title: Intraperitoneal and intravenous deliveries are not comparable in terms of drug efficacy and cell distribution in neonatal mice with hypoxia-ischemia.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Ohshima
authors.affiliation: Department of Regenerative Medicine Research, Institute of Biomedical Research Innovation, Kobe, Hyogo, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Taguchi
authors.affiliation: Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Tsuda
authors.affiliation: Division of Neonatology, Center for Maternal-Neonatal Care, Nagoya University Hospital, Nagoya, Aichi, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yamahara
authors.affiliation: Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Harada-Shiba
authors.affiliation: Department of Biochemistry, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
authors.forename: Mikiya
authors.initials: M
authors.lastname: Miyazato
authors.affiliation: Department of Obstetrics and Gynecology, Mie University School of Medicine, Tsu, Mie, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Ikeda
authors.affiliation: Department of Investigative Radiology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Iida
authors.affiliation: Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan. Electronic address: tsuji.masahiro.ri@ncvc.go.jp.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tsuji
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D016026:Bone Marrow Transplantation; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002340:Carotid Artery Diseases; D003907:Dexamethasone / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000008:administration & dosage* / Q000493:pharmacokinetics; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics; D005268:Femoral Vein; D019788:Fluorodeoxyglucose F18; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008251:Macaca; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011897:Random Allocation; D011917:Rats, Inbred Lew; D055647:Rats, Transgenic; D016896:Treatment Outcome
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D019788:Fluorodeoxyglucose F18; D016291:Dizocilpine Maleate; D003907:Dexamethasone
keywords: Cell transfusion; Dexamethasone; Intraperitoneal injection; Intravenous injection; MK-801; Mesenchymal stem cell; Mononuclear cell; Neonatal hypoxic–ischemic encephalopathy; Primate