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European Archives of Psychiatry and Clinical Neuroscience

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01-03-2010 | Original Paper

Risperidone and haloperidol promote survival of stem cells in the rat hippocampus

Authors: Gerburg Keilhoff, Gisela Grecksch, Hans-Gert Bernstein, Thomas Roskoden, Axel Becker

Published in: European Archives of Psychiatry and Clinical Neuroscience | Issue 2/2010

Abstract

Altered neuroplasticity contributes to the pathophysiology of schizophrenia. However, the idea that antipsychotics may act, at least in part, by normalizing neurogenesis has not been consistently supported. Our study seeks to determine whether hippocampal cell proliferation is altered in adult rats pretreated with ketamine, a validated model of schizophrenia, and whether chronic administration with neuroleptic drugs (haloperidol and risperidone) affect changes of cell genesis/survival. Ketamine per se has no effect on cell proliferation. Its withdrawal, however, significantly induced cell proliferation/survival in the hippocampus. Risperidone and haloperidol supported cell genesis/survival as well. During ketamine withdrawal, however, their application did not affect cell proliferation/survival additionally. TUNEL staining indicated a cell-protective potency of both neuroleptics with respect to a ketamine-induced cell death. As RT-PCR and Western blot revealed that the treatment effects of risperidone and haloperidol seemed to be mediated through activation of VEGF and MMP2. The mRNA expression of NGF, BDNF, and NT3 was unaffected. From the respective receptors, only TrkA was enhanced when ketamine withdrawal was combined with risperidone or haloperidol. Risperidone also induced BCL-2. Ketamine withdrawal has no effect on the expression of VEGF, MMP2, or BCL-2. It activated the expression of BDNF. This effect was normalized by risperidone or haloperidol. The findings indicate a promoting effect of risperidone and haloperidol on survival of young neurons in the hippocampus by enhancing the expression of the anti-apoptotic protein BCL-2 and by activation of VEGF/MMP2, whereby an interference with ketamine and thus a priority role of the NMDA system was not evident.

Ahmed MR, Gurevich VV, Dalby KN, Benovic JL, Gurevich EV (2008) Haloperidol and clozapine differentially affect the expression of arrestins, receptor kinases, and extracellular signal-regulated kinase activation. J Pharmacol Exp Ther 325:276–283CrossRefPubMed

Angelucci F, Mathe AA, Aloe L (2000) Brain-derived neurotrophic factor and tyrosine kinase receptor TrkB in rat brain are significantly altered after haloperidol and risperidone administration. J Neurosci Res 60:783–794CrossRefPubMed

Becker A, Grecksch G (2004) Ketamine-induced changes in rat behaviour: a possible animal model of schizophrenia. Test of predictive validity. Prog Neuropsychopharmacol Biol Psychiatry 28:1267–1277CrossRefPubMed

Becker A, Peters B, Schroeder H, Mann T, Huether G, Grecksch G (2003) Ketamine-induced changes in rat behaviour: a possible animal model of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 27:687–700CrossRefPubMed

Bernstein H-G, Stanarius A, Baumann B, Henning H, Krell D, Danos P, Falkai P, Bogerts B (1998) Nitric oxide synthase-containing neurons in the human hypothalamus: reduced number of immunoreactive cells in the paraventricular nucleus of depressive patients and schizophrenics. Neuroscience 83:867–875CrossRefPubMed

Buckley PF (2007) Receptor-binding profiles of antipsychotics: clinical strategies when switching between agents. J Clin Psychiatry 68:5–9CrossRefPubMed

Chen AC, Shin KH, Duman RS, Sanacora G (2001) ECS-Induced mossy fiber sprouting and BDNF expression are attenuated by ketamine pretreatment. J ECT 17:27–32CrossRefPubMed

Chen J, Zacharek A, Zhang C, Jiang H, Li Y, Roberts C, Lu M, Kapke A, Chopp M (2005) Endothelial nitric oxide synthase regulates brain-derived neurotrophic factor expression and neurogenesis after stroke in mice. J Neurosci 25:2366–2375CrossRefPubMed

Chlan-Fourney J, Ashe P, Nylen K, Juorio AV, Li XM (2002) Differential regulation of hippocampal BDNF mRNA by typical and atypical antipsychotic administration. Brain Res 954:11–20CrossRefPubMed

10.

Conley RR, Kelly DL (2002) Current status of antipsychotic treatment. Curr Drug Targets CNS Neurol Disord 1:123–128CrossRefPubMed

11.

Dawirs RR, Hildebrandt K, Teuchert-Noodt G (1998) Adult treatment with haloperidol increases dentate granule cell proliferation in the gerbil hippocampus. J Neural Transm 105:317–327CrossRefPubMed

12.

Dean RA, Butler GS, Hamma-Kourbali Y, Delbé J, Brigstock DR, Courty J, Overall CM (2007) Identification of candidate angiogenic inhibitors processed by matrix metalloproteinase 2 (MMP-2) in cell-based proteomic screens: disruption of vascular endothelial growth factor (VEGF)/heparin affine regulatory peptide (pleiotrophin) and VEGF/Connective tissue growth factor angiogenic inhibitory complexes by MMP-2 proteolysis. Mol Cell Biol 27:8454–8465CrossRefPubMed

13.

