Nerve Axons Research Articles

Induced Attenuation of Scleral TGF-β Signaling in Mutant Mice Increases Susceptibility to IOP-Induced Optic Nerve Damage.

Axonal optic nerve (ON) damage in glaucoma is characteristically associated with increased amounts of active transforming growth factor-beta 2 (TGF-β2) in the ON head. Here we investigated the functional role of scleral TGF-β signaling in glaucoma. A deficiency of Tgfbr2, which encodes for TGF-β receptor type II (TGF-βRII), the essential receptor for canonical TGF-β signaling, was induced in fibroblasts (including those of the sclera) of mutant mice. To this end, 5-week-old mice were treated with tamoxifen eye drops. Experimental glaucoma was induced in 8-week-old mice using a magnetic microbead (MB) model. After 6 weeks of high intraocular pressure (IOP), the ON axons and their somata in the retina were labeled by paraphenylenediamine (PPD) and RNA-binding protein with multiple splicing (RBPMS) immunohistochemistry, respectively, and quantified. Tamoxifen treatment resulted in a significant decrease of TGF-βRII and its mRNA in the sclera. After 6 weeks of high IOP, reduced numbers of PPD-stained ON axons were seen in MB-injected eyes in comparison with not-injected contralateral eyes. Moreover, MB injection also led to a decrease of retinal ganglion cell (RGC) somata as seen in RBPMS-stained retinal wholemounts. Axon loss and RGC loss were significantly higher in mice with a fibroblast specific deficiency of TGF-βRII in comparison with control animals. We conclude that the ablation of scleral TGF-β signaling increases the susceptibility to IOP-induced ON damage. Scleral TGF-β signaling in mutant mice appears to be beneficial for ON axon survival in experimentally induced glaucoma.

Effective treatment of optic neuropathies by intraocular delivery of MSC-sEVs through augmenting the G-CSF-macrophage pathway

Optic neuropathies, characterized by injury of retinal ganglion cell (RGC) axons of the optic nerve, cause incurable blindness worldwide. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) represent a promising "cell-free" therapy for regenerative medicine; however, the therapeutic effect on neural restoration fluctuates, and the underlying mechanism is poorly understood. Here, we illustrated that intraocular administration of MSC-sEVs promoted both RGC survival and axon regeneration in an optic nerve crush mouse model. Mechanistically, MSC-sEVs primarily targeted retinal mural cells to release high levels of colony-stimulating factor 3 (G-CSF) that recruited a neural restorative population of Ly6Clow monocytes/monocyte-derived macrophages (Mo/MΦ). Intravitreal administration of G-CSF, a clinically proven agent for treating neutropenia, or donor Ly6Clow Mo/MΦ markedly improved neurological outcomes in vivo. Together, our data define a unique mechanism of MSC-sEV-induced G-CSF-to-Ly6Clow Mo/MΦ signaling in repairing optic nerve injury and highlight local delivery of MSC-sEVs, G-CSF, and Ly6Clow Mo/MΦ as therapeutic paradigms for the treatment of optic neuropathies.

Netazepide, an Antagonist of Cholecystokinin Type 2 Receptor, Prevents Vincristine-Induced Sensory Neuropathy in Mice.

Among the vinca-alkaloid class, vincristine is a potent chemotherapeutic agent with significant neurotoxic effects and is employed to address a wide spectrum of cancer types. Recently, the therapeutic potential of the cholecystokinin type 2 receptor (CCK2R) as a target for vincristine-induced peripheral neuropathy (VIPN) was demonstrated. In this study, the impact of preventive CCK2R blockade using netazepide (Trio Medicines Ltd., London, UK) was investigated in a mouse model of vincristine-induced peripheral neuropathy. Netazepide is a highly selective CCK2R antagonist under development for the treatment of patients with gastric neuroendocrine tumors caused by hypergastrinemia secondary to chronic autoimmune atrophic gastritis. Vincristine-induced peripheral neuropathy was induced by intraperitoneal injections of vincristine at 100 µg/kg/d for 7 days (D0 to D7). Netazepide (2 mg/kg/d or 5 mg/kg/d, per os) was administered one day before vincristine treatment until D7. Vincristine induced a high tactile allodynia from D1 to D7. VIPN was characterized by dorsal root ganglion neuron (DRG) and intraepidermal nerve fiber (IENF) loss, and enlargement and loss of myelinated axons in the sciatic nerve. Netazepide completely prevented the painful symptoms and nerve injuries induced by vincristine. In conclusion, the fact that netazepide protected against vincristine-induced peripheral neuropathy in a mouse model strongly supports the assessment of its therapeutic potential in patients receiving such chemotherapy.

