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. 2006 Apr 5;12(4):488–498. doi: 10.1111/j.1750-3639.2002.tb00467.x

Drug‐induced Apoptotic Neurodegeneration in the Developing Brain

John W Olney 1,✉, David F Wozniak 1, Vesna Jevtovic‐Todorovic 2, Nuri B Farber 1, Petra Bittigau 3, Chysanthy Ikonomidou 3
PMCID: PMC8095833  PMID: 12408236

Abstract

Physiological cell death (PCD), a process by which redundant or unsuccessful neurons are deleted by apoptosis (cell suicide) from the developing central nervous system, has been recognized as a natural phenomenon for many years. Whether environmental factors can interact with PCD mechanisms to increase the number of neurons undergoing PCD, thereby converting this natural phenomenon into a pathological process, is an interesting question for which new answers are just now becoming available. In a series of recent studies we have shown that 2 major classes of drugs (those that block NMDA glutamate receptors and those that promote GABAA receptor activation), when administered to immature rodents during the period of synaptogenesis, trigger widespread apoptotic neurodegeneration throughout the developing brain. In addition, we have found that ethanol, which has both NMDA antagonist and GABAmimetic properties, triggers a robust pattern of apoptotic neurodegeneration, thereby deleting large numbers of neurons from many different regions of the developing brain. These findings provide a more likely explanation than has heretofore been available for the reduced brain mass and lifelong neurobehavioral disturbances associated with the human fetal alcohol syndrome (FAS). The period of synaptogenesis, also known as the brain growth spurt period, occurs in different species at different times relative to birth. In rats and mice it is a postnatal event, but in humans it extends from the sixth month of gestation to several years after birth. Thus, there is a period in pre‐ and postnatal human development, lasting for several years, during which immature CNS neurons are prone to commit suicide if exposed to intoxicating concentrations of drugs with NMDA antagonist or GABAmimetic properties. These findings are important, not only because of their relevance to the FAS, but because there are many agents in the human environment, other than ethanol, that have NMDA antagonist or GABAmimetic properties. Such agents include drugs that may be abused by pregnant mothers (ethanol, phencyclidine [angel dust], ketamine [Special K], nitrous oxide [laughing gas], barbiturates, benzodiazepines), and many medicinals used in obstetric and pediatric neurology (anticonvulsants), and anesthesiology (all general anesthetics are either NMDA antagonists or GABAmimetics).

