Human FGF-1 gene delivery protects against quinolinate-induced striatal and hippocampal injury in neonatal rats.
Fibroblast growth factors (FGFs) are cell mitogens and differentiating factors with neuroprotective properties in the CNS. We have already shown that endothelial cells genetically engineered to secrete human FGF-1 (RBEZ-FGF) survive implantation to neonatal rat brain (Johnston et al. (1996) J. Neurochem. 67, 1643-1652]. In this study, the effects of cell-based FGF-1 gene delivery on quinolinate-induced neurotoxicity in the developing rat brain were examined. Control endothelial cells (RBE4), and RBEZ-FGF cells were implanted into right striatum at post-natal day (PND) 7. On PND 10, quinolinate (150 nmol), an endogenous N-methyl-d-aspartate (NMDA) receptor agonist, or vehicle alone was injected into striatum ipsilateral to cell implantation. Injury was quantified in coronal sections obtained from PND 17 animals by comparing striatal and hippocampal volumes ipsilateral and contralateral to the site of quinolinate injection. Human FGF-1 specific transgene expression in vivo was shown by Northern blot and RT-PCR up to 14 days after cell implantation in control animals, and up to 4 days after quinolinate exposure. Quinolinate reduced the size of ipsilateral striatum by 37% and hippocampus by 38% in animals preimplanted with control endothelial cells. In contrast, quinolinate reduced the size of striatum by only 14% and had no effect on hippocampal size in animals preimplanted with RBEZ-FGF cells. Thus, FGF-1 gene delivery protected the developing striatum and hippocampus from quinolinate-induced volume loss by 62% and 100%, respectively. Intrastriatal quinolinate resulted in a significant decrease in density of NOS+ CA3 hippocampal neurons (-38%) without affecting the density of NOS+ neurons in hippocampal regions CA1, dentate gyrus or striatum. This response of CA3 NOS+ neurons appeared to be only partially reversed by FGF-1 gene delivery. Our results show that intracerebral FGF-1 gene expression within the developing brain can protect striatum and hippocampus from quinolinate-mediated injury.
1Department of Neurology, The Johns Hopkins University School of Medicine, USA; 2The Kennedy Krieger Research Institute, Baltimore, MD 21205, USA. hossain@kennedykrieger.org
M A
MA
Hossain
K E
KE
Fielding
W H
WH
Trescher
T
T
Ho
M A
MA
Wilson
J
J
Laterra
D000818:Animals; D000831:Animals, Newborn; D015152:Blotting, Northern; D001930:Brain Injuries / Q000139:chemically induced / Q000517:prevention & control*; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000187:drug effects / Q000293:injuries*; D004730:Endothelium, Vascular / Q000637:transplantation; D016220:Fibroblast Growth Factor 1; D016222:Fibroblast Growth Factor 2 / Q000235:genetics* / Q000502:physiology*; D051519:Fibroblast Growth Factor 4; D005346:Fibroblast Growth Factors / Q000235:genetics; D006624:Hippocampus / Q000187:drug effects / Q000293:injuries*; D006801:Humans; D007150:Immunohistochemistry; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D011518:Proto-Oncogene Proteins / Q000235:genetics; D017378:Quinolinic Acid / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D011993:Recombinant Fusion Proteins / Q000235:genetics; D014162:Transfection
C496445:FGF4 protein, human; C496447:Fgf4 protein, rat; D051519:Fibroblast Growth Factor 4; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1; D005346:Fibroblast Growth Factors; C496320:NOS1 protein, human; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D017378:Quinolinic Acid