Skip to main content
SpringerLink
Log in

Administration of mesenchymal stem cells and ziprasidone enhanced amelioration of ischemic brain damage in rats

  • Research Article
  • Published:
Molecules and Cells

Abstract

Ziprasidone is a benzisothiazolyl piperazine derivative that was developed from the chemically related antipsychotic drug tiospirone, and it improves neurological functions of the ischemic brain and is effective in treatment of schizophrenia. Mesenchymal stem cells (MSCs) are considered as a leading candidate for neurological regenerative therapy because of their neural differentiation properties in damaged brain. We investigated whether the transplantation of neural progenitor cells (NPCs) derived from adipose mesenchymal stem cells combined with ziprasidone enhances neuroprotective effects in an animal model of focal cerebral ischemia. In combination therapy groups, significant reduction of infarct volume and improvement of neurological functions were observed at 3 days after middle cerebral artery occlusion (MCAO) compared with monotherapy. Co-administration of ziprasidone and NPCs enhanced the anti-apoptotic effect and reduced the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive apoptotic cells compared with the NPCs alone group at 7 days after MCAO. Ziprasidone or the combination of ziprasidone and NPCs induced the expression of endogenous neurotrophic factor gene brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and glial cell-derived neurotrophic factor (GDNF). The immunohistochemical investigation revealed that the ziprasidone and NPCs attenuated the increased intensity of microglial marker (Iba-1) in the infarcted cortical area. Moreover, the number of transplanted NPCs on day 7 with combination therapy was significantly higher than with NPCs alone. These effects might be responsible for improved functional behavior and increased survival of NPCs. Our finding indicates that combination therapy of ziprasidone and NPCs enhances neuroprotection against ischemic brain injury.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Bai, O., Chlan-Fourney, J., Bowen, R., Keegan, D., and Li, X.-M. (2003). Expression of brain-derived neurotrophic factor mRNA in rat hippocampus after treatment with antipsychotic drugs. J. Neurosci. Res. 71, 127–131.

    Article  CAS  PubMed  Google Scholar 

  • Bliss, T., Guzman, R., Daadi, M., and Steinberg, G.K. (2007). Cell transplantation therapy for stroke. Stroke 38, 817–826.

    Article  PubMed  Google Scholar 

  • Broughton, B.R.S., Reutens, D.C., and Sobey, C.G. (2009). Apoptotic mechanisms after cerebral Ischemia. Stroke 40, e331–e339.

    Article  PubMed  Google Scholar 

  • Caley, C.F., and Cooper, C.K. (2002). Ziprasidone: the fifth atypical antipsychotic. Ann. Pharmacother. 36, 839–851.

    Article  CAS  PubMed  Google Scholar 

  • Chen, J., Sanberg, P.R., Li, Y., Wang, L., Lu, M., Willing, A.E., Sanchez-Ramos, J., and Chopp, M. (2001). Intravenous administration of human umbilical cord blood reduces behavioral deficits after stroke in rats. Stroke 32, 2682–2688.

    Article  CAS  PubMed  Google Scholar 

  • Chen, J., Li, Y., Wang, L., Lu, M., and Chopp, M. (2002). Caspase inhibition by Z-VAD increases the survival of grafted bone marrow cells and improves functional outcome after MCAO in rats. J. Neurol. Sci. 199, 17–24.

    Article  CAS  PubMed  Google Scholar 

  • Choi, D.K., Koppula, S., and Suk, K. (2011). Inhibitors of microglial neurotoxicity: focus on natural products. Molecules 16, 1021–1043.

    Article  CAS  PubMed  Google Scholar 

  • Cosi, C., Waget, A., Rollet, K., Tesori, V., and Newman-Tancredi, A. (2005). Clozapine, ziprasidone and aripiprazole but not haloperidol protect against kainic acid-induced lesion of the striatum in mice, in vivo: Role of 5-HT1A receptor activation. Brain Res. 1043, 32–41.

    Article  CAS  PubMed  Google Scholar 

  • Daniel, D.G., and Copeland, L.F. (2000). Ziprasidone: comprehensive overview and clinical use of a novel antipsychotic. Expert Opin. Invest. Drugs 9, 819–828.