AIBP: A New Safeguard against Glaucomatous Neuroinflammation.

Glaucoma is a group of ocular diseases that cause irreversible blindness. It is characterized by multifactorial degeneration of the optic nerve axons and retinal ganglion cells (RGCs), resulting in the loss of vision. Major components of glaucoma pathogenesis include glia-driven neuroinflammation and impairment of mitochondrial dynamics and bioenergetics, leading to retinal neurodegeneration. In this review article, we summarize current evidence for the emerging role of apolipoprotein A-I binding protein (AIBP) as an important anti-inflammatory and neuroprotective factor in the retina. Due to its association with toll-like receptor 4 (TLR4), extracellular AIBP selectively removes excess cholesterol from the plasma membrane of inflammatory and activated cells. This results in the reduced expression of TLR4-associated, cholesterol-rich lipid rafts and the inhibition of downstream inflammatory signaling. Intracellular AIBP is localized to mitochondria and modulates mitophagy through the ubiquitination of mitofusins 1 and 2. Importantly, elevated intraocular pressure induces AIBP deficiency in mouse models and in human glaucomatous retina. AIBP deficiency leads to the activation of TLR4 in Müller glia, triggering mitochondrial dysfunction in both RGCs and Müller glia, and compromising visual function in a mouse model. Conversely, restoring AIBP expression in the retina reduces neuroinflammation, prevents RGCs death, and protects visual function. These results provide new insight into the mechanism of AIBP function in the retina and suggest a therapeutic potential for restoring retinal AIBP expression in the treatment of glaucoma.

Estriol and commensal microflora strains regulate innate lymphoid cells functional activity in multiple sclerosis

Multiple sclerosis (MS) is an autoimmune neurodegenerative disease in which the immune system attacks myelin basic protein of nerve axons. Recently, there has been growing interest in studying the role of a newly described population of immunity cells – innate lymphoid cells (ILCs) in the pathogenesis of the disease. At the same time, it was found that during pregnancy there is a weakening of Th1-mediated autoimmune pathologies manifestations, including MS. In this work, we studied phenotypic characteristics of ILC in MS patients in comparison with healthy donors after 48 h incubation with pregnancy hormone estriol (E3) and commensal microflora cells. To activate ILC, strains of Ecsherichia coli K12 and Lactobacillus plantarum 8R-A3 were used. ILC phenotype was assessed by flow cytometry using monoclonal antibody staining. It has been established that E3 and bacterial factors are able to regulate the maturation of ILC subtypes and their cytokines in different ways. In general, the studied factors influence the phenotypic changes in ILC cells, leading to the transition from one type to another, both in healthy donors and in MS patients.

Electroacupuncture Promotes Functional Recovery after Facial Nerve Injury in Rats by Regulating Autophagy via GDNF and PI3K/mTOR Signaling Pathway.

