Injectable anti-inflammatory, antioxidant supramolecular nanofiber hydrogel for peripheral nerve injury repair and neuropathic pain relief.

The peripheral nervous system is a vital part of the body because it transfers information to coordinate all actions. Peripheral nerve injuries are detrimental to the proper function of this system and can cause loss of sense and movement. It is of utmost importance to research approaches to the treatment of peripheral nerve damage because such injuries can drastically change a person's life, and these traumatic injuries are a significant cause of physical disabilities that primarily affect the lives of young adults of working age. The aetiologies of traumatic peripheral nerve injury include penetrating injury, crush, traction, ischemia, and less common mechanisms, such as thermal-, electric shock-, radiation-, percussion-, and vibration-induced injuries (Robinson, 2004). Lacerations, for example, by glass, knives, fans, saw blades, auto metal, and long bone fractures, account for approximately 30% of serious nerve injuries. Another common injury mechanism is compression, which may involve mechanical deformation and ischemia. Manipulation of the nerve can generate a severe inflammatory reaction in the nerve, and these reactions have been likened to chemical burns with dense scarring accompanied by considerable pain (Bagheri et al., 2011).

Peripheral nerve injury (PNI) may lead to disability and neuropathic pain, which constitutes a substantial economic burden to patients and society. It was found that the peripheral nervous system (PNS) has the ability to regenerate after injury due to a permissive microenvironment mainly provided by Schwann cells (SCs) and the intrinsic growth capacity of neurons; however, the results of injury repair are not always satisfactory. Effective, long-distance axon regeneration after PNI is achieved by precise regulation of gene expression. Numerous studies have shown that in the process of peripheral nerve damage and repair, differential expression of non-coding RNAs (ncRNAs) significantly affects axon regeneration, especially expression of microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs). In the present article, we review the cellular and molecular mechanisms of axon regeneration after PNI, and analyze the roles of these ncRNAs in nerve repair. In addition, we discuss the characteristics and functions of these ncRNAs. Finally, we provide a thorough perspective on the functional mechanisms of ncRNAs in nervous injury repair, and explore the potential these ncRNAs offer as targets of nerve injury treatment.

Emerging evidence suggests that folic acid (FA) supports nerve repair, but its beneficial effects in peripheral nerve injury (PNI) remains unclear. This study aims to investigate protective effects of FA against PNI and the underlying molecular mechanisms. High-performance liquid chromatography–tandem mass spectrometry was utilized for precise quantification of metabolites. A sciatic nerve crush injury model was established in rats, followed by assessments of cell proliferation, apoptosis, and motor function using CCK-8 assays, flow cytometry, and the balance beam test, respectively. Neuromorphological observations, electromyography, and ELISA were conducted to evaluate structural, electrophysiological, and biochemical parameters. In vitro, FA restored methionine cycle balance in Schwann cells and neurons disrupted by enzyme inhibition, improving cell viability, reducing apoptosis, and preserving cellular structure. In vivo, FA supplementation restored S-adenosylmethionine and homocysteine levels in a methionine metabolism disorder model and enhanced motor function, neural morphology, neuron survival, and electrophysiological recovery after PNI. Epigenetic analyses revealed that FA modulated DNA methylation and histone modifications of the DNM3 promoter, influencing gene expression. Furthermore, FA facilitated nerve repair via the DNM3-AKT pathway, regulating apoptosis, autophagy, and oxidative stress-related enzymes. These findings highlight FA’s potential in promoting nerve repair through metabolic and epigenetic mechanisms.

