Chitosan oral administration stimulates regeneration after experimentally induced peripheral nerve injury

Expression patterns and role of PTEN in rat peripheral nerve development and injury

Anti-hyperalgesic and anti-allodynic effects of intrathecal nociceptin/orphanin FQ in rats after spinal cord injury, peripheral nerve injury and inflammation

Perioperative Nerve Injury: A Silent Scream?

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.

Peripheral nerve injury is a major clinical and public health challenge. Although a common and increasingly prevalent wartime condition (1), injury to peripheral nerves, plexuses, and roots is present in 5% of patients seen in civilian trauma centers (2). In one study, almost half of peripheral nerve injuries at trauma centers were due to motor vehicle accidents and about half required surgery (3). Peripheral nerve injuries can substantially impact quality of life through loss of function and increased risk of secondary disabilities from falls, fractures, and other injuries (2).Neurons are connected in intricate communication networks established during development to convey sensory information from peripheral receptors of sensory neurons to the central nervous system (the brain and spinal cord), and to convey commands from the central nervous system to effector organs such as skeletal muscle innervated by motor neurons. The peripheral nerve environment is quite complex, consisting of axonal projections from neurons, supporting cells such as Schwann cells and fibroblasts, and the blood supply to the nerve.Connective tissue known as endoneurium surrounds peripheral nerve axons. Within peripheral nerves, axons are grouped into fascicles surrounded by connective tissue known as perineurium. Between and surrounding groups of fascicles is the epineurium. Microvessel plexuses course longitudinally through the epineurium and send branches through the perineurium to form a vascular network of capillaries in the endoneurium (4).The primary supporting cell for peripheral nerves is the Schwann cell. Schwann cells wrap around axons in a spiral fashion multiple times and their plasma membranes form a lipid-rich tubular cover around the axon known as the myelin sheath or the neurilemma. Schwann cells and the myelin sheath support and maintain axons and help to guide axons during axonal regeneration following nerve injury (5).It has been known for quite some time that regenerating axons exhibit a strong preference for growing along the inside portion of remaining basal lamina tubes in the distal nerve stump, the well-characterized “bands of Bungner” (6–10). Schwann cells originally associated with myelinated axons form such bands all the way from the transection site to the distal end organ target. The critical concept here is that the eventual distal destination of regenerating axons is largely determined by the Schwann cell tubes as they enter at the nerve transection site (9,11,12).Recent elegant work with transgenic mice expressing fluorescent proteins in their axons has verified that most (but not all) regenerating axons distal to either a crush or a transection injury remain within a single Schwann cell band as they grow within the distal nerve stump (13,14). Within the motor system it has even been shown that the same axon predominantly reinnervates the same neuromuscular junctions, and that Schwann cell bands act as mechanical barriers to direct axon outgrowth (13).The neuronal cell body is the site of synthesis of virtually all proteins and organelles in the cell. A complex process known as anterograde transport continuously moves materials from the neuronal cell body via the axon to its terminal synapse. These transported substances include neurotransmitters that facilitate communications between the neuron and end organ tissue across a narrow extracellular space known as the synaptic cleft (5) or, as in the case of the motor neuron innervation of muscle, the neuromuscular junction (15).Conversely, end organs such as muscle produce substances that act as nerve growth factors. These make their way across the neuromuscular junction to the innervating motor neuron axon (16). Some of these substances, or chemical messengers induced by them, are packaged and conveyed by retrograde transport from the synapse via the axon to the neuronal cell body. In this manner, the neuron and its end organ are continuously informed about the status of the connection between them. It has been suggested that information from end organs takes the form of factors that sustain existing nerve cell connections and promote the regeneration of damaged nerve cells. For instance, it has long been known that muscle exerts a strong influence on developing and regenerating motor neurons, and we have recently shown that even within an individual muscle there are factors that can influence the accuracy of reinnervation (17). Recent work has elegantly shown that if a single muscle fiber is selectively lesioned, the motor neuron axon terminal making up the proximal side of the neuromuscular junction rapidly atrophies and withdraws from the muscle postsynaptic sites within a matter of hours (18).The clinical significance, prognosis, and treatment of peripheral nerve injury depend on the site and extent of the injury. Despite regeneration, extensive peripheral nerve injuries can result in the effective paralysis of the entire limb or distal portions of the limb. Two peripheral nerve injury classification schemes, the Seddon (19) and the Sunderland (20), are in common use. These classify nerve injury according to whether the injury was confined to demyelination only or a more severe disruption of axons and supporting connective tissue. According to Seddon, the most severe injuries are classified as axonotmesis and neurotmesis. Axonotmesis is a nerve injury characterized by axon disruption rather than destruction of the connective tissue framework. The connective tissue and Schwann tubes are relatively intact. This is typical of stretch injuries common in falls and motor vehicle accidents. In contrast, neurotmesis involves the disruption of the nerve trunk and the connective tissue structure. This would occur in injuries where the nerve has been completely severed or badly crushed.Prognosis is good in peripheral nerve injuries where endoneurial Schwann cell tubes remain intact. Disruption of the Schwann cell tubes results in the loss of established pathways that regenerating axons follow. For extensive injuries, surgery is usually necessary to remove damaged nerve tissue and join viable nerve ends by direct anastomosis or by a nerve tissue graft (1). Refinement of microsurgical techniques involving the introduction of the surgical microscope and microsutures has increased the accuracy of this mechanical process, yet only 10% of adults will recover normal nerve function using state-of-the-art current techniques (21–23). The limits of microsurgical techniques have been reached; this is not surprising given that the finest suture material and needles ( and microns, respectively) are still quite a bit larger than the smallest axons that need to be repaired. The major key to recovery of function following peripheral nerve lesions is the accurate regeneration of axons to their original target end organs. A recognized leader of clinical nerve repair once stated, “The core of the problem is not promoting axon regeneration, but in getting them back to where they belong” (Sunderland, 1991) (23).At the level of a mixed peripheral nerve where motor and sensory axons are intermixed, correct discriminatory choices for appropriate terminal nerve branches at the lesion site are necessary prerequisites for the subsequent successful reinnervation of appropriate end-organ targets. Motor axons previously innervating muscle may be misdirected to sensory organs, and sensory axons typically innervating skin can be misdirected to muscle. Misdirected regeneration is a major barrier to functional recovery.In order to understand axonal regeneration and the mechanisms that axons use to navigate to target tissues, our laboratory has conducted a series of studies that are now culminating in proteomic investigations to identify specific biochemical mediators that may be the underlying mechanisms that direct accurate axon regeneration. We describe our work and that of others in the development of a model of axonal regeneration in the rodent femoral nerve and what we have learned from it. Then we will lay out our current research direction illustrating how approaches in proteomics such as two-dimensional differential gel electrophoresis (2D-DIGE) and mass spectrometry can be used to identify the underlying mediators that may lead to new therapies for peripheral nerve injury.

