Bone morphogenetic proteins are involved in fetal kidney tissue transplantation-induced neuroprotection in stroke rats.
Both bone morphogenetic proteins (BMPs) and glial cell line-derived neurotrophic factor (GDNF) reduce ischemia-induced cerebral injury in rats. Intracerebral transplantation of fetal kidney tissue, which normally expresses BMPs and GDNF during development, reduces ischemic injury in cerebral cortex. In this study, we tested the hypothesis that BMP is involved in this neuroprotective response. Fetal kidney tissue was cut into small pieces and transplanted into cortical areas adjacent to the right middle cerebral artery (MCA) in adult rats. In situ hybridization of brain indicated that these fetal kidney transplants contained high levels of BMP-7 mRNA three days after grafting. Immunohistochemical analysis of grafted brain showed co-localization of BMP-7 and PAX-2 immunoreactivity in the graft, suggesting that these transplants contained BMP protein. Some animals were grafted with fetal kidney tissue after intraventricular administration (ICV) of the BMP antagonist noggin (1 micro g) or after vehicle, followed by MCA ligation for 60 min. Animals receiving fetal kidney tissue transplantation developed significantly less body asymmetry, as compared to stroke animals that either did not receive transplantation or received fetal kidney grafts and noggin pretreatment. Analysis of these brains after triphenyltetrazolium chloride staining showed that fetal kidney tissue transplantation reduced the volume of infarction in the cerebral cortex. Noggin pretreatment reduced the protection induced by fetal kidney grafting, although noggin itself did not cause increase in cerebral infarction. Eight hours after ischemia, brain homogenates were obtained from grafted and control animals to assay caspase-3 enzymatic activity. This analysis demonstrated that fetal kidney grafts significantly reduced ischemia-induced caspase-3 activity. Reduction of caspase-3 activity could also be antagonized by noggin pretreatment. In conclusion, our data suggest that fetal kidney transplantation reduces ischemia/reperfusion-induced cortical infarction and behavioral deficits in adult rats, which are, at least partially, mediated through the effect of BMPs from the transplants.
Chang
C F
CF
Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. cchang@intra.nida.nih.gov
Morales
M
M
Chou
J
J
Chen
H L
HL
Hoffer
B
B
Wang
Y
Y
D000818:Animals; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D002352:Carrier Proteins; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002544:Cerebral Infarction / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism; D016332:Fetal Tissue Transplantation / Q000502:physiology*; D007839:Functional Laterality / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007276:Injections, Intraventricular; D016030:Kidney Transplantation / Q000502:physiology*; D008026:Ligation; D008297:Male; D020768:Middle Cerebral Artery / Q000502:physiology; D009043:Motor Activity / Q000502:physiology; D051762:PAX2 Transcription Factor; D011506:Proteins / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000502:physiology; D020521:Stroke / Q000473:pathology* / Q000628:therapy*; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta; D000099176:Noggin Protein
D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D053148:Caspase 3; D020169:Caspases; D004268:DNA-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D051762:PAX2 Transcription Factor; D011506:Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D000099176:Noggin Protein; C525821:Bmp7 protein, rat; C505410:Casp3 protein, rat