Electrical stimulation of injured nerves promotes recovery in animals and humans.

The frequent poor functional outcomes after delayed surgical repair of injured human peripheral nerves results in progressive downregulation of growth-associated genes in parallel with reduced neuronal regenerative capacity under each of the experimental conditions of chronic axotomy of neurones that remain without target contact, chronic distal nerve stump denervation, and chronic muscle denervation. Brief (1 h) low-frequency (20 Hz) electrical stimulation (ES) accelerates the outgrowth of regenerating axons across the surgical site of microsurgical repair of a transected nerve. Exercise programmes also promote nerve regeneration with the combination of ES and exercise being the most effective.

Physiology of Nerve Regeneration: Key Factors Affecting Clinical Outcomes.

Functional recovery after peripheral nerve injuries is disappointing despite surgical advances in nerve repair. This review summarizes the relatively short window of opportunity for successful nerve regeneration due to the decline in the expression of growth-associated genes and in turn, the decline in regenerative capacity of the injured neurons and the support provided by the denervated Schwann cells, and the atrophy of denervated muscles. Brief, low-frequency electrical stimulation and post-injury exercise regimes ameliorate these deficits in animal models and patients, but the misdirection of regenerating nerve fibers compromises functional recovery and remains an important area of future research.

A functional tacrolimus-releasing nerve wrap for enhancing nerve regeneration following surgical nerve repair.

JOURNAL/nrgr/04.03/01300535-202501000-00036/figure1/v/2024-05-14T021156Z/r/image-tiff Axonal regeneration following surgical nerve repair is slow and often incomplete, resulting in poor functional recovery which sometimes contributes to lifelong disability. Currently, there are no FDA-approved therapies available to promote nerve regeneration.

Appropriate dosage, timing, and site of intramuscular injections of brain-derived neurotrophic factor (BDNF) promote motor recovery after facial nerve injury in rats.

Introduction/aims: Daily intramuscular injections of fibroblast growth factor 2 (FGF2) but not of brain-derived neurotrophic factor (BDNF) significantly improve whisking behavior and mono-innervation of the rat levator labii superioris (LLS) muscle 56 days after buccal nerve transection and suture (buccal-buccal anastomosis, BBA). We explored the dose-response of BDNF, FGF2, and insulin growth factor 2 (IGF2) on the same parameters, asking whether higher doses of BDNF would promote recovery.

Methods: After BBA, growth factors were injected (30 μL volume) daily into the LLS muscle over 14, 28, or 56 days.

Brief Electrical Stimulation Promotes Recovery after Surgical Repair of Injured Peripheral Nerves.

Injured peripheral nerves regenerate their axons in contrast to those in the central nervous system. Yet, functional recovery after surgical repair is often disappointing. The basis for poor recovery is progressive deterioration with time and distance of the growth capacity of the neurons that lose their contact with targets (chronic axotomy) and the growth support of the chronically denervated Schwann cells (SC) in the distal nerve stumps.

Advancing Nerve Regeneration: Translational Perspectives of Tacrolimus (FK506).

Peripheral nerve injuries have far-reaching implications for individuals and society, leading to functional impairments, prolonged rehabilitation, and substantial socioeconomic burdens. Tacrolimus, a potent immunosuppressive drug known for its neuroregenerative properties, has emerged in experimental studies as a promising candidate to accelerate nerve fiber regeneration. This review investigates the therapeutic potential of tacrolimus by exploring the postulated mechanisms of action in relation to biological barriers to nerve injury recovery.

The Role of Sensory Innervation in Homeostatic and Injury-Induced Corneal Epithelial Renewal.

The cornea is the window through which we see the world. Corneal clarity is required for vision, and blindness occurs when the cornea becomes opaque. The cornea is covered by unique transparent epithelial cells that serve as an outermost cellular barrier bordering between the cornea and the external environment.

Schwann Cells Are Key Regulators of Corneal Epithelial Renewal.

Purpose: Corneal sensory nerves protect the cornea from injury. They are also thought to stimulate limbal stem cells (LSCs) to produce transparent epithelial cells constantly, enabling vision. In other organs, Schwann cells (SCs) associated with tissue-innervating axon terminals mediate tissue regeneration.