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References

  • 1. Andreasen NC, Arndt S, Swayze V, Cizadlo T, Flaum M, O'Leary D, Ehrhardt JC, Yuh WTC (1994) Thalamic abnormalities in schizophrenia visualized through magnetic resonance image averaging. Science 266:294–298. [DOI] [PubMed] [Google Scholar]
  • 2. Barr HM, Streissguth AP (2001) Identifying maternal self‐reported alcohol use associated with fetal alcohol spectrum disorders. Alcohol: Clin Exp Res 25:283–287. [PubMed] [Google Scholar]
  • 3. Bauer‐Moffet C, Altman J (1997) The effect of ethanol chronically administered to preweanling rats on cerebellar development: a morphological study. Brain Res 119:249–268. [DOI] [PubMed] [Google Scholar]
  • 4. Benes FM, McSparren J, San‐Giovanni JP, Vincent SL (1991) Deficits in small interneurons in cingulate cortex of schizophrenic and schizoaffective patients. Arch Gen Psychiatry 48:996–1001. [DOI] [PubMed] [Google Scholar]
  • 5. Benes FM, Vincent SL, Todtenkopf M (2001) The density of pyramidal and nonpyramidal neurons in anterior cingulate cortex of schizophrenic and bipolar subjects. Biol Psychiatry 50:395–406. [DOI] [PubMed] [Google Scholar]
  • 6. Bittigau P, Pohl D, Sifrtinger M, Shimizu H, Ikeda M, Ishimaru MJ, Stadthaus D, Fuhr S, Dikranian K, Olney JW, Ikonomidou C (1998) Modeling periatric trauma: Mechanisms of neurodegeneration and potential strategies for neuroprotection. Restorative Neurology and Neuro-science 13:11–23. [PubMed] [Google Scholar]
  • 7. Bittigau P, Sifringer M, Pohl D, Stadthaus D, Ishimaru M, Shimizu H, Ikeda M, Lang D, Speer A, Olney JW, Ikonomidou C (1999) Apoptotic neurodegeneration following trauma is markedly enhanced in the immature brain. Ann Neurol 45:724–735. [DOI] [PubMed] [Google Scholar]
  • 8. Bonthius DJ, West JR (1990) Alcohol‐induced neuronal loss in developing rats; Increased brain damage with binge exposure. Alc Clin Exp Res 14:107–118. [DOI] [PubMed] [Google Scholar]
  • 9. Charriaut‐Marlangue C, Ben‐Ari Y (1995) A cautionary note on the use of the TUNEL stain to determine apoptosis. Neuroreport 7:61–64. [PubMed] [Google Scholar]
  • 10. Clarren SK, Alvord AC, Sumi SM, Streissguth AP, Smith DW (1978) Brain malformations related to prenatal exposure to ethanol. J Pediatr 92:64–67. [DOI] [PubMed] [Google Scholar]
  • 11. Collins RJ, Harmon BV, Gobé GC, Kerr JFR (1992) Internucleosomal DNA cleavage should not be the sole criterion for identifying apoptosis. Int J Radiat Biol 61:451–453. [DOI] [PubMed] [Google Scholar]
  • 12. Corso TD, Sesma MA, Tenkova TI, Der TC, Wozniak DF, Farber NB, Olney JW (1997) Multifocal brain damage induced by phencyclidine is augmented by pilocarpine. Brain Res 752:1–14. [DOI] [PubMed] [Google Scholar]
  • 13. DeOlmos JS, Ingram WR (1971) An improved cupric‐silver method for impregnation of axonal and terminal degeneration. Brain Res 33:523–529. [DOI] [PubMed] [Google Scholar]
  • 14. Dessens AB, Cohen‐Kettenis PT, Mellenbergh GJ, Koppe JG, Van de Poll NE, Boer K (2000) Association of prenatal phenobarbital and phenytoin exposure with small head size and with learning problems. Acta Paediat 89:533–541. [DOI] [PubMed] [Google Scholar]
  • 15. Dikranian K, Tenkova T, Bittigau P, Ikonomidou C, Olney JW (2000) Histological characterization of apoptotic neurodegeneration induced in the developing rat brain by drugs that block sodium channels. Soc Neurosci Abst 26:323. [Google Scholar]
  • 16. Dikranian K, Ishimaru MJ, Tenkova T, Labruyere J, Qin YQ, Ikonomidou C, Olney JW (2001) Apoptosis in the in vivo mammalian forebrain. Neurobiol Dis 8:359–379. [DOI] [PubMed] [Google Scholar]
  • 17. Dobbing J, Sands J (1979) The brain growth spurt in various mammalian species. Early Hum Dev 3:79–84. [DOI] [PubMed] [Google Scholar]
  • 18. Ellison G (1994) Competitive and non‐competitive NMDA antagonists induce similar limbic degeneration. NeuroReport 5:2688–2692. [DOI] [PubMed] [Google Scholar]
  • 19. Faingold CL, N'Gouemo P, Riaz A (1998) Ethanol and neurotransmitter interactions ‐ from molecular to integrative effects. Prog Neurobiol 55:509–535. [DOI] [PubMed] [Google Scholar]
  • 20. Famy C, Streissguth AP, Unis AS (1998) Mental illness in adults with fetal alcohol syndrome or fetal alcohol effects. Am J Psych 155:552–554. [DOI] [PubMed] [Google Scholar]
  • 21. Farber NB, Wozniak DF, Price MT, Labruyere J, Huss J, Peter H St., Olney JW (1995) Age‐specific neurotoxicity in the rat associated with NMDA receptor blockade: Potential relevance to schizophrenia Biol Psychiatry 38:788–796. [DOI] [PubMed] [Google Scholar]
