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

  • Gerburg Keilhoff
  • Gisela Grecksch
  • Hans-Gert Bernstein
  • Thomas Roskoden
  • Axel Becker
Original Paper

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.

Keywords

Animal model BrdU Ketamine Schizophrenia 

Abbreviations

5-HT2A

5-Hydroxytryptamine (serotonin) receptor 2A

BCL-2

B cell lymphoma 2

BDNF

Brain-derived neurotrophic factor

BrdU

5-Bromo-2′-deoxy-uridine

cAMP

Cyclic adenosine-3′,5′-monophosphate

cDNA

Complementary DNA

CREB

cAMP response element binding protein

CTGF

Connective tissue growth factor

DCX

Doublecortin

dUTP

2′-Deoxyuridine 5′-triphosphate

ERK

Extracellular signal-regulated kinase

Galac

Galactocerebroside

GAPDH

Glycerinaldehyde-3-phosphate-dehydrogenase

GFAP

Glial fibrillary acidic protein

HARP

Heparin affin regulatory peptide

i.p.

Intraperitoneally

JNK

c Jun-N-terminal kinase

K/H

Ketamine/haloperidol

K/R

Ketamine/risperidone

K/S

Ketamine/saline

LSAB

Labeled streptavidin biotin horseradish peroxidase

MEK

Mitogen-activated protein (MAP) kinase

MMP2

Matrix metallopeptidase 2 (gelatinase A)

NeuN

Neuronal nuclei

NGF

Nerve growth factor

NMDA

N-methyl-d-aspartate

NT3

Neurotrophin

OX42

Integrin alpha-M

PBS

Phosphate-buffered saline

PCP

Phencyclidine

PI3K

Phosphatidylinositol-3-kinase

RT-PCR

Reverse transcriptase polymerase chain reaction

S/H

Saline/haloperidol

S/R

Saline/risperidone

S/S

Saline/saline

TBS

Tris-buffered saline

TdT

Terminal deoxynucleotidyl transferase

Trk

Tyrosine kinase receptor

TUNEL

Terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling

VEGF

Vascular endothelial growth factor

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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Gerburg Keilhoff
    • 1
  • Gisela Grecksch
    • 2
  • Hans-Gert Bernstein
    • 3
  • Thomas Roskoden
    • 4
  • Axel Becker
    • 2
  1. 1.Institute of Biochemistry and Cell BiologyUniversity of MagdeburgMagdeburgGermany
  2. 2.Institute of Pharmacology and ToxicologyUniversity of MagdeburgMagdeburgGermany
  3. 3.Department of PsychiatryUniversity of MagdeburgMagdeburgGermany
  4. 4.Institute of AnatomyUniversity of MagdeburgMagdeburgGermany

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