Peripheral Nerve Matrix Hydrogel Promotes Recovery after Nerve Transection and Repair.

Background: Nerve transection is the most common form of peripheral nerve injury. Treatment of peripheral nerve injury has primarily focused on stabilization and mechanical cues to guide extension of the regenerating growth cone across the site of transection. The authors investigated the effects of a peripheral nerve matrix (PNM) hydrogel on recovery after nerve transection.

Delay modulates the immune response to nerve repair.

Effective regeneration after peripheral nerve injury requires macrophage recruitment. We investigated the activation of remodeling pathways within the macrophage population when repair is delayed and identified alteration of key upstream regulators of the inflammatory response. We then targeted one of these regulators, using exogenous IL10 to manipulate the response to injury at the repair site.

Electrical stimulation to promote muscle and motor unit force and endurance after spinal cord injury.

Fatigue is a common feature of paralysed skeletal muscle, hindering performance when subjected to functional electrical stimulation (ES) for movement. We asked whether (1) 20 Hz ES for 5% of each day (2.5 s on and 2.

Trigeminal Sensory Supply Is Essential for Motor Recovery after Facial Nerve Injury.

Recovery of mimic function after facial nerve transection is poor. The successful regrowth of regenerating motor nerve fibers to reinnervate their targets is compromised by (i) poor axonal navigation and excessive collateral branching, (ii) abnormal exchange of nerve impulses between adjacent regrowing axons, namely axonal crosstalk, and (iii) insufficient synaptic input to the axotomized facial motoneurons. As a result, axotomized motoneurons become hyperexcitable but unable to discharge.

Enlargement of the Nerve Fibers of Silenced Lumbosacral Motoneurons in Cats.

Whether neuromuscular activity influences the size of motor nerves is controversial. All neuromuscular activity in cat hindlimbs was eliminated by spinal cord isolation (SCI), namely, spinal cord transection above and below the medial gastrocnemius (MG) and soleus (SOL) motoneuron pools and L5-S3 dorsal root transection. MG, SOL and sural (SUR) nerves were removed for size measurements, eight months after SCI surgery and from age-matched control cats.

Sustained Release of Tacrolimus From a Topical Drug Delivery System Promotes Corneal Reinnervation.

Purpose: Corneal nerve fibers provide sensation and maintain the epithelial renewal process. Insufficient corneal innervation can cause neurotrophic keratopathy. Here, topically delivered tacrolimus is evaluated for its therapeutic potential to promote corneal reinnervation in rats.

Foretinib mitigates cutaneous nerve fiber loss in experimental diabetic neuropathy.

Diabetes is by far, the most common cause of neuropathy, inducing neurodegeneration of terminal sensory nerve fibers associated with loss of sensation, paresthesia, and persistent pain. Foretinib prevents die-back degeneration in cultured sensory and sympathetic neurons by rescuing mitochondrial activity and has been proven safe in prospective clinical trials. Here we aimed at investigating a potential neuroprotective effect of Foretinib in experimental diabetic neuropathy.

Rapid, automated nerve histomorphometry through open-source artificial intelligence.

We aimed to develop and validate a deep learning model for automated segmentation and histomorphometry of myelinated peripheral nerve fibers from light microscopic images. A convolutional neural network integrated in the AxonDeepSeg framework was trained for automated axon/myelin segmentation using a dataset of light-microscopic cross-sectional images of osmium tetroxide-stained rat nerves including various axonal regeneration stages. In a second dataset, accuracy of automated segmentation was determined against manual axon/myelin labels.

Optical tissue clearing enables rapid, precise and comprehensive assessment of three-dimensional morphology in experimental nerve regeneration research.

Morphological analyses are key outcome assessments for nerve regeneration studies but are historically limited to tissue sections. Novel optical tissue clearing techniques enabling three-dimensional imaging of entire organs at a subcellular resolution have revolutionized morphological studies of the brain. To extend their applicability to experimental nerve repair studies we adapted these techniques to nerves and their motor and sensory targets in rats.