  • 22. Farber NB, Price MT, Ikonomidou C, Olney JW (1999) Action of ethanol at GABAA receptors blocks neurotoxicity in the adult brain, but augments neurotoxicity in the developing brain. Soc Neurosci Abst 25:551. [Google Scholar]
  • 23. Fix AS, Long GG, Wozniak DF, Olney JW (1994) Patho‐morphologic effects of N‐methyl‐D‐aspartate antagonists in the rat posterior cingulate/retrosplenial cerebral cortex. Drug Dev Res 24:147–152. [Google Scholar]
  • 24. Grasl‐Kraupp B, Ruttkay‐Nedecky B, Koudelka H, Bukowska K, Bursch W, Schulte‐Hermann R (1995) In situ detection of fragmented DNA (TUNEL assay) fails to discriminate among apoptosis, necrosis, and autolytic cell death: a cautionary note. Hepatology 21:1465–468. [DOI] [PubMed] [Google Scholar]
  • 25. Gwag BJ, Koh JY, Demaro JA, Ying HS, Jacquin M, Choi DW (1997) Slowly triggered excitotoxicity occurs by necrosis in cortical cultures. Neuroscience 77:393–401. [DOI] [PubMed] [Google Scholar]
  • 26. Harris RA, Proctor WR, McQuilkin SJ, Klein SJ, Mascia MP, Whatley V, Whiting PJ, Dunwiddie TV (1995) Ethanol increases GABAA responses in cells stably transfected with receptor subunits. Alcohol Clin Exp Res 19:226–232. [DOI] [PubMed] [Google Scholar]
  • 27. Hartman RE, Jevtovic‐Todorovic V, Olney JW, Wozniak DF (2001) Neonatal exposure to common anesthetics leads to spatial learning deficits in juvenile rats. Soc Neurosci Abs 27:398. [Google Scholar]
  • 28. Hoffman PL, Rabe CS, Moses F, Tabakoff B (1989) N‐Methyl‐D‐aspartate receptors and ethanol: Inhibition of calcium flux and cyclic GMP production. J Neurochem 52:1937–1940. [DOI] [PubMed] [Google Scholar]
  • 29. Horvath Z, Czopf J and Buzsaki G (1997) MK‐801‐induced neuronal damage in rats. Brain Res 753:181–195. [DOI] [PubMed] [Google Scholar]
  • 30. Ikonomidou C, Qin Y, Labruyere J, Kirby C and Olney JW (1996) Prevention of trauma‐induced neurodegeneration in infant rat brain. Pediatr Res 39:1020–1027. [DOI] [PubMed] [Google Scholar]
  • 31. Ikonomidou C, Bosch F, Miksa M, Bittigau P, Vöckler J, Dikranian K, Tenkova T, Stevoska V, Turski L, Olney JW (1999) Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 283:70–74. [DOI] [PubMed] [Google Scholar]
  • 32. Ikonomidou C, Bittigau P, Ishimaru MJ, Wozniak DF, Koch C, Genz K, Price MT, Stefovska V, Hörster F, Tenkova T, Dikranian K, Olney JW (2000a) Ethanol‐induced apoptotic neurodegeneration and fetal alcohol syndrome. Science 287:1056–1060. [DOI] [PubMed] [Google Scholar]
  • 33. Ikonomidou C, Bittigau P, Ishimaru MJ, Wozniak DF, Koch C, Genz K, Price MT, Stefovska V, Hörster F, Tenkova T, Dikranian K, Olney JW. (2000b) Drug‐induced damage in the developing brain. Science 288:976–977. [DOI] [PubMed] [Google Scholar]
  • 34. Ikonomidou C, Genz K, Engelbrechten S, Dikranian K, Olney JW, Bittigau P (2000c) Antiepileptic drugs which block sodium channels cause neuronal apoptosis in the developing rat brain. Soc Neurosci Abst 26:323. [Google Scholar]
  • 35. Ishimaru M, Fukamauchi F, Olney JW (1995) Halothane prevents MK801 neurotoxicity in the rat cingulate cortex. Neurosci Lett 193:1–4. [DOI] [PubMed] [Google Scholar]
  • 36. Ishimaru MJ, Ikonomidou C, Tenkova TI, Der TC, Dikranian K, Sesma MA, Olney JW (1999) Distinguishing excitotoxic from apoptotic neurodegeneration in the developing rat brain. J Comp Neurol 408:461–476. [PubMed] [Google Scholar]
  • 37. Jevtovic‐Todorovic V, Kirby CO, Olney JW (1997) Isoflurane and propofol block neurotoxicity caused by MK801 in the rat posterior cingulate/retrosplenial cortex. J Cereb Blood Flow Metab 17:168–174. [DOI] [PubMed] [Google Scholar]
  • 38. Jevtovic‐Todorovic V, Todorovic SM, Mennerick S, Powell S, Dikranian K, Bensoff N, Zorumski CF, Olney JW (1998) Nitrous oxide (laughing gas) is an NMDA antagonist, neuroprotectant and neurotoxin. Nature Med 4:460–463. [DOI] [PubMed] [Google Scholar]
  • 39. Jevtovic‐Todorovic V, Wozniak DF, Benshoff N, Olney JW (2001) Commonly used anesthesia protocol causes neuronal suicide in the immature rat brain. Soc Neurosci Abst 27:398. [Google Scholar]
  • 40. Jones KL, Smith DW (1973) Recognition of the fetal alcohol syndrome in early infancy. Lancet ii:999–1001. [DOI] [PubMed] [Google Scholar]
  • 41. Jones KL, Smith DW (1975) The fetal alcohol syndrome. Teratology 12:1–10. [DOI] [PubMed] [Google Scholar]
  • 42. Jones KL, Smith DW, Ulleland CN, Streissguth AP (1973) Pattern of malformation in offspring of chronic alcoholic mothers. Lancet i: 1267–1271. [DOI] [PubMed] [Google Scholar]
