PDGFs protect hippocampal neurons against energy deprivation and oxidative injury: Evidence for induction of antioxidant pathways

Abstract

Platelet-derived growth factors (PDGFs) and PDGF receptors are expressed in brain, where their functions are largely unknown. We tested the hypothesis that PDGFs play a role in promoting the survival of neurons exposed to metabolic and oxidative insults. Exposure of rat and mouse hippocampal cell cultures to glucose-deficient medium or the hydroxyl radical-promoting agent FeSO4 resulted in progressive neuronal loss. Pretreatment of cultures with PDGF-AA or PDGF-BB resulted in highly significant attenuation of glucose deprivation- and FeSO4-induced neuronal degeneration. In each injury paradigm the neuroprotective actions of the PDGFs were concentration dependent (3-100 ng/ml). In the case of glucose deprivation, significant protection was seen when cells were exposed to PDGFs prior to, or up to 8 hr following, the onset of glucose deprivation. Pretreatment with PDGFs was required for protection against FeSO4-induced oxidative injury. Western blot and immunocytochemical analyses demonstrated that cultured embryonic hippocampal neurons expressed both PDGF α-and β-receptors. PDGFs induced tyrosine phosphorylation of several proteins including a band at 180 kDa, the molecular weight of PDGF receptors. Induction of peroxide accumulation in neurons by FeSO4 was attenuated in cultures pretreated with PDGFs, suggesting that PDGFs enhanced cellular antioxidant mechanisms. Measurements of anti-oxidant enzyme activities in control and PDGF-treated cultures showed that both PDGF-AA and PDGF-BB increased both catalase and glutathione peroxidase activities, and PDGF-AA also increased superoxide dismutase activities. These findings suggest that PDGFs, which are widely expressed in brain and induced in response to injury, may play roles in protecting neurons against metabolic and oxidative insults.