    Article  CAS  Google Scholar 

  • De Keyser, J., Sulter, G., and Luiten, P.G. (1999a). Clinical trials with neuroprotective drugs in acute ischaemic stroke: are we doing the right thing?. Trends Neurosci. 22, 535–540.

    Article  PubMed  Google Scholar 

  • De Keyser, J., Sulter, G., and Luiten, P.G. (1999b). Clinical trials with neuroprotective drugs in acute ischaemic stroke: are we doing the right thing? Trends Neurosci. 22, 535–540.

    Article  PubMed  Google Scholar 

  • Dirnagl, U., Iadecola, C., and Moskowitz, M.A. (1999). Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci. 22, 391–397.

    Article  CAS  PubMed  Google Scholar 

  • Hong, I.K., Jeong, N.H., Kim, J.R., Do, B.-R., Kim, H.K., and Kang, S.G. (2008). Differentiation of dopaminergic and cholinergic neurons from mesenchymal-like stem cells derived from the adipose tissue. Dev. Reprod. 12, 31–39.

    Google Scholar 

  • Hoogduijn, M.J., Popp, F., Verbeek, R., Masoodi, M., Nicolaou, A., Baan, C., and Dahlke, M.-H. (2010). The immunomodulatory properties of mesenchymal stem cells and their use for immunotherapy. Int. Immunopharmacol. 10, 1496–1500.

    Article  CAS  PubMed  Google Scholar 

  • Kaengkan, P., Baek, S.E., Choi, Y.W., Kam, K.-Y., Kim, J.Y., Wu, Y.R., Do, B.-R., and Kang, S.G. (2013). Combination effect of phydroxybenzyl alcohol and mesenchymal stem cells on the recovery of brain damage in a rat model of brain ischemia. Animal Cell. Syst. 17, 160–169.

    Article  CAS  Google Scholar 

  • Kam, K.-Y., Jalin, A.M.A., Choi, Y.W., Kaengkan, P., Park, S.W., Kim, Y.H., and Kang, S.G. (2012). Ziprasidone attenuates brain injury after focal cerebral ischemia induced by middle cerebral artery occlusion in rats. Prog. Neuropsychopharmacol. Biol. Psychiatry 39, 69–74.

    Article  CAS  PubMed  Google Scholar 

  • Lauterbach, E.C., Shillcutt, S.D., Victoroff, J., Coburn, K.L., and Mendez, M.F. (2010). Psychopharmacological neuroprotection in neurodegenerative disease: heuristic clinical applications. J. Neuropsychiatry Clin. Neurosci. 22, 130–154.

    Article  PubMed  Google Scholar 

  • Liu, B., and Hong, J.S. (2003). Role of microglia in inflammationmediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention. J. Pharmacol. Exp. Ther. 304, 1–7.

    Article  CAS  PubMed  Google Scholar 

  • Longa, E.Z., Weinstein, P.R., Carlson, S., and Cummins, R. (1989). Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20, 84–91.

    Article  CAS  PubMed  Google Scholar 

  • Mauri, M., Lentini, D., Gravati, M., Foudah, D., Biella, G., Costa, B., Toselli, M., Parenti, M., and Coco, S. (2012). Mesenchymal stem cells enhance GABAergic transmission in co-cultured hippocampal neurons. Mol. Cell. Neurosci. 49, 395–405.

    Article  CAS  PubMed  Google Scholar 

  • Nemeroff, C.B., Lieberman, J.A., Weiden, P.J., Harvey, P.D., Newcomer, J.W., Schatzberg, A.F., Kilts, C.D., and Daniel, D.G. (2005). From clinical research to clinical practice: a 4-year review of ziprasidone. CNS Spectr. 10, 1–20.

    PubMed  Google Scholar 

  • Pandya, R.S., Mao, L., Zhou, H., Zhou, S., Zeng, J., Popp, A.J., and Wang, X. (2011). Central nervous system agents for ischemic stroke: neuroprotection mechanisms. Cent. Nerv. Syst. Agents Med. Chem. 11, 81–97.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Paxinos, G., and Watson, C. (2007). The Rat Brain in Stereotaxic Coordinates (Academic Press).