To explore the mechanism of electroacupuncture (EA) in promoting recovery of the facial function with the involvement of autophagy, glial cell line-derived neurotrophic factor (GDNF), and phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway. Seventy-two male Sprague-Dawley rats were randomly allocated into the control, sham-operated, facial nerve injury (FNI), EA, EA+3-methyladenine (3-MA), and EA+GDNF antagonist groups using a random number table, with 12 rats in each group. An FNI rat model was established with facial nerve crushing method. EA intervention was conducted at Dicang (ST 4), Jiache (ST 6), Yifeng (SJ 17), and Hegu (LI 4) acupoints for 2 weeks. The Simone's 10-Point Scale was utilized to monitor the recovery of facial function. The histopathological evaluation of facial nerves was performed using hematoxylin-eosin (HE) staining. The levels of Beclin-1, light chain 3 (LC3), and P62 were detected by immunohistochemistry (IHC), immunofluorescence, and reverse transcription-polymerase chain reaction, respectively. Additionally, IHC was also used to detect the levels of GDNF, Rai, PI3K, and mTOR. The facial functional scores were significantly increased in the EA group than the FNI group (P<0.05 or P<0.01). HE staining showed nerve axons and myelin sheaths, which were destroyed immediately after the injury, were recovered with EA treatment. The expressions of Beclin-1 and LC3 were significantly elevated and the expression of P62 was markedly reduced in FNI rats (P<0.01); however, EA treatment reversed these abnormal changes (P<0.01). Meanwhile, EA stimulation significantly increased the levels of GDNF, Rai, PI3K, and mTOR (P<0.01). After exogenous administration with autophagy inhibitor 3-MA or GDNF antagonist, the repair effect of EA on facial function was attenuated (P<0.05 or P<0.01). EA could promote the recovery of facial function and repair the facial nerve damages in a rat model of FNI. EA may exert this neuroreparative effect through mediating the release of GDNF, activating the PI3K/mTOR signaling pathway, and further regulating the autophagy of facial nerves.

BDNF and cAMP are neuroprotective in a porcine model of traumatic optic neuropathy.

Traumatic optic neuropathy (TON) is a devastating condition that can occur after blunt or penetrating trauma to the head, leading to visual impairment or blindness. Despite these debilitating effects, no clinically available therapeutic targets neuroprotection or promotes axon regeneration in this or any optic neuropathy. Limited data in large-animal models are a major obstacle to advancing treatments toward clinical therapeutics. To address this issue, we refined a surgical model of TON in Yucatan minipigs. First, we validated the model by demonstrating visual impairment by flash visual-evoked potential and retinal ganglion cell degeneration and death. Next, we developed and optimized a delivery method and nontoxic dosing of intravitreal brain-derived neurotrophic factor (BDNF) and cAMP. Finally, we showed that intravitreal injection of BDNF and cAMP rescued visual function and protected against retinal ganglion cell death and optic nerve axon degeneration. Together these data in a preclinical large-animal model advance our understanding of and ability to model TON and further identify and develop candidate clinical therapeutics.

The effect of carotid sinus neurectomy for carotid restenosis: a study protocol for a double-blinded and randomized controlled trial

BackgroundPatients undergoing carotid endarterectomy (CEA) have a high restenosis rate, which increases the risk of stroke, and there is still a lack of effective treatment for restenosis. The cause of stenosis is related to local inflammatory reactions. Some basic studies have shown that the inflammatory response causing arterial stenosis is closely related to the nerve axons distributed in its outer membrane, and that removal of the nerve is effective in reducing the inflammatory response to prevent arterial stenosis. Therefore, we propose to design a randomized controlled trial to study whether disconnecting the carotid sinus nerve during a CEA operation can reduce carotid arterial restenosis.Method/designThis study is a randomized, double-blind, single-center study. We will recruit 276 patients, who will be randomly divided into the experimental group and the control group. Based on the standard CEA operation, the operator will search for the carotid sinus nerve on the surface of the internal carotid artery and will entirely transect it in the experimental group. Both groups will be guided with the same postoperative treatment and will be followed up every 3 months for 3 years after the operation. The main indices observed will be the carotid restenosis rate, incidence and nature of carotid plaque, and carotid blood flow velocity. Other indices will be arrhythmia, blood pressure variability, and biomarkers of atherosclerosis, such as blood lipids, hypersensitive C-reactive protein (hs-CRP), homocysteine, and total bilirubin.DiscussionIt is expected that carotid sinus nerve transection will significantly reduce the occurrence of restenosis after CEA, decrease the incidence of ischemic stroke, and realize the effective primary prevention of stroke.Trial registrationChiCTR2300073652. Registered on July 18, 2023.

Diabetic peripheral neuropathy: pathogenetic mechanisms and treatment.