Understanding patterns of peripheral nerve injuries (PNIs) and brachial plexus injuries (BPIs) is essential to preventing and appropriately managing nerve injuries. We sought to assess the incidence, cause, and severity of PNIs and BPIs sustained by patients with trauma. We conducted a retrospective review of the Trauma Registry Database (January 2002 to December 2020) to identify patients with PNIs or BPIs. We evaluated data from 24 905 patients with trauma; 335 (1.3%) sustained PNIs (81% male; mean age 36 yr, standard deviation [SD] 16 yr) and 64 (0.3%) sustained BPIs (84% male; mean age 35, SD 15 yr). Nerves in the upper extremities were more commonly affected than those in the lower extremities. Sharp injuries (39.4%) and motorcycle accidents (32.8%) were the most frequent causes of PNIs and BPIs, respectively. Other common causes of PNI were motor vehicle collisions (16.7%) and gunshot wounds (12.8%). Many patients with PNIs (69.0%) and BPIs (53%) underwent operative management. The most frequent reconstruction for PNI was primary nerve repair (66%), while nerve transfers (48%) were more frequently used for BPI. Nerve injuries in the trauma population have decreased over the last 3 decades with shifts in mechanisms of injury and use of imaging, electrodiagnostic tests, and surgery. Nerve injuries are often complex and time-sensitive to treat; understanding changes in trends is important to ensure optimal patient management.