Neuropathic pain is a chronic debilitating disease that is often unresponsive to currently available treatments. Emerging lines of evidence indicate that reactive oxygen species (ROS) are required for the development and maintenance of neuropathic pain. However, little is known about endogenous mechanisms that neutralize the pain-relevant effects of ROS. In the present study, we tested whether the stress-responsive antioxidant protein Sestrin 2 (Sesn2) blocks the ROS-induced neuropathic pain processing in vivo. We observed that Sesn2 mRNA and protein expression was up-regulated in peripheral nerves after spared nerve injury, a well-characterized model of neuropathic pain. Sesn2 knockout (Sesn2(-/-)) mice exhibited considerably increased late-phase neuropathic pain behavior, while their behavior in acute nociceptive and in inflammatory pain models remained unaffected. The exacerbated neuropathic pain behavior of Sesn2(-/-) mice was associated with elevated ROS levels and an enhanced activating transcription factor 3 up-regulation in sensory neurons, and it was reversed by the ROS scavenger N-tert-Butyl-α-phenylnitrone. In contrast, administration of the ROS donor tert-butyl hydroperoxide induced a prolonged pain behavior in naive Sesn2(-/-) mice. We show that the antioxidant function of Sesn2 limits neuropathic pain processing in vivo. Sesn2 controls ROS-dependent neuropathic pain signaling after peripheral nerve injury and may, thus, provide a potential new target for the clinical management of chronic neuropathic pain conditions.

Google Trends Analysis of Peripheral Nerve Disease and Surgery

Peripheral nerve injury (PNI) is a public health problem that can lead to sensory and motor deficits as well as neuropathic pain and secondary lesions. We explored the effects of the combination of MaR1 and NGF on sciatic nerve regeneration, reduction of neuropathic pain, and anti-inflammation, and further elucidated the associated molecular mechanisms. After treatment of PC12 (adrenal pheochromocytoma cells) cells with NGF, MaR1 and H₂O₂, changes in proliferation were detected by CCK8; cell migration ability was detected by Transwell; reactive oxygen species (ROS) and apoptosis were detected by flow cytometry; and the mRNA expression of the inflammatory factors IL-1β, IL-6, and TNF-α was detected by qRT-PCR. Western blot detected the protein expression of β-catenin, P62, GSK-3β, LC3B, NF200, S100, MBP; Immunofluorescence analysis of LC3B expression; During recovery experiments, observe changes following treatment with GSK-3β activators and the autophagy agonist rapamycin. PNI model was constructed using 6-week-old male SD rats, NGF, MaR1 or saline was injected locally, and the drug was administered 3 times on alternate days after surgery, sciatic nerve function index analysis and muscle atrophy test were performed after surgery; the gastrocnemius muscle wet weight ratio and HE staining were observed after the samples were taken after surgery, and NF200, S100, MBP, β-catenin, and P62 were detected by Western blot, GSK-3β, LC3B levels; the expression of NF200, β-catenin, P62, GSK-3β, LC3B was detected by immunohistochemistry. NGF and MaR1 were non-toxic and the combination of NGF and MaR1 increased the proliferation and migration of PC12 cells, reduced H₂O₂ induced ROS production, inhibited apoptosis, and had a significant anti-inflammatory effect. In vivo studies showed that MaR1 and NGF combined could more effectively promote nerve repair and recovery of sensory and motor functions in SD rats, and reduce gastrocnemius muscle atrophy.The combination of MaR1 and NGF inhibited autophagy through GSK-3β/β-catenin signaling pathway to regulate the growth and repair of sciatic nerve. And the GSK-3β agonist DIF-3 and the autophagy activator rapamycin antagonize this effect. The combination of MaR1 and NGF promotes sciatic nerve repair and motor function recovery and reduces local inflammation by inhibiting autophagy through the GSK-3β/β-catenin pathway.