  • 43. Kerns KA, Don A, Mateer CA, Streissguth AP (1977) Implementation for a compensatory memory system in a school age child with severe memory impairment. J Learn Disab 30:685–693. [Google Scholar]
  • 44. Kerr JFR, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with wideranging implications in tissue kinetics. British J Cancer 26:239–257. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45. Kim SH, Price MT, Olney JW, Farber NB (1999) Excessive cerebrocortical release of acetylcholine induced by NMDA antagonists is reduced by gabaergic and μ‐2adrenergic agonists. Mol Psychiatry 4:344–352. [DOI] [PubMed] [Google Scholar]
  • 46. Lovinger DM, White G, Weight FF (1989) Ethanol inhibits NMDA‐activated ion current in hippocampal neurons. Science 243:1721–1724. [DOI] [PubMed] [Google Scholar]
  • 47. Mennerick S, Jevtovic‐Todorovic V, Todorovic SM, Shen W, Olney JW, Zorumski CF (1998) Effect of nitrous oxide on excitatory and inhibitory synaptic transmission in hippocampal cultures. J Neurosci 18:9716–26. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48. Mennerick S, Zorumski CF (2000) Neural activity and survival in the developing nervous system. Mol Neurobiol 22:41–54. [DOI] [PubMed] [Google Scholar]
  • 49. Olney JW, Labruyere J, Price MT (1989) Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs. Science 244:1360–1362. [DOI] [PubMed] [Google Scholar]
  • 50. Olney JW, Labruyere J, Wang G, Wozniak DF, Price MT, Sesma MA (1991) NMDA antagonist neurotoxicity: Mechanism and prevention. Science 254:1515–1518. [DOI] [PubMed] [Google Scholar]
  • 51. Olney JW, Wozniak DF, Price MT, Tenkova T, Dikranian K, Ikonomidou C (1999) Ethanol induces widespread apoptotic neurodegeneration in the infant mouse brain. Soc Neurosci Abst 25:550. [Google Scholar]
  • 52. Olney JW, Tenkova T, Dikranian K, Qin YQ, Labruyere J, Ikonomidou C (2002a) Ethanol‐induced apoptotic neurodegeneration in the developing C57BL/6 mouse brain. Dev Brain Res 133:115–126. [DOI] [PubMed] [Google Scholar]
  • 53. Olney JW, Tenkova T, Dikranian K, Muglia LJ, Jermakowicz WJ, D'Sa C, Roth KA (2002b) Ethanol‐induced caspase‐3 activation in the developing mouse brain. Neurobiol Dis 9:205–219. [DOI] [PubMed] [Google Scholar]
  • 54. Pierce DR, West JR (1987) Severity of alcohol‐induced deficits in rats during the third trimester equivalent is determined by the pattern of exposure. Alcohol Suppl 5:461–465. [PubMed] [Google Scholar]
  • 55. Pohl D, Bittigau P, Ishimaru MJ, Stadthaus D, Hübner C, Olney JW, Turski L, Ikonomidou C. (1999) N‐Methyl‐D‐aspartate antagonists and apoptotic cell death triggered by head trauma in developing rat brain. Proc Nat Acad Sci U S A 96:2508–2513. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56. Samson HH (1986) Microcephaly and the fetal alcohol syndrome: human and animal studies In: West JR (ed), Alcohol and brain development. ( New York : Oxford Univ Press; ); pp. 167–183. [Google Scholar]
  • 57. Sapp DW, Ye HH (1998) Ethanol‐GABA(A) receptor interactions: a comparison between cell lines and cerebellar Purkinje cells. J Pharmacol Exp Ther 284:768–776. [PubMed] [Google Scholar]
  • 58. Sloviter RS, Dean E, Neubort S (1993) An electron microscopic analysis of adrenalectomy‐induced hippocampal granule cell degeneration in the rat; apoptosis in the adult central nervous system. J Comp Neurol 330:337–351. [DOI] [PubMed] [Google Scholar]
  • 59. Stratton K, Howe C, Battaglia F Fetal Alcohol Syndrome: Diagnosis, Epidemiology, Prevention and Treatment. Washington D.C. , National Academy Press: 1996. [Google Scholar]
  • 60. Streissguth AP, O'Malley K (2000) Neuropsychiatric implications and long‐term consequences of Fetal Alcohol Spectrum Disorders. Semin Clin Neuropsych 5:177–190. [DOI] [PubMed] [Google Scholar]
  • 61. Sulik KK, Johnston MC, Webb MA (1981) Fetal alcohol syndrome: embryogenesis in a mouse model. Science 214:936–938. [DOI] [PubMed] [Google Scholar]
  • 62. Swayze VW 2nd, Johnson VP, Hanson JW, Piven J, Sato Y, Andreasen NC (1997) Magnetic resonance imaging of brain anomalies in fetal alcohol syndrome. Pediatrics 99:232–240. [DOI] [PubMed] [Google Scholar]
  • 63. Wozniak DF, Dikranian K, Ishimaru M, Nardi A, Corso TD, Olney JW, Fix AS (1999) Disseminated corticolimbic neuronal degeneration induced in rat brain by MK‐801. Neurobiol Dis 5:305–322. [DOI] [PubMed] [Google Scholar]

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