Tacrolimus (FK506) is a widely used immunosuppressant in organ transplantation. However, it also has neurotrophic activity that occurs independently of its immunosuppressive effects. Other neurotrophic immunophilin ligands that do not exhibit immunosuppression have subsequently been developed and studied in various models of nerve injury. This article reviews the literature on the use of tacrolimus and other immunophilin ligands in peripheral nerve, cranial nerve and spinal cord injuries. The most convincing evidence of enhanced nerve regeneration is seen with systemic administration of tacrolimus in peripheral nerve injury, although clinical use is limited due to its immunosuppressive side effects. Local tacrolimus delivery to the site of nerve repair in peripheral and cranial nerve injury is less effective but requires further investigation. Tacrolimus can enhance outcomes in nerve allograft reconstruction and accelerates reinnervation of complex functional allograft transplants. Other non-immunosuppressive immunophilins ligands such as V-10367 and FK1706 demonstrate enhanced neuroregeneration in the peripheral nervous system and CNS. Mixed results are found in the application of immunophilin ligands to treat spinal cord injury. Immunophilin ligands have great potential in the treatment of nerve injury, but further preclinical studies are necessary to permit translation into clinical trials.

Myelination of the peripheral nervous system is required for axonal function and long term stability. After peripheral nerve injury, Schwann cells transition from axon myelination to a demyelinated state that supports neuronal survival and ultimately remyelination of axons. Reprogramming of gene expression patterns during development and injury responses is shaped by the actions of distal regulatory elements that integrate the actions of multiple transcription factors. We used ChIP-seq to measure changes in histone H3K27 acetylation, a mark of active enhancers, to identify enhancers in myelinating rat peripheral nerve and their dynamics after demyelinating nerve injury. Analysis of injury-induced enhancers identified enriched motifs for c-Jun, a transcription factor required for Schwann cells to support nerve regeneration. We identify a c-Jun-bound enhancer in the gene for Runx2, a transcription factor induced after nerve injury, and we show that Runx2 is required for activation of other induced genes. In contrast, enhancers that lose H3K27ac after nerve injury are enriched for binding sites of the Sox10 and early growth response 2 (Egr2/Krox20) transcription factors, which are critical determinants of Schwann cell differentiation. Egr2 expression is lost after nerve injury, and many Egr2-binding sites lose H3K27ac after nerve injury. However, the majority of Egr2-bound enhancers retain H3K27ac, indicating that other transcription factors maintain active enhancer status after nerve injury. The global epigenomic changes in H3K27ac deposition pinpoint dynamic changes in enhancers that mediate the effects of transcription factors that control Schwann cell myelination and peripheral nervous system responses to nerve injury.

