Abstract
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. Ca2+ overload has been shown to mediate the neurotoxic effects of oxidative stress and excitotoxicity. We examined the effects of PDGFs on H2O2-induced Ca2+ overload in primary cultured neurons to further clarify their neuroprotective mechanism. H2O2-induced Ca2+ 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 Ca2+ 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 Ca2+ overload and inactivation of calpain and suggests that PDGF-BB may be a potential therapeutic target of neurological diseases.
Highlights
Oxidative stress and excitotoxicity play important roles in the pathogenesis of a number of neurological diseases, including ischemic infarction, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer’s, Huntington’s, and Parkinson’s diseases [1,2,3]
platelet-derived growth factor (PDGF)-AA significantly inhibited this [Ca2+]i overload. This inhibition was partial, and [Ca2+]i after H2O2 in neurons pretreated with PDGF-AA was significantly higher than that in control neurons without the H2O2 treatment. [Ca2+]i in neurons pretreated with PDGF-BB was significantly lower than that in neurons pretreated with PDGF-AA at 15 and 30 min and was similar to that in the controls at 30 min
The H2O2-induced Ca2+ increase and calpain activation in cultured neurons were markedly suppressed by PDGF and were suggested to be the targets of a neuroprotective mechanism by PDGF
Summary
Oxidative stress and excitotoxicity play important roles in the pathogenesis of a number of neurological diseases, including ischemic infarction, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer’s, Huntington’s, and Parkinson’s diseases [1,2,3]. Ca2+ has been shown to mediate the cytotoxicity of oxidative stress and excitotoxicity, and cellular Ca2+ overload or the perturbation of intracellular Ca2+ compartmentalization induced by these noxious stimuli can cause cytotoxicity and trigger cell death including both apoptotic and necrotic cell death [4,5,6]; these mechanisms of cellular injury have yet to be elucidated in adequate detail to prevent and treat neurological diseases [7, 8]. Our recent studies demonstrated that PDGF-AA and -BB protected cultured neurons against oxidative stress and suppressed H2O2-induced caspase-3 activation through PDGFR-α or -β expressed on these cells [23]. The neuroprotective mechanism underlying PDGFR signaling has not yet been clarified We identified another neuroprotective pathway mediated by PDGFs. PDGF-AA and PDGF-BB suppressed the Ca2+ overload induced by H2O2 in primary cultured mouse cortical neurons. This study provides a novel insight into the mechanism underlying the neuroprotective effects of PDGF against oxidative stress
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