    Google Scholar 

  • Rosa, A.R., Franco, C., Torrent, C., Comes, M., Cruz, N., Horga, G., Benabarre, A., and Vieta, E. (2008). Ziprasidone in the treatment of affective disorders: a review. CNS Neurosci. Therapeutics 14, 278–286.

    Article  CAS  Google Scholar 

  • Savitz, S.I., Rosenbaum, D.M., Dinsmore, J.H., Wechsler, L.R., and Caplan, L.R. (2002). Cell transplantation for stroke. Ann. Neurol. 52, 266–275.

    Article  PubMed  Google Scholar 

  • Seeger, T.F., Seymour, P.A., Schmidt, A.W., Zorn, S.H., Schulz, D.W., Lebel, L.A., McLean, S., Guanowsky, V., Howard, H.R., and Lowe, J.A. (1995). Ziprasidone (CP-88,059): a new antipsychotic with combined dopamine and serotonin receptor antagonist activity. J. Pharmacol. Exp. Ther. 275, 101–113.

    CAS  PubMed  Google Scholar 

  • Suda, S., Shimazaki, K., Ueda, M., Inaba, T., Kamiya, N., Katsura, K.-i., and Katayama, Y. (2011). Combination therapy with bone marrow stromal cells and FK506 enhanced amelioration of ischemic brain damage in rats. Life Sci. 89, 50–56.

    Article  CAS  PubMed  Google Scholar 

  • Takahashi, K., Yasuhara, T., Shingo, T., Muraoka, K., Kameda, M., Takeuchi, A., Yano, A., Kurozumi, K., Agari, T., Miyoshi, Y., et al. (2008). Embryonic neural stem cells transplanted in middle cerebral artery occlusion model of rats demonstrated potent therapeutic effects, compared to adult neural stem cells. Brain Res. 1234, 172–182.

    Article  CAS  PubMed  Google Scholar 

  • Terry, A.V., Parikh, V., Gearhart, D.A., Pillai, A., Hohnadel, E., Warner, S., Nasrallah, H.A., and Mahadik, S.P. (2006). Time-dependent effects of haloperidol and ziprasidone on nerve growth factor, cholinergic neurons, and spatial learning in rats. J. Pharmacol. Exp. Ther. 318, 709–724.

    Article  CAS  PubMed  Google Scholar 

  • Woodbury, D., Schwarz, E.J., Prockop, D.J., and Black, I.B. (2000). Adult rat and human bone marrow stromal cells differentiate into neurons. J. Neurosci. Res. 61, 364–370.

    Article  CAS  PubMed  Google Scholar 

  • Zhao, Y., Guan, Y., Xu, Y., Li, Y., and Wu, W. (2012). Sodium Ferulate combined with bone marrow stromal cell treatment ameliorating rat brain ischemic injury after stroke. Brain Res. 1450, 157–165.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biological Sciences, Institute of Basic Science, Inje University, Gimhae, 621-749, Korea

    Phatcharida Kaengkan, Seung Eun Baek, Ji Yeong Kim & Sung Goo Kang

  2. Department of Occupational Therapy and UHRC, Inje University, Gimhae, 621-749, Korea

    Kyung-Yoon Kam

  3. Bioengineering Institute, Hurim Biocell Inc., Seoul, 153-803, Korea

    Byung-Rok Do

  4. Department of Rehabilitation Medicine Gyeongsang National University, Jinju, 660-751, Korea

    Eun Shin Lee

Authors
  1. Phatcharida Kaengkan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Seung Eun Baek
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ji Yeong Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kyung-Yoon Kam
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Byung-Rok Do
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eun Shin Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sung Goo Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sung Goo Kang.

About this article

Cite this article

Kaengkan, P., Baek, S.E., Kim, J.Y. et al. Administration of mesenchymal stem cells and ziprasidone enhanced amelioration of ischemic brain damage in rats. Mol Cells 36, 534–541 (2013). https://doi.org/10.1007/s10059-013-0235-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10059-013-0235-2

Keywords

Search

Navigation