Reduction of ischemic brain injury by topical application of glial cell line-derived neurotrophic factor after permanent middle cerebral artery occlusion in rats

H. Kitagawa, T. Hayashi, Y. Mitsumoto, N. Koga, Y. Itoyama, Koji Abe

Research output: Contribution to journalArticle

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Abstract

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 sire nick labeling (TUNEL) staining was performed for the detection of DNA fragmentation. lmmunoreactivities 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.

Original languageEnglish
Pages (from-to)1417-1422
Number of pages6
JournalStroke
Volume29
Issue number7
Publication statusPublished - Jul 1998

Fingerprint

Glial Cell Line-Derived Neurotrophic Factor
Middle Cerebral Artery Infarction
Brain Injuries
Caspase 1
Brain Edema
In Situ Nick-End Labeling
DNA Fragmentation
Caspases
Caspase 3
Caspase 2
Staining and Labeling
DNA Nucleotidylexotransferase
Biotin
Edema
Neurons
Water
Brain

Keywords

  • Caspases
  • Cerebral ischemia
  • GDNF
  • Middle cerebral artery occlusion
  • Rats

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Neuroscience(all)

Cite this

Reduction of ischemic brain injury by topical application of glial cell line-derived neurotrophic factor after permanent middle cerebral artery occlusion in rats. / Kitagawa, H.; Hayashi, T.; Mitsumoto, Y.; Koga, N.; Itoyama, Y.; Abe, Koji.

In: Stroke, Vol. 29, No. 7, 07.1998, p. 1417-1422.

Research output: Contribution to journalArticle

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N2 - 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 sire nick labeling (TUNEL) staining was performed for the detection of DNA fragmentation. lmmunoreactivities 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.

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