Advertisement

Minocycline exacerbates apoptotic neurodegeneration induced by the NMDA receptor antagonist MK-801 in the early postnatal mouse brain

  • Ioana Inta
  • Miriam A. Vogt
  • Anne S. Vogel
  • Markus Bettendorf
  • Peter Gass
  • Dragos Inta
Short Communication

Abstract

NMDA receptor (NMDAR) antagonists induce in perinatal rodent cortical apoptosis and protracted schizophrenia-like alterations ameliorated by antipsychotic treatment. The broad-spectrum antibiotic minocycline elicits antipsychotic and neuroprotective effects. Here we tested, if minocycline protects also against apoptosis triggered by the NMDAR antagonist MK-801 at postnatal day 7. Surprisingly, minocycline induced widespread cortical apoptosis and exacerbated MK-801-triggered cell death. In some areas such as the subiculum, the pro-apoptotic effect of minocycline was even more pronounced than that elicited by MK-801. These data reveal among antipsychotics unique pro-apoptotic properties of minocycline, raising concerns regarding consequences for brain development and the use in children.

Keywords

Minocycline MK-801 Caspase-3 Neurotoxicity Neurodevelopment Schizophrenia 

Notes

Acknowledgments

We thank to Katja Lankisch, Natascha Pfeiffer and Christof Dormann for their excellent technical support. This work was supported by a grant from the Olympia-Morata-Programm of the Medical Faculty of the University of Heidelberg to I.I., the Sonderforschungsbereich (SFB) 636/B03 and the German Ministry of Education and Research (BMBF, 01GQ1003B) to P.G.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interests.

