Mannitol facilitates neurotrophic factor up‐regulation and behavioural recovery in neonatal hypoxic‐ischaemic rats with human umbilical cord blood grafts

We recently demonstrated that blood–brain barrier permeabilization using mannitol enhances the therapeutic efficacy of systemically administered human umbilical cord blood (HUCB) by facilitating the entry of neurotrophic factors from the periphery into the adult stroke brain. Here, we examined wheth...

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Bibliographic Details
Published in:Journal of cellular and molecular medicine 2010-04, Vol.14 (4), p.914-921
Main Authors: Yasuhara, T., Hara, K., Maki, M., Xu, L., Yu, G., Ali, M. M., Masuda, T., Yu, S. J., Bae, E. K., Hayashi, T., Matsukawa, N., Kaneko, Y., Kuzmin‐Nichols, N., Ellovitch, S., Cruz, E. L., Klasko, S. K., Sanberg, C. D., Sanberg, P. R., Borlongan, C. V.
Format: Article
Language:English
Subjects:
Animals
Animals, Newborn
Antibodies
Asymmetry
Behavior, Animal - drug effects
Blood-brain barrier
Bone marrow
Brain
Brain - drug effects
Brain - pathology
Brain injury
Brain-derived neurotrophic factor
Carotid arteries
Cell Survival - drug effects
Cell therapy
cerebral palsy
Cord blood
Cord Blood Stem Cell Transplantation
Dendrites - drug effects
Dendrites - pathology
Enzyme-linked immunosorbent assay
Glial cell line-derived neurotrophic factor
Graft Survival - drug effects
Hippocampus - drug effects
Hippocampus - pathology
Humans
Hypoxia
Hypoxia-Ischemia, Brain - metabolism
Hypoxia-Ischemia, Brain - pathology
Hypoxia-Ischemia, Brain - therapy
Ischemia
Laboratory animals
Mannitol
Mannitol - pharmacology
Motor ability
Neonates
Nerve growth factor
Nerve Growth Factors - genetics
Nerve Growth Factors - metabolism
neurotrophic factor
Rats
Rats, Sprague-Dawley
stem cells
Stroke
Transplantation
Transplants & implants
Umbilical cord
Up-regulation
Up-Regulation - drug effects
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Summary:We recently demonstrated that blood–brain barrier permeabilization using mannitol enhances the therapeutic efficacy of systemically administered human umbilical cord blood (HUCB) by facilitating the entry of neurotrophic factors from the periphery into the adult stroke brain. Here, we examined whether the same blood–brain barrier manipulation approach increases the therapeutic effects of intravenously delivered HUCB in a neonatal hypoxic‐ischaemic (HI) injury model. Seven‐day‐old Sprague–Dawley rats were subjected to unilateral HI injury and then at day 7 after the insult, animals intravenously received vehicle alone, mannitol alone, HUCB cells (15k mononuclear fraction) alone or a combination of mannitol and HUCB cells. Behavioural tests at post‐transplantation days 7 and 14 showed that HI animals that received HUCB cells alone or when combined with mannitol were significantly less impaired in motor asymmetry and motor coordination compared with those that received vehicle alone or mannitol alone. Brain tissues from a separate animal cohort from the four treatment conditions were processed for enzyme‐linked immunosorbent assay at day 3 post‐transplantation, and revealed elevated levels of GDNF, NGF and BDNF in those that received HUCB cells alone or when combined with mannitol compared with those that received vehicle or mannitol alone, with the combined HUCB cells and mannitol exhibiting the most robust neurotropic factor up‐regulation. Histological assays revealed only sporadic detection of HUCB cells, suggesting that the trophic factor–mediated mechanism, rather than cell replacement per se, principally contributed to the behavioural improvement. These findings extend the utility of blood–brain barrier permeabilization in facilitating cell therapy for treating neonatal HI injury.
ISSN:1582-1838
1582-4934
DOI:10.1111/j.1582-4934.2008.00671.x