Releasing ‘brakes’ to nerve regeneration: intrinsic molecular targets

Abstract

Restoring critical neuronal architecture after peripheral nerve injury is challenging. Although immediate regenerative responses to peripheral axon injury involve the synthesis of regeneration-associated proteins in neurons and Schwann cells, an unfavorable balance between growth facilitatory and growth inhibitory signaling impairs the growth continuum of injured peripheral nerves. Molecules involved with the signaling network of tumor suppressors play crucial roles in shifting the balance between growth and restraint during axon regeneration. An understanding of the molecular framework of tumor suppressor molecules in injured neurons and its impact on stage-specific regeneration events may expose therapeutic intervention points. In this review we discuss how signaling networks of the specific tumor suppressors PTEN, Rb1, p53, p27 and p21 are altered in injured peripheral nerves and how this impacts peripheral nerve regeneration. Insights into the roles and importance of these pathways may open new avenues for improving the neurological deficits associated with nerve injury.

Regeneration of long-distance peripheral nerve defects after delayed reconstruction in healthy and diabetic rats is supported by immunomodulatory chitosan nerve guides

“…The tested nerve guides alone are, however, not sufficient to support a degree of axonal and functional motor recovery similar to that after immediate nerve reconstruction. It is, however, a known fact that nerve regeneration after delayed reconstruction is impaired [36, 37] and the possible strategies to improve it range widely from targeting molecular cues [38] to supplementary treatment strategies, like intra-surgical electrostimulation or rehabilitation exercise [36]. …”

Diabetic neuropathy and the sensory neuron: New aspects of pathogenesis and their treatment implications

“…From this point of view, our laboratory has focused on manipulating intrinsic “brake” molecules to regulate growth pathways. Such “brakes” include those within the class of “tumor suppressors” that help to inhibit oncogenic growth. PTEN is the first example of this type of therapeutic target studied in diabetes mellitus, a molecule that inhibits the PI3K–Akt signaling pathway (Figure ).…”

Neuronal functions of FOXO/DAF-16

“…These factors include neurotrophic factors and structural proteins that orchestrate the repair and regrowth of nerves. Induction of the regeneration program peaks at one week post injury, then declines over the course of 2-3 months [62]. Regeneration also depends on Schwann cells, which provide growth support to the regenerating axons.…”

“…Regeneration also depends on Schwann cells, which provide growth support to the regenerating axons. Similar to C. elegans , regeneration of peripheral nerves also declines with age in mammals [63, 64], and the PI3K-AKT signaling pathway has been implicated in the process of regeneration [62]. However, in contrast to what has been observed in the nematode, IGF-1 can stimulate regeneration of mammalian axons in response to injury [65].…”