References

  1. 1.
    Zhang L, Zhao J (2014) Profile of minocycline and its potential in the treatment of schizophrenia. Neuropsychiatr Dis Treat 10:1103–1111. doi: 10.102147/NDT.S64236 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Liu F, Guo X, Wu R, Ou J, Zheng Y, Zhang B, Xie L, Zhang L, Yang L, Yang S, Yang J, Ruan Y, Zeng Y, Xu X, Zhao J (2014) Minocycline supplementation for treatment of negative symptoms in early-phase schizophrenia: a double blind, randomized, controlled trial. Schizophr Res 153:169–176. doi: 10.1016/j.schres.2014.01.011 CrossRefPubMedGoogle Scholar
  3. 3.
    Zhang L, Shirayama Y, Iyo M, Hashimoto K (2007) Minocycline attenuates hyperlocomotion and prepulse inhibition deficits in mice after administration of the NMDA receptor antagonist dizocilpine. Neuropsychopharmacology 32:2004–2010. doi: 10.1038/sj.npp.1301313 CrossRefPubMedGoogle Scholar
  4. 4.
    Tikka T, Fiebich BL, Goldsteins G, Keinanen R, Koistinaho J (2001) Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia. J Neurosci 21:2580–2588PubMedGoogle Scholar
  5. 5.
    Olney JW, Labruyere J, Price MT (1989) Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs. Science 244:1360–1362CrossRefPubMedGoogle Scholar
  6. 6.
    Ikonomidou C, Bosch F, Miksa M, Bittigau P, Vockler J, Dikranian K, Tenkova TI, Stefovska V, Turski L, Olney JW (1999) Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 283:70–74CrossRefPubMedGoogle Scholar
  7. 7.
    Lim AL, Taylor DA, Malone DT (2012) Consequences of early life MK-801 administration: long-term behavioural effects and relevance to schizophrenia research. Behav Brain Res 227:276–286. doi: 10.1016/j.bbr.2011.10.052 CrossRefPubMedGoogle Scholar
  8. 8.
    Lima-Ojeda JM, Vogt MA, Pfeiffer N, Dormann C, Köhr G, Sprengel R, Gass P, Inta D (2013) Pharmacological blockade of GluN2B-containing NMDA receptors induces antidepressant-like effects lacking psychotomimetic action and neurotoxicity in the perinatal and adult rodent brain. Prog Neuropsychopharmacol Biol Psychiatry 45:28–33. doi: 10.1016/j.pnpbp.2013.04.017 CrossRefPubMedGoogle Scholar
  9. 9.
    Herdegen T, Blume A, Buschmann T, Georgakopoulos E, Winter C, Schmid W, Hsieh TF, Zimmermann M, Gass P (1997) Expression of activating transcription factor-2, serum response factor and cAMP/Ca response element binding protein in the adult rat brain following generalized seizures, nerve fibre lesion and ultraviolet irradiation. Neuroscience 81:199–212CrossRefPubMedGoogle Scholar
  10. 10.
    Bisler S, Schleicher A, Gass P, Stehle JH, Zilles K, Staiger JF (2002) Expression of c-Fos, ICER, Krox-24 and JunB in the whisker-to-barrel pathway of rats: time course of induction upon whisker stimulation by tactile exploration of an enriched environment. J Chem Neuroanat 23:187–198CrossRefPubMedGoogle Scholar
  11. 11.
    Filipovic D, Zlatkovic J, Inta D, Bjelobaba I, Stojiljkovic M, Gass P (2011) Chronic isolation stress predisposes the frontal cortex but not the hippocampus to the potentially detrimental release of cytochrome c from mitochondria and the activation of caspase-3. J Neurosci Res 89:1461–1470. doi: 10.1002/jnr.22687 CrossRefPubMedGoogle Scholar
  12. 12.
    Paxinos G, Halliday G, Watson C, Koutcherov Y, Wang HQ (2007) Atlas of the developing mouse brain. Academic Press, LondonGoogle Scholar
  13. 13.
    Nicholson DW, Ali A, Thornberry NA, Vaillancourt JP, Ding CK, Gallant M, Gareau Y, Griffin PR, Labelle M, Lazebnik YA et al (1995) Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature 376:37–43CrossRefPubMedGoogle Scholar
  14. 14.
    Krajewska M, Wang HG, Krajewski S, Zapata JM, Shabaik A, Gascoyne R, Reed JC (1997) Immunohistochemical analysis of in vivo patterns of expression of CPP32 (Caspase-3), a cell death protease. Cancer Res 57:1605–1613PubMedGoogle Scholar
  15. 15.
    Olney JW, Tenkova T, Dikranian K, Muglia LJ, Jermakowicz WJ, D’Sa C, Roth KA (2002) Ethanol-induced caspase-3 activation in the in vivo developing mouse brain. Neurobiol Dis 9:205–219CrossRefPubMedGoogle Scholar
  16. 16.
    Wang CZ, Johnson KM (2007) The role of caspase-3 activation in phencyclidine-induced neuronal death in postnatal rats. Neuropsychopharmacology 32:1178–1194. doi: 10.1038/sj.npp.1301202 CrossRefPubMedGoogle Scholar
  17. 17.
    Chen M, Ona VO, Li M, Ferrante RJ, Fink KB, Zhu S, Bian J, Guo L, Farrell LA, Hersch SM, Hobbs W, Vonsattel JP, Cha JH, Friedlander RM (2000) Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med 6:797–801. doi: 10.1038/77528 CrossRefPubMedGoogle Scholar
  18. 18.
    Tsuji M, Wilson MA, Lange MS, Johnston MV (2004) Minocycline worsens hypoxic-ischemic brain injury in a neonatal mouse model. Exp Neurol 189:58–65CrossRefPubMedGoogle Scholar
  19. 19.
    Potter EG, Cheng Y, Natale JE (2009) Deleterious effects of minocycline after in vivo target deprivation of thalamocortical neurons in the immature, metallothionein-deficient mouse brain. J Neurosci Res 87:1356–1368. doi: 10.1002/jnr.21963 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Arnoux I, Hoshiko M, Sanz Diez A, Audinat E (2014) Paradoxical effects of minocycline in the developing mouse somatosensory cortex. Glia 62:399–410. doi: 10.1002/glia.22612 CrossRefPubMedGoogle Scholar
  21. 21.
    Tran TD, Cronise K, Marino MD, Jenkins WJ, Kelly SJ (2000) Critical periods for the effects of alcohol exposure on brain weight, body weight, activity and investigation. Behav Brain Res 116:99–110. doi: 10.1016/S0166-4328(00)00263-1 CrossRefPubMedGoogle Scholar
  22. 22.
    Ikonomidou C, Mosinger JL, Salles KS, Labruyere J, Olney JW (1989) Sensitivity of the developing rat brain to hypobaric/ischemic damage parallels sensitivity to N-methyl-aspartate neurotoxicity. J Neurosci 9:2809–2818PubMedGoogle Scholar
  23. 23.
    Hardingham GE, Bading H (2010) Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat Rev Neurosci 11:682–696. doi: 10.1038/nrn2911 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Anastasio NC, Xia Y, O’Connor ZR, Johnson KM (2009) Differential role of N-methyl-d-aspartate receptor subunits 2A and 2B in mediating phencyclidine-induced perinatal neuronal apoptosis and behavioral deficits. Neuroscience 163:1181–1191. doi: 10.1016/j.neuroscience.2009.07.058 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Manev R, Manev H (2009) Minocycline, schizophrenia and GluR1 glutamate receptors. Prog Neuropsychopharmacol Biol Psychiatry 33:166. doi: 10.1016/j.pnpbp.2008.11.004 CrossRefPubMedGoogle Scholar
  26. 26.
    Inta D, Filipovic D, Lima-Ojeda JM, Dormann C, Pfeiffer N, Gasparini F, Gass P (2012) The mGlu5 receptor antagonist MPEP activates specific stress-related brain regions and lacks neurotoxic effects of the NMDA receptor antagonist MK-801: significance for the use as anxiolytic/antidepressant drug. Neuropharmacology 62:2034–2039. doi: 10.1016/j.neuropharm.2011.12.035 CrossRefPubMedGoogle Scholar
  27. 27.
    Jevtovic-Todorovic V, Hartman RE, Izumi Y, Benshoff ND, Dikranian K, Zorumski CF, Olney JW, Wozniak DF (2003) Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci 23:876–882PubMedGoogle Scholar
  28. 28.
    Wang C, McInnis J, Ross-Sanchez M, Shinnick-Gallagher P, Wiley JL, Johnson KM (2001) Long-term behavioral and neurodegenerative effects of perinatal phencyclidine administration: implications for schizophrenia. Neuroscience 107:535–550CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Ioana Inta
    • 1
  • Miriam A. Vogt
    • 2
  • Anne S. Vogel
    • 2
  • Markus Bettendorf
    • 1
  • Peter Gass
    • 2
  • Dragos Inta
    • 2
  1. 1.Division of Pediatric EndocrinologyUniversity Children’s Hospital HeidelbergHeidelbergGermany
  2. 2.Department of Psychiatry and Psychotherapy, Medical Faculty Mannheim, Central Institute for Mental Health MannheimUniversity of HeidelbergHeidelbergGermany

Personalised recommendations