Deppmann CD, Mihalas S, Sharma N, Lonze BE, Niebur E, Ginty DD (2008) A model for neuronal competition during development. Science 320:369–373CrossRefPubMed

14.

Falkai P, Bogerts B (1986) Cell loss in the hippocampus of schizophrenics. Eur Arch Psychiatry Neurol Sci 236:154–161CrossRefPubMed

15.

Fuchs E (2007) Neurogenesis in the adult brain: is there an association with mental disorders? Eur Arch Psychiatry Clin Neurosci 257:247–249CrossRefPubMed

16.

Garcia LS, Comim CM, Valvassori SS, Réus GZ, Barbosa LM, Andreazza AC, Sterz L, Fries GR, Gavioli EC, Kapczinski F, Quevedo J (2008) Acute administration of ketamine induces antidepressant-like effects in the forced swimming test and increases BDNF levels in the rat hippocampus. Prog Neuropsychopharmacol Biol Psychiatry 32:140–144CrossRefPubMed

17.

Gomes E, Rockwell P (2008) p38 MAPK as a negative regulator of VEGF/VEGFR2 signaling pathway in serum deprived human SK-N-SH neuroblastoma cells. Neurosci Lett 431:95–100PubMed

18.

Grayson B, Idris NF, Neill JC (2007) Atypical antipsychotics attenuate a sub-chronic PCP-induced cognitive deficit in the novel object recognition task in the rat. Behav Brain Res 184:31–38CrossRefPubMed

19.

Green W, Patil P, Marsden CA, Bennett GW, Wigmore PM (2006) Treatment with olanzapine increases cell proliferation in the subventricular zone and prefrontal cortex. Brain Res 1070:242–245CrossRefPubMed

20.

Heckers S (2001) Neuroimaging studies of the hippocampus in schizophrenia. Hippocampus 11:520–528CrossRefPubMed

21.

Heckers S (2004) The hippocampus in schizophrenia. Am J Psychiatry 161:2138–2139CrossRefPubMed

22.

Heckers S, Konradi C (2002) Hippocampal neurons in schizophrenia. J Neural Transm 109:891–905CrossRefPubMed

23.

Impey S, McCorkle SR, Cha-Molstad H, Dwyer JM, Yochum GS, Boss JM, McWeeney S, Dunn JJ, Mandel G, Goodman RH (2004) Defining the CREB regulon: a genome-wide analysis of transcription factor regulatory regions. Cell 119:1041–1054PubMed

24.

Ispanovic E, Haas TL (2006) JNK and PI3 K differentially regulate MMP-2 and MT1-MMP mRNA and protein in response to actin cytoskeleton reorganization in endothelial cells. Am J Physiol Cell Physiol 291:C579–C588CrossRefPubMed

25.

Jarskog LF, Gilmore JH, Selinger ES, Lieberman JA (2000) Cortical bcl-2 protein expression and apoptotic regulation in schizophrenia. Biol Psychiatry 48:641–650CrossRefPubMed

26.

Jarskog LF, Miyamoto S, Lieberman JA (2007) Schizophrenia: new pathological insights and therapies. Annu Rev Med 58:49–61CrossRefPubMed

27.

Jarskog LF, Selinger ES, Lieberman JA, Gilmore JH (2004) Apoptotic proteins in the temporal cortex in schizophrenia: high Bax/Bcl-2 ratio without caspase-3 activation. Am J Psychiatry 161:109–115CrossRefPubMed

28.

Jentsch JD, Roth RH (1999) The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia. Neurophsychopharmacology 20:201–225CrossRef

29.

Kapur S, Seeman P (2002) NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D-2 and serotonin 5-HT2 receptors—implications for models of schizophrenia. Mol Psychiatry 7:837–844CrossRefPubMed

30.

Kato T, Monji A, Hashioka S, Kanba S (2007) Risperidone significantly inhibits interferon-γ-induced microglial activation in vitro. Schizophr Res 92:108–115CrossRefPubMed

31.

Keilhoff G, Bernstein HG, Becker A, Grecksch G, Wolf G (2004) Increased neurogenesis in a ketamine-model of schizophrenia. Biol Psychiatry 56:317–322CrossRefPubMed

32.

Kippin TE, Kapur S, van der Kooy D (2005) Dopamine specifically inhibits forebrain neural stem cell proliferation, suggesting a novel effect of antipsychotic drugs. J Neurosci 25:5815–5823CrossRefPubMed

33.

Kuhn HG, Biebl M, Wilhelm D, Li M, Friedlander RM, Winkler J (2005) Increased generation of granule cells in adult Bcl-2-overexpressing mice: a role for cell death during continued hippocampal neurogenesis. Eur J Neurosci 22:1907–1915CrossRefPubMed

34.

Large CH (2007) Do NMDA receptor antagonist models of schizophrenia predict the clinical efficacy of antipsychotic drugs? J Psychopharm 21:283–301CrossRef

35.