Diabetic peripheral neuropathy (DPN) refers to the development of peripheral nerve dysfunction in patients with diabetes when other causes are excluded. Diabetic distal symmetric polyneuropathy (DSPN) is the most representative form of DPN. As one of the most common complications of diabetes, its prevalence increases with the duration of diabetes. 10-15% of newly diagnosed T2DM patients have DSPN, and the prevalence can exceed 50% in patients with diabetes for more than 10 years. Bilateral limb pain, numbness, and paresthesia are the most common clinical manifestations in patients with DPN, and in severe cases, foot ulcers can occur, even leading to amputation. The etiology and pathogenesis of diabetic neuropathy are not yet completely clarified, but hyperglycemia, disorders of lipid metabolism, and abnormalities in insulin signaling pathways are currently considered to be the initiating factors for a range of pathophysiological changes in DPN. In the presence of abnormal metabolic factors, the normal structure and function of the entire peripheral nervous system are disrupted, including myelinated and unmyelinated nerve axons, perikaryon, neurovascular, and glial cells. In addition, abnormalities in the insulin signaling pathway will inhibit neural axon repair and promote apoptosis of damaged cells. Here, we will discuss recent advances in the study of DPN mechanisms, including oxidative stress pathways, mechanisms of microvascular damage, mechanisms of damage to insulin receptor signaling pathways, and other potential mechanisms associated with neuroinflammation, mitochondrial dysfunction, and cellular oxidative damage. Identifying the contributions from each pathway to neuropathy and the associations between them may help us to further explore more targeted screening and treatment interventions.

Mapping of individual sensory nerve axons from digits to spinal cord with the transparent embedding solvent system.

Achieving uniform optical resolution for a large tissue sample is a major challenge for deep imaging. For conventional tissueclearing methods, loss of resolution and quality in deep regions is inevitable due to limited transparency. Here we describe the Transparent Embedding Solvent System (TESOS) method, which combines tissue clearing, transparent embedding, sectioning and block-face imaging. We used TESOS to acquire volumetric images of uniform resolution for an adult mouse whole-body sample. The TESOS method is highly versatile and can be combined with different microscopy systems to achieve uniformly high resolution. With a light sheet microscope, we imaged the whole body of an adult mouse, including skin, at a uniform 0.8 × 0.8 × 3.5 μm3 voxel resolution within 120 h. With a confocal microscope and a 40×/1.3 numerical aperture objective, we achieved a uniform sub-micron resolution in the whole sample to reveal a complete projection of individual nerve axons within the central or peripheral nervous system. Furthermore, TESOS allowed the first mesoscale connectome mapping of individual sensory neuron axons spanning 5 cm from adult mouse digits to the spinal cord at a uniform sub-micron resolution.

A Perspective on Electrical Stimulation and Sympathetic Regeneration in Peripheral Nerve Injuries.

Peripheral nerve injuries (PNIs) are common and devastating. The current standard of care relies on the slow and inefficient process of nerve regeneration after surgical intervention. Electrical stimulation (ES) has been shown to both experimentally and clinically result in improved regeneration and functional recovery after PNI for motor and sensory neurons; however, its effects on sympathetic regeneration have never been studied. Sympathetic neurons are responsible for a myriad of homeostatic processes that include, but are not limited to, blood pressure, immune response, sweating, and the structural integrity of the neuromuscular junction. Almost one quarter of the axons in the sciatic nerve are from sympathetic neurons, and their importance in bodily homeostasis and the pathogenesis of neuropathic pain should not be underestimated. Therefore, as ES continues to make its way into patient care, it is not only important to understand its impact on all neuron subtypes, but also to ensure that potential adverse effects are minimized. This piece gives an overview of the effects of ES in animals models and in humans while offering a perspective on the potential effects of ES on sympathetic axon regeneration.

Icariin prevents methylmercury-induced experimental neurotoxicity: Evidence from cerebrospinal fluid, blood plasma, brain samples, and in-silico investigations

