title: PI3-K/Akt and ERK pathways activated by VEGF play opposite roles in MPP+-induced neuronal apoptosis.
abstract: Vascular endothelial growth factor (VEGF), a specific pro-angiogenic peptide, has shown neuroprotective effects in the Parkinson's disease (PD) models, but the underlying mechanisms remain elusive. In this study, the neuroprotective properties of VEGF on 1-methyl-4-phenylpyridinium ion (MPP(+))-induced neurotoxicity in primary cerebellar granule neurons were investigated. Pretreatment of VEGF prevented MPP(+)-induced neuronal apoptosis in a concentration- and time-dependent manner. And this prevention was blocked by PTK787/ZK222584, a VEGF receptor-2 specific inhibitor. Both inhibition of the Akt pathway and activation of the extracellular signal-regulated kinase (ERK) pathway contribute to MPP(+)-induced neuronal apoptosis. VEGF reversed the inhibition of phosphoinositide 3-kinase (PI3-K)/Akt pathway caused by MPP(+), but further enhanced the activation of ERK induced by MPP(+). Interestingly, VEGF and PD98059 (an ERK kinase inhibitor) play a synergistic role in protecting neurons from MPP(+)-induced toxicity. Collectively, these findings suggest that the PI3-K/Akt and ERK pathways activated by VEGF play opposite roles in MPP(+)-induced neuronal apoptosis. This finding offers not only a new and clinically significant modality as to how VEGF exerts its neuroprotective effects but also a novel therapeutic strategy for PD by differentially regulating PD-associated signaling pathways.
authors.affiliation: Department of Applied Biology and Chemical Technology, Institute of Modern Medicine, The Hong Kong Polytechnic University, Hong Kong.
authors.forename: Wei
authors.initials: W
authors.lastname: Cui
authors.forename: Wenming
authors.initials: W
authors.lastname: Li
authors.forename: Renwen
authors.initials: R
authors.lastname: Han
authors.forename: Shinghung
authors.initials: S
authors.lastname: Mak
authors.forename: Huan
authors.initials: H
authors.lastname: Zhang
authors.forename: Shengquan
authors.initials: S
authors.lastname: Hu
authors.forename: Jianhui
authors.initials: J
authors.lastname: Rong
authors.forename: Yifan
authors.initials: Y
authors.lastname: Han
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D004334:Drug Administration Schedule; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D009410:Nerve Degeneration / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010300:Parkinson Disease / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D061251:Primary Cell Culture; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*
chemical_list: D015655:1-Methyl-4-phenylpyridinium; D018696:Neuroprotective Agents; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D042461:Vascular Endothelial Growth Factor A