Small proline-rich repeat protein 1A (SPRR1A) is expressed in dorsal root ganglion (DRG) neurons following peripheral nerve injury but it is not known whether SPRR1A is differentially expressed following injury to peripheral versus central DRG projections and a detailed characterization of expression in sensory neuron subpopulations and spinal cord has not been performed. Here we use immunocytochemical techniques to characterize SPRR1A expression following sciatic nerve, dorsal root, and dorsal column injury in adult mice. SPRR1A was not detected in naïve spinal cord, DRG, or peripheral nerves and there was minimal expression following injury to the centrally projecting branches of DRG neurons. However, following peripheral (sciatic) nerve injury, intense SPRR1A immunoreactivity was observed in the dorsal horn and motoneurons of the spinal cord, in L4/5 DRG neurons, and in the injured nerve. A time-course study comparing expression following sciatic nerve crush and transection revealed maximum SPRR1A levels at day 7 in both models. However, while SPRR1A was downregulated to baseline by 30 days postlesion following crush injury, it remained elevated 30 days after transection. Cell-size and double-labeling studies revealed that SPRR1A was expressed by DRG cells of all sizes and colocalized with classical markers of DRG subpopulations and their primary afferent terminals. High coexpression of SPRR1A with activating transcription factor-3 and growth-associated protein-43 was observed, indicating that it is expressed by injured and regenerating neurons. This study supports the hypothesis that SPRR1A is a regeneration-associated gene and that SPRR1A provides a valuable marker to assess the regenerative potential of injured neurons.

Current management of peripheral trigeminal nerve injuries

Peripheral nerve injury is defined as a condition determined at least 48 hours after regional blockade in the form of sensory and/or motor disturbances in the area of innervation of the affected nerve, confirmed by the results of neurological examination. The incidence of transient neuropathies associated with peripheral nerve blockade is 2.2%, with permanent neurologic deficits ranging from 2 to 4 per 10,000 blockades. Although postoperative nerve injury is rare, when such complications do occur, they present significant problems for both the patient and the anesthesiologist. The aim of the work was to summarize the data presented in modern scientific literature on the prevention and treatment of peripheral nerve injuries during regional anesthesia. We searched for publications for the period from 2014 to 2024 by keywords in Russian and English: peripheral nerve, injuries, regional anesthesia, neurological complications, prevention of nerve injuries in PubMed, Elibrary, and CyberLeninka. The search revealed 383 publications, of which 433 were excluded because they described peripheral nerve injuries no associated with regional anesthesia. The remaining 50 publications formed the basis of this review. The review presents the anatomy of peripheral nerves, classification of their injuries, details mechanical, intraneural, ischemic and neurotoxic mechanisms of nerve injury. Methods of prevention of nerve injuries are outlined. It is shown that the combined use of neurostimulation, which helps to identify the nerves, ultrasound navigation, which helps to visualize the nerve, pressure monitor during injection, which helps to avoid nerve injury, are the key to safe regional anesthesia. The diagnosis of nerve injuries is described, which includes, in addition to the clinical signs, computed tomography and electrophysiologic examinations. The algorithm of observation of a patient with suspected nerve injury after regional anesthesia is given. The methods of treatment of peripheral nerve injury, including physiotherapy, drug treatment, low-frequency electrical stimulation, low-intensity ultrasound, and phototherapy, are described in detail. Peripheral nerve injuries during regional blockade is rare and is more often neuropraxic in nature, hence transient and has a favorable prognosis. The combined use of neurostimulation, ultrasound navigation and pressure monitoring during injection are the key to successful and safe regional blockade. Treatment of nerve injuries requires a multidisciplinary. The development of national recommendations for the prevention of nerve injuries during regional blockade will help anesthesiologists to reduce the risk of complications.

Patient-Reported Outcome After Peripheral Nerve Injury

Persistent and profound peripheral nerve injuries following reverse total shoulder arthroplasty

Management of peripheral nerve injury

The peripheral nervous system is an integral component of the neural connection between the CNS and the end organs. Injuries involving this system are often complex and require a thorough understanding of the management strategies of these injuries to help optimize recovery. Recent advances in MRI may lead to its becoming a useful tool in managing peripheral nerve injuries; however, good clinical acumen and the understanding of the anatomy and classification of nerve injuries remain the most important aspects. This chapter will therefore address the anatomy of a peripheral nerve, the classification of nerve injuries and the utility of MRI in diagnoses of peripheral nerve injuries and discuss the evaluation and treatment of injuries to peripheral and cranial nerves.