Activation of MAP kinases, Akt and PDGF receptors in injured peripheral nerves

Abstract

A number of receptor tyrosine kinases (RTKs) and the downstream phosphatidylinositol-3-kinase (PI3K)/Akt and mitogen-activated protein (MAP) kinase signaling pathways have been critically involved in peripheral nerve regeneration. Here, we examined the activation of PI3K/Akt and MAP kinase pathways, and platelet-derived growth factor receptors (PDGFRs) in the distal segments of crushed rat sciatic nerve from 3 to 28 days after injury. In Western blot analyses, the phosphorylated forms of extracellular signal-regulated protein kinase (ERK) and c-Jun NH(2)-terminal kinases (JNKs) were highly augmented on days 3 and 7 and on days 7 and 14 after injury, respectively. Phosphorylated Akt and p38 consistently increased from 3 to 28 days after injury. Phosphorylated PDGFR-alpha and -beta were also increased from 3 to 14 days. In the immunohistological analyses, phosphorylated ERK and PDGFR-alpha were co-localized in many activated Schwann cells and regrowing axons 3 days after injury, while PDGFR-beta was localized in a few spindle-shaped cells. The detected temporal profile of RTK signaling appears to be crucial for the regulation of Schwann cell proliferation and following redifferentiation. Furthermore, the immunohistological studies suggested a role of ERK and PDGFR-alpha in axon regeneration as well.

PRGD/PDLLA conduit potentiates rat sciatic nerve regeneration and the underlying molecular mechanism

“…Our study demonstrated the activation levels of ERK in both group A and B were abundantly detected in regenerated axons and increased from day 7e35 after injury. The p-ERK activation level in group B were highly expressed in both intervals, (1.46 and 1.96 times, respectively) more than that in group A, and (1.39 and 2.45 times, respectively) than that in group C. This evidence is consistent with the conclusion of previous studies [15,44], which reported that the higher phosphorylation of ERK was observed in the regenerated axons compared to the normal intact nerve from different time intervals between one and 30 days after nerve injury. Although the mechanism of ERK signaling pathway stimulation is not clarified, the elevated p-ERK in the end stumps may be due to the induction of mediatory signals activated at the lesion site [41,45].…”

Platelet-Rich Plasma Promotes Axon Regeneration, Wound Healing, and Pain Reduction: Fact or Fiction

“…Although PDGF and its receptor are present on Schwann cells in vitro and in vivo [248], upon denervation, Schwann cells increase their expression of PDGF receptors [248,297,298] and expression and release of PDGF [297]. Thus, the administration of exogenous PDGF to injured peripheral axons enhances the extent of their regeneration by direct action on the injured axons [297,299], but also by inducing Schwann cell proliferation, differentiation, myelin formation, and triggering their upregulation of the synthesis and release of neurotrophic factors [246], which act directly on injured axons to promote them to regenerate [247,248]. This influence is increased when PDGF is administered simultaneously with IGF-1 [299].…”

Implications for Differentiation of Endogenous Stem Cells: Therapeutic Effect from Icariside II on a Rat Model of Postprostatectomy Erectile Dysfunction

“…p38 MAPK pathway is essential for the proper differentiation of many hematopoietic, mesenchymal, and epithelial stem/progenitor cells, and disruption of this kinase pathway has pathological consequences in many organs [27]. In addition, accumulating evidence suggests the p38 MAPK pathway is crucially involved in the nerve injury [28]. Although p38 MAPK has been detected to participate in neural degeneration following peripheral nerve injury, it also is abundantly expressed in regenerating nerves, suggesting that the activation of the p38 participates in the normal regeneration process [29].…”