The PDGF B-chain is involved in the ontogenic susceptibility of the developing rat brain to NMDA toxicity.
Hypoxic-ischemic (H-I) injury to neonatal brains can cause a life-long neuronal deficit because of increased susceptibility in the neonatal period. Excitotoxicity due to overstimulation of the N-methyl-d-aspartate receptor (NMDAR) is assumed to be the basis of the injury. However, the ontogenic profile of the susceptibility does not directly correlate with the levels of NMDAR expression. Platelet-derived growth factor B-chain (PDGF-B) has been reported to protect neurons by suppressing the NMDA-evoked current and translocating the glutamate transporter to the cell membrane. Thus, we assessed the relationship between the susceptibility to H-I injury and the expression of PDGF-B in neonatal rat brain. PDGF-B infusion before and after an intrastriatal NMDA injection significantly reduced the size of the lesions in 7-day-old rats, when they are most susceptible and the neuronal expression of PDGF-B is low. Fourteen-day-old neonatal rats were found to be resistant to NMDA injury, even though NMDARs are expressed at high levels in the brain at this age. Inhibition of PDGF-B protein synthesis by antisense oligodeoxynucleotides increased the size of the NMDA-induced lesions up to 6-fold at postnatal day 14, when PDGF-B is expressed at high levels in neurons. These data suggest that PDGF-B is an important physiological modulator of NMDAR excitability in the developing brain, and that the balance between the expression of NMDAR and PDGF-B partly determines the ontogenic susceptibility to brain injury. Enhancement of the PDGF-B/receptor signal pathway might rescue neonatal brains at risk of H-I injury.
Department of Pediatrics, Shiga University of Medical Science, Shiga, Japan.
Tomoko
T
Egawa-Tsuzuki
Masaki
M
Ohno
Naoto
N
Tanaka
Yoshihiro
Y
Takeuchi
Hidetaka
H
Uramoto
Roland
R
Faigle
Keiko
K
Funa
Yoko
Y
Ishii
Masakiyo
M
Sasahara
D000375:Aging; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects* / Q000254:growth & development / Q000473:pathology; D019556:COS Cells; D002522:Chlorocebus aethiops; D004247:DNA / Q000378:metabolism; D004198:Disease Susceptibility; D004347:Drug Interactions; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D015151:Immunoblotting / Q000379:methods; D007150:Immunohistochemistry / Q000379:methods; D016202:N-Methylaspartate / Q000633:toxicity*; D020320:Oligoribonucleotides, Antisense / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014162:Transfection
D018690:Excitatory Amino Acid Agonists; D020320:Oligoribonucleotides, Antisense; D020574:Proto-Oncogene Proteins c-sis; D016202:N-Methylaspartate; D004247:DNA