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that causes significant neurodegeneration. Methylmercury (MeHg+) is a neurotoxin that induces axonal neurodegeneration and motor nerve degeneration by destroying oligodendrocytes, degenerating white matter, inducing apoptosis, excitotoxicity, and reducing myelin basic protein (MBP). This study examines the inhibition of SIRT-1 (silence information regulator 1), Nrf-2 (nuclear factor E2-related factor 2), HO-1 (heme oxygenase 1), and TDP-43 (TAR-DNA-binding protein 43) accumulation in the context of ALS, as well as the modulation of these proteins by icariin (15 and 30 mg/kg, orally), a glycoside flavonoid with neuroprotective properties. Neuroprotective icariin activates SIRT-1, Nrf-2, and HO-1, mitigating inflammation and neuronal injury in neurodegenerative disorders. In-vivo and in-silico testing of experimental ALS models confirmed icariin efficacy in modulating these cellular targets. The addition of sirtinol 10 mg/kg, an inhibitor of SIRT-1, helps determine the effectiveness of icariin. In this study, we also examined neurobehavioral, neurochemical, histopathological, and LFB (Luxol fast blue) markers in various biological samples, including Cerebrospinal fluid (CSF), blood plasma, and brain homogenates (Cerebral Cortex, Hippocampus, Striatum, mid-brain, and Cerebellum). These results demonstrate that the administration of icariin ameliorates experimental ALS and that the mechanism underlying these benefits is likely related to regulating the SIRT-1, Nrf-2, and HO-1 signaling pathways.

Regenerative Peripheral Nerve Interface (RPNI) Surgery for Mitigation of Neuroma and Postamputation Pain.

A neuroma occurs when a regenerating transected peripheral nerve has no distal target to reinnervate. Symptomatic neuromas are a common cause of postamputation pain that can lead to substantial disability1-3. Regenerative peripheral nerve interface (RPNI) surgery may benefit patients through the use of free nonvascularized muscle grafts as physiologic targets for peripheral nerve reinnervation for mitigation of neuroma and postamputation pain. An RPNI is constructed by implanting the distal end of a transected peripheral nerve into a free nonvascularized skeletal muscle graft. The neuroma or free end of the affected nerve is identified, transected, and skeletonized. A free muscle graft is then harvested from the donor thigh or from the existing amputation site, and the distal end of each transected nerve is implanted into the center of the free muscle graft with use of 6-0 nonabsorbable suture. This can be done acutely at the time of amputation or as an elective procedure at any time postoperatively. Nonsurgical treatments of neuromas include desensitization, chemical or anesthetic injections, biofeedback, transcutaneous electrical nerve stimulation, topical lidocaine, and/or other medications (e.g., antidepressants, anticonvulsants, and opioids). Surgical treatment of neuromas includes neuroma excision, nerve capping, excision with transposition into bone or muscle, nerve grafting, and targeted muscle reinnervation. Creation of an RPNI is a simple and reproducible surgical option to prevent neuroma formation that leverages several biologic processes and addresses many limitations of existing neuroma-treatment strategies. Given the understanding that neuromas will form when regenerating axons are not presented with end organs for reinnervation, any strategy that reduces the number of aimless axons within a residual limb should serve to reduce symptomatic neuromas. The use of free muscle grafts offers a vast supply of denervated muscle targets for regenerating nerve axons and facilitates the reestablishment of neuromuscular junctions without sacrificing denervation of any residual muscles. Articles describing RPNI surgery for postamputation pain have shown favorable outcomes, with significant reduction in neuroma pain and phantom pain scores at approximately 7 months postoperatively4,5. Neuroma pain scores were reduced by 71% and phantom pain scores were reduced by 53%4. Prophylactic RPNI surgery is also associated with substantially lower incidence of symptomatic neuromas (0% versus 13.3%) and a lower rate of phantom limb pain (51.1% versus 91.1%)5 compared with the rates in patients who did not undergo RPNI surgery. Ask the patient preoperatively to point at the site of maximal tenderness, as this can serve as a guide for where the symptomatic neuroma may be located. The incision can be made either through the previous site of the amputation or directly over the site of maximal tenderness longitudinally. The pitfall of incising directly over the site is creating another incision with its attendant risk of wound infection.Excise the terminal neuroma with a knife until healthy-appearing axons are visualized.The free nonvascularized skeletal muscle graft can be obtained from local muscle (preferred) or from a separate donor site. A separate donor site can introduce donor-site morbidity and complications, including hematoma and pain.The harvested skeletal muscle graft should ideally be approximately 35 mm long, 20 mm wide, and 5 mm thick in order to ensure survivability and to prevent central necrosis. The harvesting can be performed with curved Mayo scissors.The peripheral nerve should be implanted parallel to the direction of the muscle fibers, and the epineurium should be secured to the free muscle graft at 1 or 2 places. One suture should be utilized to tack the distal end of the epineurium to the middle of the bed of the muscle graft. Another suture should be utilized to start the wrapping of the muscle graft around the nerve using a bite through the muscle, a bite through the epineurium of the proximal end of the nerve, and another bite through the other muscle edge in order to form a cylindrical wrap around the nerve.Wrap the entire muscle graft by taking only bites of muscle graft around the nerve to secure the muscle graft in a cylindrical structure using 2 to 4 more sutures.Avoid locating the RPNI near weight-bearing surfaces of the residual limb when closing. The RPNI should be in the muscular tissue, deep to the subcutaneous tissue and dermis.Do perform intraneural dissection for large-caliber nerves to create several (normally 2 to 4) distinct RPNIs, to avoid too many regenerating axons in a single free muscle graft.

