Dilong: Role in Peripheral Nerve Regeneration

Abstract

Dilong, also known as earthworm, has been widely used in traditional Chinese medicine (TCM) for thousands of years. Schwann cell migration and proliferation are critical for the regeneration of injured nerves and Schwann cells provide an essentially supportive role for neuron regeneration. However, the molecular mechanisms of migration and proliferation induced by dilongs in Schwann cells remain unclear. Here, we discuss the molecular mechanisms that includes (i) migration signaling, MAPKs (mitogen-activated protein kinases), mediated PAs and MMP2/9 pathway; (ii) survival and proliferative signaling, IGF-I (insulin-like growth factor-I)-mediated PI3K/Akt pathways and (iii) cell cycle regulation. Dilong stimulate RSC96 cell proliferation and migration. It can induce phosphorylation of ERK1/2 and p38, but not JNK, and activate the downstream signaling expression of PAs (plasminogen activators) and MMPs (matrix metalloproteinases) in a time-dependent manner. In addition, Dilong stimulated ERK1/2 and p38 phosphorylation was attenuated by pretreatment with chemical inhibitors (U0126 and SB203580), and small interfering ERK1/2 and p38 RNA, resulting in migration and uPA-related signal pathway inhibition. Dilong also induces the phosphorylation of IGF-I-mediated PI3K/Akt pathway, activates protein expression of PCNA (proliferating cell nuclear antigen) and cell cycle regulatory proteins (cyclin D1, cyclin E and cyclin A) in a time-dependent manner. In addition, it accelerates G1-phase progression with earlier S-phase entry and significant numbers of cells entered the S-phase. The siRNA-mediated knockdown of PI3K that significantly reduces PI3K protein expression levels, resulting in Bcl2 survival factor reduction, revealing a marked blockage of G1 to S transition in proliferating cells. These results reveal the unknown RSC96 cell migration and proliferation mechanism induced by dilong, which find use as a new medicine for nerve regeneration.

Study of analgesic effect of earthworm extract

“…Although, we could not demonstrate any toxic effects of EE in our experiments, to the best of our knowledge, it exhibited no gross toxic effects. Furthermore, our observation is in tune with the recent studies conducted by Chang et al [ 30 ] and Li et al [ 31 ], who have shown that EE can improve peripheral nerve regeneration and exhibits analgesic activity. Simultaneously, we used naloxone, an antagonist of opioid receptor [ 21 ] which plays a pivotal role in central nociceptive system, to block opioid receptor, and found that naloxone exhibited no effects on analgesic effects of EE in mice.…”

Lumbricus rubellus Protein Fraction DLBS1033N Increases Nerve Growth Factor Expression via Tyrosine Kinase Activation

“…Some studies, however, have revealed that earthworm extract can be used in nerve regeneration treatments. Chang et al (2011a;2011b) reported that Dilong can promote Schwann cells proliferation and migration. Dilong is consisted of earthworm Pheretima aspergillum.…”

Hypoxia-Induced Upregulation of miR-132 Promotes Schwann Cell Migration After Sciatic Nerve Injury by Targeting PRKAG3

“…Thus, it is of great significance to understand the mechanisms underlying SC migration after peripheral nerve injury and further identify targets to promote SC migration and peripheral nerve regeneration. Growth factors that regulate SC migration have been widely investigated, such as glial-cell-line-derived neurotrophic factor (GDNF) and neuregulin-1 (NRG1), which activate MAPK pathway to stimulate SC migration [22]. Our group has also identified several miRNAs that are involved in phenotype modulation of SCs during peripheral nerve regeneration [11][12][13].…”