R thanks Council of Scientific and Industrial Research for Senior Research Fellowship.

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  1. Molecular Neurobiology and Cell Biology Unit, Centre for Neuroscience, Department of Biotechnology, Cochin University of Science and Technology, Cochin, 682022, Kerala, India

    T. R. Anju, P. K. Korah, S. Jayanarayanan & C. S. Paulose

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  1. T. R. Anju
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  2. P. K. Korah
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  3. S. Jayanarayanan
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  4. C. S. Paulose
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Correspondence to C. S. Paulose.

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Anju, T.R., Korah, P.K., Jayanarayanan, S. et al. Enhanced brain stem 5HT2A receptor function under neonatal hypoxic insult: role of glucose, oxygen, and epinephrine resuscitation. Mol Cell Biochem 354, 151–160 (2011). https://doi.org/10.1007/s11010-011-0814-5

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