Effect of repeated allogeneic bone marrow mononuclear cell transplantation on brain injury following transient focal cerebral ischemia in rats

Life Sci. 2014 Jan 24;95(1):22-8. doi: 10.1016/j.lfs.2013.12.016. Epub 2013 Dec 22.

Abstract

Aims: Transplantation of bone marrow mononuclear cells (BMMCs) exerts neuroprotection against cerebral ischemia. We examined the therapeutic timepoint of allogeneic BMMC transplantation in a rat model of focal cerebral ischemia, and determined the effects of repeated transplantation outside the therapeutic window.

Main methods: Male Sprague-Dawley rats were subjected to 90 minute focal cerebral ischemia, followed by intravenous administration of 1 × 10(7) allogeneic BMMCs or vehicle at 0, 3 or 6 h after reperfusion or 2 × 10(7) BMMCs 6 h after reperfusion. Other rats administered 1 × 10(7) BMMCs at 6 h after reperfusion received additional BMMC transplantation or vehicle 9 h after reperfusion. Infarct volumes, neurological deficit scores and immunohistochemistry were evaluated 24 or 72 h after reperfusion.

Key findings: Infarct volumes at 24 h were significantly decreased in transplantation rats at 0 and 3 h, but not at 6 h, after reperfusion, compared to vehicle-treatment. Even high dose BMMC transplantation at 6h after reperfusion was ineffective. Repeated BMMC transplantation at 6 and 9h after reperfusion reduced infarct volumes and significantly improved neurological deficit scores at 24 and 72 h. Immunohistochemistry showed repeated BMMC transplantation reduced ionized calcium-binding adapter molecule 1, 4-hydroxy-2-nonenal and 8-hydroxydeoxyguanosine expression at 24 and 72 h after reperfusion.

Significance: Intravenous allogeneic BMMCs were neuroprotective following transient focal cerebral ischemia, and the therapeutic time window of BMMC transplantation was >3 h and <6 h after reperfusion in this model. Repeated transplantation at 6 and 9 h after reperfusion suppressed inflammation and oxidative stress in ischemic brains, resulting in improved neuroprotection.

Keywords: Allogeneic transplantation; Bone marrow; Cerebral ischemia; Neuroprotection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 8-Hydroxy-2'-Deoxyguanosine
  • Aldehydes / metabolism
  • Animals
  • Bone Marrow Transplantation / methods*
  • Brain Injuries / etiology
  • Brain Injuries / therapy*
  • Calcium-Binding Proteins / metabolism
  • Deoxyguanosine / analogs & derivatives
  • Deoxyguanosine / metabolism
  • Disease Models, Animal
  • Immunohistochemistry
  • Inflammation / etiology
  • Inflammation / therapy
  • Ischemic Attack, Transient / complications*
  • Leukocytes, Mononuclear / transplantation*
  • Male
  • Microfilament Proteins / metabolism
  • Oxidative Stress
  • Rats
  • Rats, Sprague-Dawley
  • Time Factors
  • Transplantation, Homologous

Substances

  • Aif1 protein, rat
  • Aldehydes
  • Calcium-Binding Proteins
  • Microfilament Proteins
  • 8-Hydroxy-2'-Deoxyguanosine
  • Deoxyguanosine
  • 4-hydroxy-2-nonenal