Glaucoma or not glaucoma? ‐ How to navigate problematic cases?

Optic neuropathies refer to a group of eye conditions that involve acute or chronic damage to the optic nerve, which is responsible for transmitting visual information from the eye to the brain. The optic nerve is made up of millions of nerve fibres that can be affected by a variety of primary or secondary insults, leading to progressive neurodegeneration of optic nerve axons, being projections of retinal ganglion cells. The most common optic neuropathies that we should consider in differential diagnosis represent glaucoma, ischemic, inflammatory, toxic, hereditary, traumatic, and compressive optic neuropathies.Although the visual field test is one of the most basic and oldest diagnostic method in ophthalmology, it represents a sophisticated test that allows to differentiate ongoing pathology, based on features of observed scotomas. The specific features include localization, steepness, relativity and symmetry of visual field defects. By combining those features with clinical anamnesis, imaging techniques and electrophysiological data, properly used visual fields can be a powerful tool to provide patients and other medical specialists with further direction of diagnostic process and treatment. This course aims to provide a series of cases‐based analysis of different visual field results, to establish certain universal rules and to provide useful tips, how to diagnose difficult glaucoma cases using perimetry and how to rule out non‐glaucomatous neuropathies, allowing to speed up and to properly direct the diagnostic process.

NK-клетки, предобработанные эстриолом и клетками комменсальной флоры, регулируют созревание Treg и Th17 из CD4+ лимфоцитов у больных рассеянным склерозом и здоровых доноров

Multiple sclerosis (MS) is an inflammatory chronic disease of the central nervous system, one of the pathogenetic mechanisms of which is an immune-mediated attack to the myelin sheath of nerve axons under the control of autoreactive T cells. NK cells, one of subtypes of ILC cells, have the ability to regulate autoimmune mechanisms through the production of cytokines or cytotoxic effects directly against effector cells, such as autoreactive T cells or antigen-presenting cells. At the same time, they can also lyse microglial, astrocyte, and oligodendrocyte cells, indicating a dual function of NK cells in MS. The influence of the pregnancy hormone estriol (E3) and commensal microflora on the ability of NK cells to modulate the level of T regulatory (Treg) and IL-17-producing (Th17) lymphocytes from patients with multiple sclerosis (MS) in comparison with healthy donors was studied. To activate NK cells, Ecsherichia coli K12 and Lactobacillus plantarum 8R-A3 strains were used. The phenotype of Treg and Th17 cells was assessed by flow cytometry using monoclonal antibody staining. It was found that NK cells incubated with E3 and E. coli stimulate the formation of Tregs, and pretreatment of NK cells with L. plantarum inhibits the formation of Th17 from CD4+ lymphocytes. In general, regulatory lymphocytes from MS patients turned out to be more sensitive to the influence of NK cells than cells from healthy donors.

Neurofilaments in health and Charcot-Marie-Tooth disease.