Neuropathic pain is a complex and debilitating condition resulting from nerve damage, characterized by sensations such as burning, tingling, and shooting pain. It is often associated with conditions such as multiple sclerosis (MS), Guillain-Barré syndrome (GBS), and diabetic polyneuropathy. Conventional pain therapies frequently provide limited relief and are accompanied by significant side effects, emphasizing the need to explore alternative treatment options. Phytochemicals, which are bioactive compounds derived from plants, have gained attention for their potential in neuropathic pain management due to their diverse pharmacological properties, including anti-inflammatory, antioxidant, and neuroprotective effects. This review evaluates the mechanisms by which specific phytochemicals, such as curcumin, resveratrol, and capsaicin, influence neuropathic pain pathways, particularly their role in modulating inflammatory processes, reducing oxidative stress, and interacting with ion channels and signaling pathways. While curcumin and resveratrol are primarily considered dietary supplements, their roles in managing neuropathic pain require further clinical investigation to establish their efficacy and safety. In contrast, capsaicin is an active ingredient derived from chili peppers that has been developed into approved topical treatments widely used for managing neuropathic and musculoskeletal pain. However, not all phytochemicals have demonstrated consistent efficacy in managing neuropathic pain, and their effects can vary depending on the compound and the specific condition. The pathophysiology of neuropathic pain, involving maladaptive changes in the somatosensory nervous system, peripheral and central sensitization, and glial cell activation, is also outlined. Overall, this review emphasizes the need for continued high-quality clinical studies to fully establish the therapeutic potential of phytochemicals in neuropathic pain management.

Anesthesia Literature Review

A self-assembling peptide-based hydrogel containing NF-κB inhibitors and NGF for peripheral nerve injury repair

Chronic neuropathic pain (NP) has become a worldwide public health problem. This study was aimed to establish graded NP model to investigate the effect of CREB1 on nerve repair and NP after peripheral nerve injury. Based on NP model, we measured the 50% paw withdrawal threshold (PWT) of rat hind paws and sciatic functional index (SFI). Luxol fast blue staining was performed to measure the ratio of distal myelin sheath to proximal (DPR). The c-Fos, GFAP, CX3CR1 and IBA-1 expressions in spinal cord were measured by Western blot. The expression levels of CREB1 and ATF-3 in dorsal root ganglion (DRG) were both measured. Intrathecal injection was performed by using recombinant CREB, or anti-CREB antibody for NP model, respectively. The above indexes were detected. In NP model, the 50% PWTs and DPR were gradually reduced and SFI was increased. The c-Fos, GFAP, CX3CR1 and IBA-1 expressions were increased compared to control group. The CREB1 and ATF-3 expressions in DRG showed gradually increase. With the injection of recombinant CREB, the similar changes were found in rats compared with NP model. While after anti-CREB1 antibody injection, all effects of CREB1 were impaired. Likewise, anti-CREB1 antibody treatment increased 50% PWT and DPR, decreased SFI, decreased expressions of c-Fos, GFAP, CX3CR1 and IBA-1. Besides, ATF-3 expression was inhibited by CREB1 suppression. CREB1 involved in the regulation of NP and nerve repair process, suggesting that CREB1 has potential as a new target for the treatment of chronic NP.

PurposePain disrupts the daily and social lives of patients with neuropathic pain. Effective treatment of neuropathic pain is difficult. Pharmacological treatments for neuropathic pain are limited, and 40–60% of patients do not achieve even partial relief of their pain. This study created a chronic constriction injury (CCI) model in rats to examine the effects of regular exercise on neuropathic pain relief, elucidate the mechanism, and determine the effects of neuropathic pain in the hippocampus.MethodsCCI model rats were randomly divided into exercise (Ex) and no exercise (No-Ex) groups. Normal rats (Normal group) were used as controls. The Ex group exercised on a treadmill at 20 m/min for 30 min, 5 days per week for 5 weeks post-CCI. The 50% pain response threshold was assessed by mechanical stimulation. Using immunohistochemistry, we examined activation of glial cells (microglia and astrocytes) by CCR2 and TRAF6 expression in the spinal cord dorsal horn and DCX and PROX1 expression in the hippocampal dentate gyrus.ResultsThe 50% pain response threshold was significantly lower in the Ex than in the No-Ex group at 5 weeks post-CCI, indicating pain relief. In the spinal cord dorsal horn, IBA1, CCR2, and TRAF6 expression was markedly lower in the Ex group than in the No-Ex group at 3 weeks post-CCI. IBA1, GFAP, CCR2, and TRAF6 expression was markedly lower in the Ex group than in the No-Ex group at 5 weeks post-CCI. In the hippocampus, DCX, but not PROX1, expression was significantly higher in the Ex group than in the No-Ex group at 3 weeks post-CCI. At 5 weeks post-CCI, both DCX and PROX1 expression was markedly increased in the Ex group compared to the No-Ex group.ConclusionOur findings suggest that regular exercise can improve the neuropathic pain-induced neurogenic dysfunction in the hippocampal dentate gyrus.

