title: Administration of mesenchymal stem cells and ziprasidone enhanced amelioration of ischemic brain damage in rats.
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.
authors.affiliation: Department of Biological Sciences, Institute of Basic Science, Inje University, Gimhae, 621-749, Korea.
authors.forename: Phatcharida
authors.initials: P
authors.lastname: Kaengkan
authors.forename: Seung Eun
authors.initials: SE
authors.lastname: Baek
authors.forename: Ji Yeong
authors.initials: JY
authors.lastname: Kim
authors.forename: Kyung-Yoon
authors.initials: KY
authors.lastname: Kam
authors.forename: Byung-Rok
authors.initials: BR
authors.lastname: Do
authors.forename: Eun Shin
authors.initials: ES
authors.lastname: Lee
authors.forename: Sung Goo
authors.initials: SG
authors.lastname: Kang
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000503:physiopathology / Q000628:therapy*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D017628:Microglia / Q000187:drug effects; D020932:Nerve Growth Factor / Q000378:metabolism; D058953:Neural Stem Cells / Q000637:transplantation*; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000494:pharmacology; D010879:Piperazines / Q000008:administration & dosage* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D051100:Glial Cell Line-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; D010879:Piperazines; D013844:Thiazoles; C092292:ziprasidone; D020932:Nerve Growth Factor