The differences between high and low-dose administration of VEGF to dopaminergic neurons of in vitro and in vivo Parkinson's disease model.
Vascular endothelial growth factor (VEGF) has previously been shown to display neuroprotective effects on dopaminergic (DA) neurons. In this study, we investigated whether the effects of VEGF were dose-dependent or not. First, VEGF was shown to be neuroprotective on 6-hydroxydopamine (6-OHDA)-treated murine DA neurons in vitro, although the 1 ng/ml of VEGF displayed more neuroprotective effects than 100 ng/ml. Furthermore, using 2 sizes of capsules (small/large) with different secreting quantities, 6-OHDA-treated rats receiving the small capsule filled with VEGF-secreting cells (BHK-VEGF) into the striatum showed a significant decrease in amphetamine-induced rotational behavior in number and a significant preservation of TH-positive fibers compared to those receiving the large BHK-VEGF capsule as well as those receiving BHK-Control capsule. Rats receiving the large BHK-VEGF capsule showed much more glial proliferation, angiogenesis, and brain edema around the capsule than those with the small one. High-dose administration of VEGF might cause poor circulation related to brain edema, although low-dose administration of VEGF displays neuroprotective effects on DA neurons. Our results demonstrate the importance of administration dose of VEGF, suggesting that low-dose administration of VEGF might be desirable for Parkinson's disease.
Yasuhara
Takao
T
Department of Neurological Surgery, Okayama University Graduate School of Medicine Dentistry, 2-5-1, Shikata-cho, Okayama 700-8558, Japan. tyasu37@cc.okayama-u.ac.jp
Shingo
Tetsuro
T
Muraoka
Kenichiro
K
wen Ji
Yuan
Y
Kameda
Masahiro
M
Takeuchi
Akira
A
Yano
Akimasa
A
Nishio
Shinsaku
S
Matsui
Toshihiro
T
Miyoshi
Yasuyuki
Y
Hamada
Hirofumi
H
Date
Isao
I
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004343:Drug Implants; D005260:Female; D066298:In Vitro Techniques; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D017072:Neostriatum / Q000187:drug effects; D009410:Nerve Degeneration / Q000139:chemically induced; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D016627:Oxidopamine; D010300:Parkinson Disease / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage*
D015259:Dopamine Agents; D004343:Drug Implants; D018696:Neuroprotective Agents; D042461:Vascular Endothelial Growth Factor A; D016627:Oxidopamine; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine