Article

Neuroprotective effects of PDGF against oxidative stress and the signaling pathway involved.

Department of Pathology, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Toyama, Japan.
Journal of Neuroscience Research (impact factor: 2.74). 12/2009; 88(6):1273-84. DOI:10.1002/jnr.22302
Source: PubMed

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.

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Keywords

Cre-loxP system
 
extracellular signal-regulated kinase
 
H(2)O(2)-induced oxidative stress
 
low level
 
major signaling pathways
 
mitogen-activated protein kinase kinase
 
PDGF beta-receptor
 
PDGF-AA induced activation
 
PDGF-BB stimulation
 
PDGF-BB-induced cytoprotection
 
PDGFR-beta-depleted neurons
 
phosphatidylinositol 3-kinase
 
PI3-K/Akt pathway
 
platelet-derived growth factor
 
preferentially activated
 
primary cultured mouse cortical neurons
 
selective deletion
 
signaling pathways
 
suppressed H(2)O(2)-induced caspase-3 activation
 
wild-type neurons
 

Lianshun Zheng