Makiko Ohshima1, Akihiko Taguchi2, Hidetoshi Tsuda1, Yoshiaki Sato3, Kenichi Yamahara1, Mariko Harada-Shiba1, Mikiya Miyazato4, Tomoaki Ikeda5, Hidehiro Iida6, Masahiro Tsuji7. 1. Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan. 2. Department of Regenerative Medicine Research, Institute of Biomedical Research Innovation, Kobe, Hyogo, Japan. 3. Division of Neonatology, Center for Maternal-Neonatal Care, Nagoya University Hospital, Nagoya, Aichi, Japan. 4. Department of Biochemistry, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan. 5. Department of Obstetrics and Gynecology, Mie University School of Medicine, Tsu, Mie, Japan. 6. Department of Investigative Radiology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan. 7. Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan. Electronic address: tsuji.masahiro.ri@ncvc.go.jp.
Abstract
BACKGROUND AND PURPOSE: Most therapeutic agents are administered intravenously (IV) in clinical settings and intraperitoneally (IP) in preclinical studies with neonatal rodents; however, it remains unclear whether intraperitoneal (IP) injection is truly an acceptable alternative for intravenous (IV) injection in preclinical studies. The objective of our study is to clarify the differences in the therapeutic effects of drugs and in the distribution of infused cells after an IP or IV injection in animals with brain injury. METHODS: Dexamethasone or MK-801, an N-methyl-d-aspartate receptor antagonist was administered either IP or IV in a mouse model of neonatal hypoxic-ischemic encephalopathy. Green fluorescent protein-expressing mesenchymal stem cells (MSCs) or mononuclear cells (MNCs) were injected IP or IV in the mouse model. Two hours and 24h after the administration of the cells, we investigated the cell distributions by immunohistochemical staining. We also investigated distribution of IV administered MNCs labeled with 2-[18F]fluoro-2-deoxy-d-glucose in a juvenile primate, a macaque with stroke 1h after the administration. RESULTS: IP and IV administration of dexamethasone attenuated the brain injury to a similar degree. IP administration of MK-801 attenuated brain injury, whereas IV administration of MK-801 did not. The IV group showed a significantly greater number of infused cells in the lungs and brains in the MSC cohort and in the spleen, liver, and lung in the MNC cohort compared to the IP group. In the macaque, MNCs were detected in the spleen and liver in large amounts, but not in the brain and lungs. CONCLUSIONS: This study demonstrated that the administration route influences the effects of drugs and cell distribution. Therefore, a preclinical study may need to be performed using the optimal administration route used in a clinical setting.
BACKGROUND AND PURPOSE: Most therapeutic agents are administered intravenously (IV) in clinical settings and intraperitoneally (IP) in preclinical studies with neonatal rodents; however, it remains unclear whether intraperitoneal (IP) injection is truly an acceptable alternative for intravenous (IV) injection in preclinical studies. The objective of our study is to clarify the differences in the therapeutic effects of drugs and in the distribution of infused cells after an IP or IV injection in animals with brain injury. METHODS:Dexamethasone or MK-801, an N-methyl-d-aspartate receptor antagonist was administered either IP or IV in a mouse model of neonatal hypoxic-ischemicencephalopathy. Green fluorescent protein-expressing mesenchymal stem cells (MSCs) or mononuclear cells (MNCs) were injected IP or IV in the mouse model. Two hours and 24h after the administration of the cells, we investigated the cell distributions by immunohistochemical staining. We also investigated distribution of IV administered MNCs labeled with 2-[18F]fluoro-2-deoxy-d-glucose in a juvenile primate, a macaque with stroke1h after the administration. RESULTS: IP and IV administration of dexamethasone attenuated the brain injury to a similar degree. IP administration of MK-801attenuated brain injury, whereas IV administration of MK-801 did not. The IV group showed a significantly greater number of infused cells in the lungs and brains in the MSC cohort and in the spleen, liver, and lung in the MNC cohort compared to the IP group. In the macaque, MNCs were detected in the spleen and liver in large amounts, but not in the brain and lungs. CONCLUSIONS: This study demonstrated that the administration route influences the effects of drugs and cell distribution. Therefore, a preclinical study may need to be performed using the optimal administration route used in a clinical setting.
Authors: Giuliana Castello Coatti; Miriam Frangini; Marcos C Valadares; Juliana Plat Gomes; Natalia O Lima; Natale Cavaçana; Amanda F Assoni; Mayra V Pelatti; Alexander Birbrair; Antonio Carlos Pedroso de Lima; Julio M Singer; Francisco Marcelo M Rocha; Giovani Loiola Da Silva; Mario Sergio Mantovani; Lucia Inês Macedo-Souza; Merari F R Ferrari; Mayana Zatz Journal: Stem Cell Rev Rep Date: 2017-10 Impact factor: 5.739