Liu J, Suzuki T, Seki T, Namba T, Tanimura A, Arai H (2006) Effects of repeated phencyclidine administration on adult hippocampal neurogenesis in the rat. Synapse 60:56–60CrossRefPubMed

36.

Malberg JE (2004) Implications of adult hippocampal neurogenesis in antidepressant action. J Psychiatry Neurosci 29:196–205PubMed

37.

Nätzker S, Heinemann T, Figuera-Perez S, Schnieders B, Schmidt RR, Sandhoff K, van Echten-Deckert G (2002) Cis-4-methylsphingosine phosphate induces apoptosis in neuroblastoma cells by opposite effects on p38 and ERK mitogen-activated protein kinases. Biol Chem 383:1885–1894CrossRefPubMed

38.

Newton SS, Duman RS (2007) Neurogenic actions of atypical antipsychotic drugs and therapeutic implications. CNS Drugs 21:715–725CrossRefPubMed

39.

Nixon K, Crews FT (2004) Temporally specific burst in cell proliferation increases hippocampal neurogenesis in protracted abstinence from alcohol. J Neurosci 24:9714–9722CrossRefPubMed

40.

Ostenfeld T, Svendsen CN (2004) Requirement for neurogenesis to proceed through the division of neuronal progenitors following differentiation of epidermal growth factor and fibroblast growth factor-2-responsive human neural stem cells. Stem Cells 22:798–811CrossRefPubMed

41.

Packer MA, Stasiv Y, Benraiss A, Chmielnicki E, Grinberg A, Westphal H, Goldman SA, Enikolopov G (2003) Nitric oxide negatively regulates mammalian adult neurogenesis. Proc Natl Acad Sci USA 100:9566–9571CrossRefPubMed

42.

Reif A, Fritzen S, Finger M, Strobel A, Lauer M, Schmitt A, Lesch KP (2006) Neural stem cell proliferation is decreased in schizophrenia, but not in depression. Mol Psychiatry 11:514–522CrossRefPubMed

43.

Reif A, Schmitt A, Fritzen S, Lesch KP (2007) Neurogenesis and schizophrenia: dividing neurons in a divided mind? Eur Arch Psychiatry Clin Neurosci 257:290–299CrossRefPubMed

44.

Riedel M, Spellmann I, Strassnig M, Douhet A, Dehning S, Opgen-Rhein M, Valdevit R, Engel RR, Kleindienst N, Müller N, Möller HJ (2007) Effects of risperidone and quetiapine on cognition in patients with schizophrenia and predominantly negative symptoms. Eur Arch Psychiatry Clin Neurosci 257:360–370CrossRefPubMed

45.

Roskoden T, Heese K, Otten U, Schwegler H (1999) Modulation of mRNA expression of the neurotrophins of the nerve growth factor family and their receptors in the septum and hippocampus of rats after transient postnatal thyroxine treatment. II. Effects on p75 and trk receptor expression. Exp Brain Res 127:307–313CrossRefPubMed

46.

Schmajuk NA (2001) Hippocampal dysfunction in schizophrenia. Hippocampus 11:599–613CrossRefPubMed

47.

Seeman P (2002) Atypical antipsychotics: mechanism of action. Can J Psychiatry 47:27–38PubMed

48.

Seeman P (2006) Targeting the dopamine D2 receptor in schizophrenia. Expert Opin Ther Targets 10:515–531CrossRefPubMed

49.

Taupin P (2006) BrdU immunohistochemistry for studying adult neurogenesis: paradigms, pitfalls, limitations, and validation. Brain Res Rev 53:198–214CrossRefPubMed

50.

Toro CT, Deakin JFW (2007) Adult neurogenesis and schizophrenia: a window on abnormal early brain development? Schizophr Res 90:1–14CrossRefPubMed

51.

Wakade CG, Mahadik SP, Waller JL, Chiu FC (2002) Atypical neuroleptics stimulate neurogenesis in adult rat brain. J Neurosci Res 69:72–79CrossRefPubMed

52.

Warner-Schmidt JL, Duman RS (2007) VEGF is an essential mediator of the neurogenic and behavioral actions of antidepressants. Prog Natl Acad Sci USA 104:4647–4652CrossRef

53.

Yang BH, Son H, Kim SH, Nam JH, Choi JH, Lee JS (2004) Phosphorylation of ERK and CREB in cultured hippocampal neurons after haloperidol and risperidone administration. Psychiatry Clin Neurosci 58:262–267CrossRefPubMed

Title: Risperidone and haloperidol promote survival of stem cells in the rat hippocampus
Authors: Gerburg Keilhoff
Gisela Grecksch
Hans-Gert Bernstein
Thomas Roskoden
Axel Becker
Publication date: 01-03-2010
Publisher: Springer-Verlag
Published in: European Archives of Psychiatry and Clinical Neuroscience / Issue 2/2010
Print ISSN: 0940-1334
Electronic ISSN: 1433-8491
DOI: https://doi.org/10.1007/s00406-009-0033-1

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Risperidone and haloperidol promote survival of stem cells in the rat hippocampus

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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