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Mol. Cells 2013; 36(6): 534-541

Published online November 28, 2013

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

© The Korean Society for Molecular and Cellular Biology

Administration of Mesenchymal Stem Cells and Ziprasidone Enhanced Amelioration of Ischemic Brain Damage in Rats

Phatcharida Kaengkan, Seung Eun Baek, Ji Yeong Kim, Kyung-Yoon Kam, Byung-Rok Do, Eun Shin Lee, and Sung Goo Kang

Department of Biological Sciences, Institute of Basic Science, 1Department of Occupational Therapy and UHRC, Inje University, Gimhae 621-749, Korea,
2Bioengineering Institute, Hurim Biocell Inc., Seoul 153-803, Korea, 3Department of Rehabilitation Medicine Gyeongsang National University, Jinju
660-751, Korea

Received: August 22, 2013; Revised: October 25, 2013; Accepted: November 4, 2013

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.

Keywords combination therapy, ischemic brain, mesenchymal stem cell, ziprasidone

Article

Research Article

Mol. Cells 2013; 36(6): 534-541

Published online December 31, 2013 https://doi.org/10.1007/s10059-013-0235-2

Copyright © The Korean Society for Molecular and Cellular Biology.

Administration of Mesenchymal Stem Cells and Ziprasidone Enhanced Amelioration of Ischemic Brain Damage in Rats

Phatcharida Kaengkan, Seung Eun Baek, Ji Yeong Kim, Kyung-Yoon Kam, Byung-Rok Do, Eun Shin Lee, and Sung Goo Kang

Department of Biological Sciences, Institute of Basic Science, 1Department of Occupational Therapy and UHRC, Inje University, Gimhae 621-749, Korea,
2Bioengineering Institute, Hurim Biocell Inc., Seoul 153-803, Korea, 3Department of Rehabilitation Medicine Gyeongsang National University, Jinju
660-751, Korea

Received: August 22, 2013; Revised: October 25, 2013; Accepted: November 4, 2013

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.

Keywords: combination therapy, ischemic brain, mesenchymal stem cell, ziprasidone

Mol. Cells
May 31, 2023 Vol.46 No.5, pp. 259~328
COVER PICTURE
The alpha-helices in the lamin filaments are depicted as coils, with different subdomains distinguished by various colors. Coil 1a is represented by magenta, coil 1b by yellow, L2 by green, coil 2a by white, coil 2b by brown, stutter by cyan, coil 2c by dark blue, and the lamin Ig-like domain by grey. In the background, cells are displayed, with the cytosol depicted in green and the nucleus in blue (Ahn et al., pp. 309-318).

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