Abstract
Brain-derived neurotrophic factor (BDNF) is important in supporting neuronal development. BDNF imbalance due to excessive neuronal inhibition can result in the apoptotic degeneration of developing neurons. Since general anesthetics cause profound depression of neuronal activity and are known to induce widespread degeneration in the developing brain, we studied their potential to activate BDNF-mediated developmental neuroapoptosis. When P7 rats (at the peak of brain development) were exposed to a commonly-used and highly pro-apoptotic anesthesia protocol (midazolam, isoflurane, nitrous oxide) for a period of 2, 4 or 6 h, we found that anesthesia modulates the key steps in BDNF-activated apoptotic cascade in two of the most vulnerable brain regions—cerebral cortex and thalamus in time-dependent fashion by activating both Trk-dependent (in thalamus) and Trk-independent p75NTR dependent (in cerebral cortex) neurotrophic pathways. β-estradiol, a sex hormone that upregulates the protein levels of the activated Akt, protects against anesthesia-induced neuroapoptosis.
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References
Bibel M, Barde YA (2000) Neurotrophins: key regulators of cell fate and cell shape in the vertebrate nervous system. Genes Dev 14:2919–2937
Kaplan DR, Miller FD (2000) Neurotrophin signal transduction in the nervous system. Curr Opin Neurobiol 10:381–389
Dudek H, Datta SR, Franke TF, Birnbaum MJ et al (1997) Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science 275:661–665
Thoenen H (1995) Neurotrophins and neuronal plasticity. Science 270:593–598
Bittigau P, Sifringer M, Genz K, Reith E et al (2002) Antiepileptic drugs and apoptotic neurodegeneration in the developing brain. Proc Nat Acad Sci 99:15089–15094
Ikonomidou C, Bosch F, Miksa M, Bittigau P et al (1999) Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 283:70–74
Ikonomidou C, Bittigau P, Ishimaru MJ, Wozniak DF et al (2000) Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome. Science 287:1056–1060
Jevtovic-Todorovic V, Hartman RE, Izumi Y, Benshoff ND et al (2003) Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci 23:876–882
Yon J-H, Daniel-Johnson J, Carter LB, Jevtovic-Todorovic V (2005) Anesthesia induces neuronal cell death in the developing rat brain via the intrinsic and extrinsic apoptotic pathways. Neuroscience 35:815–827
Dobbing J, Sands J (1979) Comparative aspects of the brain growth spurt. Early Hum Dev 3:79–83
Jevtovic-Todorovic V, Todorovic SM, Mennerick S, Powell S et al (1998) Nitrous oxide (laughing gas) is an NMDA antagonist, neuroprotectant and neurotoxin. Nat Med 4:460–463
Jevtovic-Todorovic V, Benshoff N, Olney JW (2000) Ketamine potentiates cerebrocortical damage induced by the common anaesthetic agent nitrous oxide in adult rats. Br J Pharmacol 130:1692–1698
West MJ (1999) Stereological methods for estimating the total number of neurons and synapses: issues of precision and bias. Trends Neurosci 22:51–61
Akama KT, McEwen BS (2003) Estrogen stimulates postsynaptic density-95 rapid protein synthesis via the Akt/protein kinase B pathway. J Neurosci 23:2333–2339
Bibel M, Hoppe E, Barde YA (1999) Biochemical and functional interactions between the neurotrophin receptors Trk and p75NTR. EMBO J 18:616–622
Davey F, Davies AM (1998) TrkB signalling inhibits p75-mediated apoptosis induced by nerve growth factor in embryonic proprioceptive neurons. Curr Biol 8:915–918
Jiang Y, Woronicz JD, Liu W, Goeddel DV (1999) Prevention of constitutive TNF receptor 1 signaling by silencer of death domains. Science 283:543–546
Zundel W, Giaccia A (1998) Inhibition of the anti-apoptotic PI(3)K/Akt/Bad pathway by stress. Genes Dev 12:1941–1946
Zhou H, Summers SA, Birnbaum MJ, Pittman RN (1998) Inhibition of Akt kinase by cell-permeable ceramide and its implications for ceramide-induced apoptosis. J Biol Chem 273:16568–16575
Movsesyan VA, Yakovlev AG, Dabaghyan EA, Stoica BA et al (2002) Ceramide induces neuronal apoptosis through the caspase-9/caspase-3 pathway. Biochem Biophys Res Commun 299:201–207
Yamashita T, Tucker KL, Barde YA (1999) Neurotrophin binding to the p75 receptor modulates Rho activity and axonal outgrowth. Neuron 24:585–593
Crockett DP, Harris SL, Egger MD (2000) Neurotrophin receptor (p75) in the trigeminal thalamus of the rat: development, response to injury, transient vibrissa-related patterning, and retrograde transport. Anat Rec 259:446–460
McQuillen PS, DeFreitas MF, Zada G, Shatz CJ (2002) A novel role for p75NTR in subplate growth cone complexity and visual thalamocortical innervation. J Neurosci 22:3580–3593
Tang Y, Zhou H, Chen A, Pittman RN et al (2000) The Akt proto-oncogene links Ras to Pak and cell survival signals. J Biol Chem 275:9106–9109
Roux PP, Bhakar AL, Kennedy TE, Barker PA (2001) The p75 neurotrophin receptor activates Akt (protein kinase B) through a phosphatidylinositol 3-kinase-dependent pathway. J Biol Chem 276:23097–23104
Yon J-H, Carter LB, Reiter RJ, Jevtovic-Todorovic V (2005) Melatonin reduces the severity of anesthesia-induced apoptotic neurodegeneration in the developing rat brain. Neurobiol Disease (in press)
Zhang J, Geula C, Lu C, Koziel H et al (2003) Neurotrophins regulate proliferation and survival of two microglial cell lines in vitro. Exp Neurol 183:469–481
Daval JL, Vert P (2004) Apoptosis and neurogenesis after transient hypoxia in the developing rat brain. Semin Perinatol 28:257–263
Harada C, Harada T, Quah HM, Namekata K et al (2005) Role of neurotrophin-4/5 in neural cell death during retinal development and ischemic retinal injury in vivo. Invest Ophthalmol Vis Sci 46:669–673
Kissin I, Brown PT, Bradley EL Jr (1990) Sedative and hypnotic midazolam-morphine interactions in rats. Anesth Analg 71:137–143
Hornbein TF, Eger EI, Winter PM, Smith G et al (1982) The minimum alveolar concentration of nitrous oxide in man. Anesth Analg 61:553–556
Mahmoudi NW, Cole DJ, Shapiro HM (1989) Insufficient anesthetic potency of nitrous oxide in the rat. Anesthesiology 70:345–349
Stevens WC, Kingston HGG (1992) Inhalation anesthesia. In: Barash PG, Cullen BF, Stoelting RK (eds) Clinical Anesthesia. Lippincott, Philadelphia, pp 385–412
Orliaguet G, Vivien B, Langeron O, Bouhemad B et al (2001) Minimum alveolar concentration of volatile anesthetics in rats during postnatal maturation. Anesthesiology 95:734–739
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Lu, L.X., Yon, JH., Carter, L.B. et al. General anesthesia activates BDNF-dependent neuroapoptosis in the developing rat brain. Apoptosis 11, 1603–1615 (2006). https://doi.org/10.1007/s10495-006-8762-3
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DOI: https://doi.org/10.1007/s10495-006-8762-3