Many studies have recently highlighted the role of photobiomodulation (PBM) in neuropathic pain (NP) relief after spinal cord injury (SCI), suggesting that it may be an effective way to relieve NP after SCI. However, the underlying mechanisms remain unclear. This study aimed to determine the potential mechanisms of PBM in NP relief after SCI. We performed systematic observations and investigated the mechanism of PBM intervention in NP in rats after SCI. Using transcriptome sequencing, we screened CXCL10 as a possible target molecule for PBM intervention and validated the results in rat tissues using reverse transcription-polymerase chain reaction and western blotting. Using immunofluorescence co-labeling, astrocytes and microglia were identified as the cells responsible for CXCL10 expression. The involvement of the NF-κB pathway in CXCL10 expression was verified using inhibitor pyrrolidine dithiocarbamate (PDTC) and agonist phorbol-12-myristate-13-acetate (PMA), which were further validated by an in vivo injection experiment. Here, we demonstrated that PBM therapy led to an improvement in NP relative behaviors post-SCI, inhibited the activation of microglia and astrocytes, and decreased the expression level of CXCL10 in glial cells, which was accompanied by mediation of the NF-κB signaling pathway. Photobiomodulation inhibit the activation of the NF-κB pathway and reduce downstream CXCL10 expression. The NF-κB pathway inhibitor PDTC had the same effect as PBM on improving pain in animals with SCI, and the NF-κB pathway promoter PMA could reverse the beneficial effect of PBM. Our results provide new insights into the mechanisms by which PBM alleviates NP after SCI. We demonstrated that PBM significantly inhibited the activation of microglia and astrocytes and decreased the expression level of CXCL10. These effects appear to be related to the NF-κB signaling pathway. Taken together, our study provides evidence that PBM could be a potentially effective therapy for NP after SCI, CXCL10 and NF-kB signaling pathways might be critical factors in pain relief mediated by PBM after SCI.

Considerations in evaluating new treatment alternatives following peripheral nerve injuries: A prospective clinical study of methods used to investigate sensory, motor and functional recovery

Peripheral nerve injuries commonly occur due to trauma, like a traffic accident. Peripheral nerves get severed, causing motor neuron death and potential muscle atrophy. The current golden standard to treat peripheral nerve lesions, especially lesions with large (≥ 3 cm) nerve gaps, is the use of a nerve autograft or reimplantation in cases where nerve root avulsions occur. If not tended early, degeneration of motor neurons and loss of axon regeneration can occur, leading to loss of function. Although surgical procedures exist, patients often do not fully recover, and quality of life deteriorates. Peripheral nerves have limited regeneration, and it is usually mediated by Schwann cells and neurotrophic factors, like glial cell line-derived neurotrophic factor, as seen in Wallerian degeneration. Glial cell line-derived neurotrophic factor is a neurotrophic factor known to promote motor neuron survival and neurite outgrowth. Glial cell line-derived neurotrophic factor is upregulated in different forms of nerve injuries like axotomy, sciatic nerve crush, and compression, thus creating great interest to explore this protein as a potential treatment for peripheral nerve injuries. Exogenous glial cell line-derived neurotrophic factor has shown positive effects in regeneration and functional recovery when applied in experimental models of peripheral nerve injuries. In this review, we discuss the mechanism of repair provided by Schwann cells and upregulation of glial cell line-derived neurotrophic factor, the latest findings on the effects of glial cell line-derived neurotrophic factor in different types of peripheral nerve injuries, delivery systems, and complementary treatments (electrical muscle stimulation and exercise). Understanding and overcoming the challenges of proper timing and glial cell line-derived neurotrophic factor delivery is paramount to creating novel treatments to tend to peripheral nerve injuries to improve patients’ quality of life.

Injectable, antioxidative, and neurotrophic factor-deliverable hydrogel for peripheral nerve regeneration and neuropathic pain relief