Intraperitoneal and intravenous deliveries are not comparable in terms of drug efficacy and cell distribution in neonatal mice with hypoxia-ischemia.

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.

• Authors: Makiko Ohshima, Akihiko Taguchi, Hidetoshi Tsuda, Yoshiaki Sato, Kenichi Yamahara, Mariko Harada-Shiba, Mikiya Miyazato, Tomoaki Ikeda, Hidehiro Iida, Masahiro Tsuji
• Journal: Brain & development (Brain Dev) Vol. 37 Issue 4 Pg. 376-86 (Apr 2015) ISSN: 1872-7131 [Electronic] Netherlands
• PMID: 25034178 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Chemical References

• Excitatory Amino Acid Antagonists
• Neuroprotective Agents
• Fluorodeoxyglucose F18
• Dizocilpine Maleate
• Dexamethasone

Topics

• Animals
• Animals, Newborn
• Bone Marrow Transplantation
• Brain (drug effects, metabolism)
• Carotid Artery Diseases
• Dexamethasone (administration & dosage, pharmacokinetics)
• Disease Models, Animal
• Dizocilpine Maleate (administration & dosage, pharmacokinetics)
• Excitatory Amino Acid Antagonists (administration & dosage, pharmacokinetics)
• Femoral Vein
• Fluorodeoxyglucose F18
• Hypoxia-Ischemia, Brain (drug therapy, metabolism)
• Injections, Intraperitoneal
• Injections, Intravenous
• Leukocytes, Mononuclear (metabolism)
• Macaca
• Male
• Mice
• Neuroprotective Agents (administration & dosage, pharmacokinetics)
• Random Allocation
• Rats, Inbred Lew
• Rats, Transgenic
• Treatment Outcome