Intracerebral chondroitinase ABC and heparan sulfate proteoglycan glypican improve outcome from chronic stroke in rats

Physical and chemical constraints imposed by the periinfarct glial scar may contribute to the limited clinical improvement often observed after ischemie brain injury. To investigate the role of some of these mediators in outcome from cerebral ischemia, we treated rats with the growth-inhibitory chon...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2012-06, Vol.109 (23), p.9155-9160
Main Authors: Hill, Justin J., Jin, Kunlin, Mao, Xiao Ou, Xie, Lin, Greenberg, David A.
Format: Article
Language:English
Subjects:
Animals
Antibodies
Astrocytes
Behavioral neuroscience
Biological Sciences
Blotting, Western
Brain damage
Brain-Derived Neurotrophic Factor - metabolism
Central nervous system
Chondroitin ABC Lyase - administration & dosage
Chondroitin ABC Lyase - pharmacology
Chondroitin ABC Lyase - therapeutic use
Fibroblast Growth Factor 2 - metabolism
Gene expression
Glial Fibrillary Acidic Protein - immunology
Glypicans
Glypicans - administration & dosage
Glypicans - pharmacology
Glypicans - therapeutic use
Immunohistochemistry
Infusions, Intra-Arterial
Ischemia
Microtubule-Associated Proteins - immunology
Neurites
Neurites - drug effects
Neurocan - administration & dosage
Neurocan - pharmacology
Neurocan - therapeutic use
Neurons
Proteins
Psychomotor Performance - drug effects
Rats
Rats, Sprague-Dawley
Rodents
Scars
Spinal cord
Stroke
Stroke - drug therapy
Stroke - enzymology
Strokes
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Summary:Physical and chemical constraints imposed by the periinfarct glial scar may contribute to the limited clinical improvement often observed after ischemie brain injury. To investigate the role of some of these mediators in outcome from cerebral ischemia, we treated rats with the growth-inhibitory chondroitin sulfate proteoglycan neurocan, thegrowth-stimulating heparan sulfate proteoglycan glypican, or the chondroitin sulfate proteoglycandegrading enzyme chondroitinase ABC. Neurocan, glypican, or chondroitinase ABC was infused directly into the infarct cavity for 7 d, beginning 7 d after middle cerebral artery occlusion. Glypican and chondroitinase ABC reduced glial fibrillary acidic protein immunoreactivity and increased microtubule-associated protein-2 ¡ mmunoreactivity in the periinfarct region, and glypican-and chondroitinase ABC-treated rats showed behavioral improvement compared with neurocan-or saline-treated rats. Glypican and chondroitinase ABC also increased neurite extension in cortical neuron cultures. Glypican increased fibroblast growth factor-2 expression and chondroitinase ABC increased brain-derived neurotrophic factor expression in these cultures, whereas no such effects were seen following neurocan treatment. Thus, treatment with glypican or enzymatic disruption of neurocan with chondroitinase ABC improves gross anatomical, histological, and functional outcome in the chronic phase of experimental stroke in rats. Changes in growth factor expression and neuritogenesis may help to mediate these effects.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1205697109