From the Department of Neurology, Tohoku University School of Medicine,
Sendai, Japan, and the Third Tokushima Institute of New Drug Research (Y.M.,
N.K.), Otsuka Pharmaceutical Co, Ltd, Tokushima, Japan.
Correspondence to Dr Koji Abe, Department of Neurology, Okayama University Medical School, 2–5-1 Shikatacho, Okayama, 700-8558, Japan.
Background and Purpose—Glial cell
line–derived neurotrophic factor (GDNF) plays important roles in the
survival and recovery of some mature neurons under pathological
conditions. However, the effect of GDNF in ameliorating
ischemic brain injury has not been well documented. Therefore,
we investigated a possible effect of GDNF on the changes of infarct
size, brain edema, DNA fragmentation, and immunoreactivities for
caspases after permanent middle cerebral artery occlusion (MCAO)
in rats.
Methods—For the estimation of ischemic brain injury, we
calculated the infarct size of MCA region and also measured the brain
water content as edema formation at 24 hours after the MCAO. Terminal
deoxynucleotidyl transferase–mediated dUTP-biotin
in situ nick labeling (TUNEL) staining was performed for the detection
of DNA fragmentation. Immunoreactivities for caspase-1 (ICE), caspase-2
(Nedd-2), and caspase-3 (CPP32) were stained.
Results—Both infarct size and brain edema after permanent MCAO
were significantly reduced by topical application of GDNF (48% and
30% decreases, P=0.01). TUNEL staining and
immunoreactivities for caspases were markedly induced at 12 hours after
permanent MCAO in the vehicle-treated animals. However, the spatial
distribution of those immunohistochemically positive cells was
dissociative in each caspase. Induction of TUNEL staining and
immunoreactivities for caspases-1 and -3 was greatly reduced with GDNF
treatment, whereas the reduction of caspase-2 staining was only
minimum.
Conclusions—These data suggest that the reduction of infarct size
and brain edema by GDNF was greatly associated with the reduction of
DNA fragmentation and apoptotic signals predominantly through
caspases-1 and -3 cascades.
Associate
Editor for Basic Science,
School of Medicine,
Medical College of Virginia,
Richmond, Virginia
© 1998 American Heart Association, Inc.
Original Contributions
Reduction of Ischemic Brain Injury by Topical Application of Glial Cell Line–Derived Neurotrophic Factor After Permanent Middle Cerebral Artery Occlusion in Rats
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