Peripheral nerves preferentially regenerate in intramuscular endoneurial tubes to reinnervate denervated skeletal muscles.

Schwann cells are essential for peripheral nerve regeneration but, over short distances in acellular nerve grafts, extracellular matrix (ECM) molecules can support growth. The ECM molecules are present also on denervated muscle surfaces where they can support nerve growth. In this study, we addressed the efficacy of the ECM molecules of denervated muscle to support nerve fiber regeneration and muscle reinnervation.

Local FK506 drug delivery enhances nerve regeneration through fresh, unprocessed peripheral nerve allografts.

Objective: Nerve allografts offer many advantages in the reconstruction of peripheral nerve gaps: they retain their native microstructure, contain pro-regenerative Schwann cells, are widely available, and avoid donor site morbidity. Unfortunately, clinical use of nerve allografts is limited by the need for systemic immunosuppression and its adverse effects. To eliminate the toxicity of the systemic immunosuppressant FK506, we developed a local FK506 drug delivery system (DDS) to provide drug release over 28 days.

Failures of nerve regeneration caused by aging or chronic denervation are rescued by restoring Schwann cell c-Jun.

After nerve injury, myelin and Remak Schwann cells reprogram to repair cells specialized for regeneration. Normally providing strong regenerative support, these cells fail in aging animals, and during chronic denervation that results from slow axon growth. This impairs axonal regeneration and causes significant clinical problems.

Peripheral Nerve Regeneration and Muscle Reinnervation.

Injured peripheral nerves but not central nerves have the capacity to regenerate and reinnervate their target organs. After the two most severe peripheral nerve injuries of six types, crush and transection injuries, nerve fibers distal to the injury site undergo Wallerian degeneration. The denervated Schwann cells (SCs) proliferate, elongate and line the endoneurial tubes to guide and support regenerating axons.

Electrical stimulation to enhance peripheral nerve regeneration: Update in molecular investigations and clinical translation.

Peripheral nerve injuries are common and frequently result in incomplete functional recovery even with optimal surgical treatment. Permanent motor and sensory deficits are associated with significant patient morbidity and socioeconomic burden. Despite substantial research efforts to enhance peripheral nerve regeneration, few effective and clinically feasible treatment options have been found.

Neutralizing BDNF and FGF2 injection into denervated skeletal muscle improve recovery after nerve repair.

Background: After facial nerve injury and surgical repair in rats, recovery of vibrissal whisking is associated with a high proportion of mono-innervated neuro-muscular junctions (NMJs). Our earlier work with Sprague Dawley (SD)/Royal College of Surgeons (RCS) rats, which are blind and spontaneously restore NMJ-monoinnervation and whisking, showed correlations between functional recovery and increase of fibroblast growth factor-2 (FGF2) and brain-derived neurotrophic factor (BDNF) in denervated vibrissal muscles.

Methods: We used normally sighted rats (Wistar), in which NMJ-polyinnervation is highly correlated with poor whisking recovery, and injected the vibrissal muscle levator labii superioris (LLS) with combinations of BDNF, anti-BDNF, and FGF2 at different postoperative periods after facial nerve injury.

Medial gastrocnemius muscles fatigue but do not atrophy in paralyzed cat hindlimb after long-term spinal cord hemisection and unilateral deafferentation.

This study of medial gastrocnemius (MG) muscle and motor units (MUs) after spinal cord hemisection and deafferentation (HSDA) in adult cats, asked 1) whether the absence of muscle atrophy and unaltered contractile speed demonstrated previously in HSDA-paralyzed peroneus longus (PerL) muscles, was apparent in the unloaded HSDA-paralyzed MG muscle, and 2) how ankle unloading impacts MG muscle and MUs after dorsal root sparing (HSDA-SP) with foot placement during standing and locomotion. Chronic isometric contractile forces and speeds were maintained for up to 12 months in all conditions, but fatigability increased exponentially. MU recordings at 8-11½ months corroborated the unchanged muscle force and speed with significantly increased fatigability; normal weights of MG muscle confirmed the lack of disuse atrophy.