title: Neuroprotective effects of PDGF against oxidative stress and the signaling pathway involved.
abstract: The neuroprotective effects of platelet-derived growth factor (PDGF) and the major signaling pathways involved in these were examined using primary cultured mouse cortical neurons subjected to H(2)O(2)-induced oxidative stress. The specific function of the PDGF beta-receptor (PDGFR-beta) was examined by the selective deletion of the corresponding gene using the Cre-loxP system in vitro. In wild-type neurons, PDGF-BB enhanced the survival of these neurons and suppressed H(2)O(2)-induced caspase-3 activation. The prosurvival effect of PDGF-AA was less than that of PDGF-BB. PDGF-BB highly activated Akt, extracellular signal-regulated kinase (ERK), c-jun amino-terminal kinase (JNK) and p38. PDGF-AA activated these molecules at lesser extent than PDGF-BB. In particular, PDGF-AA induced activation of Akt was at very low level. The neuroprotective effects of PDGF-BB were antagonized by inhibitors of phosphatidylinositol 3-kinase (PI3-K), mitogen-activated protein kinase kinase (MEK), JNK and p38. The PDGFR-beta-depleted neurons showed increased vulnerability to oxidative stress, and less responsiveness to PDGF-BB-induced cytoprotection and signal activation, in which Akt activation was most strongly suppressed. After all, these results demonstrated the neuroprotective effects of PDGF and the signaling pathways involved against oxidative stress. The effects of PDGF-BB were more potent than those of PDGF-AA. This might be due to the activation and additive effects of two PDGFRs after PDGF-BB stimulation. Furthermore, the PI3-K/Akt pathway that was deduced to be preferentially activated by PDGFR-beta may explain the potent effects of PDGF-BB.
authors.affiliation: Department of Pathology, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Toyama, Japan.
authors.forename: Lianshun
authors.initials: L
authors.lastname: Zheng
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ishii
authors.forename: Ayano
authors.initials: A
authors.lastname: Tokunaga
authors.forename: Takeru
authors.initials: T
authors.lastname: Hamashima
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
authors.forename: Qing-Li
authors.initials: QL
authors.lastname: Zhao
authors.forename: Shin
authors.initials: S
authors.lastname: Ishizawa
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Fujimori
authors.forename: Yo-Ichi
authors.initials: Y
authors.lastname: Nabeshima
authors.forename: Hisashi
authors.initials: H
authors.lastname: Mori
authors.forename: Takashi
authors.initials: T
authors.lastname: Kondo
authors.forename: Masakiyo
authors.initials: M
authors.lastname: Sasahara
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D000077214:Becaplermin; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000201:enzymology / Q000502:physiology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000201:enzymology / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011994:Recombinant Proteins; C075278:platelet-derived growth factor A; D000077214:Becaplermin; D006861:Hydrogen Peroxide; D020797:Receptor, Platelet-Derived Growth Factor beta; D051057:Proto-Oncogene Proteins c-akt; C505409:Casp3 protein, mouse; D053148:Caspase 3