The peripheral nerve system has an intrinsic regenerative capacity in response to traumatic injury. To better understand the molecular events occurring after peripheral nerve injury, in the current study, a rat model of sciatic nerve crush injury was used. Injured nerves harvested at 0, 1, 4, 7, and 14 days post injury were subjected to deep RNA sequencing for examining global gene expression changes. According to the temporally differential expression patterns of a huge number of genes, 3 distinct phases were defined within the post-injury period of 14 days: the acute, sub-acute, and post-acute stages. Each stage showed its own characteristics of gene expression, which were associated with different categories of diseases and biological functions and canonical pathways. Ingenuity pathway analysis revealed that genes involved in inflammation and immune response were significantly up-regulated in the acute phase, and genes involved in cellular movement, development, and morphology were up-regulated in the sub-acute stage, while the up-regulated genes in the post-acute phase were mainly involved in lipid metabolism, cytoskeleton reorganization, and nerve regeneration. All the data obtained in the current study may help to elucidate the molecular mechanisms underlying peripheral nerve regeneration from the perspective of gene regulation, and to identify potential therapeutic targets for the treatment of peripheral nerve injury.

Dorsal root ganglia (DRG) neurons spontaneously undergo neurite growth after nerve injury. MicroRNAs (miRNAs), as small, non-coding RNAs, negatively regulate gene expression in a variety of biological processes. The roles of miRNAs in the regulation of responses of DRG neurons to injury stimuli, however, are not fully understood. Here, microarray analysis was performed to profile the miRNAs in L4-L6 DRGs following rat sciatic nerve transection. The 26 known miRNAs were differentially expressed at 0, 1, 4, 7, 14 d post injury, and the potential targets of the miRNAs were involved in nerve regeneration, as analyzed by bioinformatics. Among the 26 miRNAs, microRNA-222 (miR-222) was our research focus because its increased expression promoted neurite outgrowth while it silencing by miR-222 inhibitor reduced neurite outgrowth. Knockdown experiments confirmed that phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a major inhibitor of nerve regeneration, was a direct target of miR-222 in DRG neurons. In addition, we found that miR-222 might regulate the phosphorylation of cAMP response element binding protein (CREB) through PTEN, and c-Jun activation might enhance the miR-222 expression. Collectively, our data suggest that miR-222 could regulate neurite outgrowth from DRG neurons by targeting PTEN.

Peripheral nerve injury is a global problem that causes disability and severe socioeconomic burden. Brain-derived neurotrophic factor (BDNF) benefits peripheral nerve regeneration and becomes a promising therapeutic molecule. In the current study, we found that microRNA-1 (miR-1) directly targeted BDNF by binding to its 3′-UTR and caused both mRNA degradation and translation suppression of BDNF. Moreover, miR-1 induced BDNF mRNA degradation primarily through binding to target site 3 rather than target site 1 or 2 of BDNF 3′-UTR. Following rat sciatic nerve injury, a rough inverse correlation was observed between temporal expression profiles of miR-1 and BDNF in the injured nerve. The overexpression or silencing of miR-1 in cultured Schwann cells (SCs) inhibited or enhanced BDNF secretion from the cells, respectively, and also suppressed or promoted SC proliferation and migration, respectively. Interestingly, BDNF knockdown could attenuate the enhancing effect of miR-1 inhibitor on SC proliferation and migration. These findings will contribute to the development of a novel therapeutic strategy for peripheral nerve injury, which overcomes the limitations of direct administration of exogenous BDNF by using miR-1 to regulate endogenous BDNF expression.

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After peripheral nerve injury, the degenerative debris and inflammatory alterations at the injury site may block the elongation of regenerating axons to reach target organs. Tissue plasminogen activator (tPA), a serine protease, has a capability of degrading matrix molecules and cell adhesions. In this study, we found that either tPA or miR-340 was differentially expressed in the injured nerve after sciatic nerve injury, and that the expressions of tPA and miR-340 were negatively correlated to each other. Moreover, miR-340 and tPA were co-localized in sciatic nerve. miR-340 regulated tPA through direct targeting of the 3'-UTR of tPA. Functionally, over- or under-expression of miR-340 reduced or augmented the fibrinolytic activity and migration ability of cultured Schwann cells as well as tPA secretion from the cells, respectively. In rats with sciatic nerve crush injury, dysregulation of the miR-340 expression in the injury site affected the cell debris removal and axonal regrowth. Obviously, unlike many previous studies that investigate the functional impact of miRNAs on peripheral nerve regeneration in the perspective of miRNA regulation of neural cell behaviors, the present study focused on miRNA regulation of debris clearance, thus updating our understanding of the regulatory roles of miRNAs in peripheral nerve regeneration.

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Chitooligosaccharides (COSs) are the biodegradation products of chitosan that have been demonstrated with neuroaffinity and/or neuroprotective actions. In this study, we investigated the possible benefits of treatment with COSs on nerve regeneration after crush injuries to peripheral nerves. The rabbits with the crushed common peroneal nerve were treated by daily intravenous injection of 1.5 or 3 mg/kg body weight of COSs or identical volume of saline (as the control) for a 6-week period. At the end of COSs treatment, electrophysiological assessments, Meyer's trichrome and Masson trichrome staining, and transmission electron microscopy were used to evaluate the regeneration of injured common peroneal nerve and atrophy of the tibialis posterior muscle. The results showed that the compound muscle action potentials, the number of regenerated myelinated nerve fibers, the thickness of regenerated myelin sheaths, and the cross-sectional area of tibialis posterior muscle fibers were significantly improved in the nerves that received COSs treatment and the results with COSs treatment displayed a dose-dependent pattern. This study demonstrated that COSs accelerated peripheral nerve regeneration after crush injury to rabbit common peroneal nerves. The COSs could probably become a potential neuroprotective agent for improvement of peripheral nerve regeneration after the injury and deserve for further studies.