PDGF suppresses oxidative stress induced Ca2+ overload and calpain activation in neurons.
Oxidative stress is crucially involved in the pathogenesis of neurological diseases such as stroke and degenerative diseases. We previously demonstrated that platelet-derived growth factors (PDGFs) protected neurons from H2O2-induced oxidative stress and indicated the involvement of PI3K-Akt and MAP kinases as an underlying mechanism. Ca(2+) overload has been shown to mediate the neurotoxic effects of oxidative stress and excitotoxicity. We examined the effects of PDGFs on H2O2-induced Ca(2+) overload in primary cultured neurons to further clarify their neuroprotective mechanism. H2O2-induced Ca(2+) overload in neurons in a dose-dependent manner, while pretreating neurons with PDGF-BB for 24 hours largely suppressed it. In a comparative study, the suppressive effects of PDGF-BB were more potent than those of PDGF-AA. We then evaluated calpain activation, which was induced by Ca(2+) overload and mediated both apoptotic and nonapoptotic cell death. H2O2-induced calpain activation in neurons in a dose-dependent manner. Pretreatment of PDGF-BB completely blocked H2O2-induced calpain activation. To the best of our knowledge, the present study is the first to demonstrate the mechanism underlying the neuroprotective effects of PDGF against oxidative stress via the suppression of Ca(2+) overload and inactivation of calpain and suggests that PDGF-BB may be a potential therapeutic target of neurological diseases.
Institute of Anatomy and Cell Biology, School of Medicine, Zhejiang University, Hangzhou, China ; Department of Pathology, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194, Japan.
Lian-Shun
LS
Zheng
Department of Pathology, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194, Japan.
Yoko
Y
Ishii
Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Toyama, Japan.
Qing-Li
QL
Zhao
Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Toyama, Japan.
Takashi
T
Kondo
Department of Pathology, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194, Japan.
Masakiyo
M
Sasahara
D000818:Animals; D000077214:Becaplermin; D002118:Calcium / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D042541:Intracellular Space / Q000378:metabolism; D007477:Ions; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology*
D007477:Ions; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; C075278:platelet-derived growth factor A; D000077214:Becaplermin; D006861:Hydrogen Peroxide; D002154:Calpain; D002118:Calcium