Neurofilaments (NFs) are the most abundant component of mature neurons, that interconnect with actin and microtubules to form the cytoskeleton. Specifically expressed in the nervous system, NFs present the particularity within the Intermediate Filament family of being formed by four subunits, the neurofilament light (NF-L), medium (NF-M), heavy (NF-H) proteins and α-internexin or peripherin. Here, we review the current knowledge on NF proteins and neurofilaments, from their domain structures and their model of assembly to the dynamics of their transport and degradation along the axon. The formation of the filament and its behaviour are regulated by various determinants, including post-transcriptional (miRNA and RBP proteins) and post-translational (phosphorylation and ubiquitination) modifiers. Altogether, the complex set of modifications enable the neuron to establish a stable but elastic NF array constituting the structural scaffold of the axon, while permitting the local expression of NF proteins and providing the dynamics necessary to fulfil local demands and respond to stimuli and injury. Thus, in addition to their roles in mechano-resistance, radial axonal outgrowth and nerve conduction, NFs control microtubule dynamics, organelle distribution and neurotransmission at the synapse. We discuss how the studies of neurodegenerative diseases with NF aggregation shed light on the biology of NFs. In particular, the NEFL and NEFH genes are mutated in Charcot-Marie-Tooth (CMT) disease, the most common inherited neurological disorder of the peripheral nervous system. The clinical features of the CMT forms (axonal CMT2E, CMT2CC; demyelinating CMT1F; intermediate I-CMT) with symptoms affecting the central nervous system (CNS) will allow us to further investigate the physiological roles of NFs in the brain. Thus, NF-CMT mouse models exhibit various degrees of sensory-motor deficits associated with CNS symptoms. Cellular systems brought findings regarding the dominant effect of NF-L mutants on NF aggregation and transport, although these have been recently challenged. Neurofilament detection without NF-L in recessive CMT is puzzling, calling for a re-examination of the current model in which NF-L is indispensable for NF assembly. Overall, we discuss how the fundamental and translational fields are feeding each-other to increase but also challenge our knowledge of NF biology, and to develop therapeutic avenues for CMT and neurodegenerative diseases with NF aggregation.

Comparison of the Biomechanics of the Mouse Astrocytic Lamina Cribrosa Between Glaucoma and Optic Nerve Crush Models.

The strain response of the mouse astrocytic lamina (AL) to an ex vivo mechanical test was compared between two protocols: eyes that underwent sustained intraocular pressure (IOP) increase and eyes after optic nerve crush. Chronic IOP elevation was induced by microbead injection or the optic nerve was crushed in mice with widespread green fluorescence. After 3 days or 6 weeks, eyes were inflation tested by a published method of two-photon fluorescence to image the AL. Digital volume correlation was used to calculate strains. Optic nerve axon damage was also evaluated. In the central AL but not the peripheral AL, four strains were greater in eyes at the 3-day glaucoma time point than control (P from 0.029 to 0.049, n = 8 eyes per group). Also, at this time point, five strains were greater in the central AL compared to the peripheral AL (P from 0.041 to 0.00003). At the 6-week glaucoma time point, the strains averaged across the specimen, in the central AL, and the peripheral AL were indistinguishable from the respective controls. Strains were not significantly different between controls and eyes 3 days or 6 weeks after crush (n = 8 and 16). We found alterations in the ex vivo mechanical behavior in eyes from mice with experimental glaucoma but not in those with crushed optic nerves. The results of this study demonstrate that significant axon injury does not directly affect mechanical behavior of the astrocytic lamina.

Axonal mapping of motor and sensory components within the ulnar nerve and its branches.

Intrinsic function is indispensable for dexterous hand movements. Distal ulnar nerve defects can result in intrinsic muscle dysfunction and sensory deficits. Although the ulnar nerve's fascicular anatomy has been extensively studied, quantitative and topographic data on motor axons traveling within this nerve remain elusive. The ulnar nerves of 14 heart-beating organ donors were evaluated. The motor branches to the flexor carpi ulnaris (FCU) and flexor digitorum profundus (FDP) muscles and the dorsal branch (DoBUN) as well as 3 segments of the ulnar nerve were harvested in 2-cm increments. Samples were subjected to double immunofluorescence staining using antibodies against choline acetyltransferase and neurofilament. Samples revealed more than 25,000 axons in the ulnar nerve at the forearm level, with a motor axon proportion of only 5%. The superficial and DoBUN showed high axon numbers of more than 21,000 and 9300, respectively. The axonal mapping of more than 1300 motor axons revealed an increasing motor/sensory ratio from the proximal ulnar nerve (1:20) to the deep branch of the ulnar nerve (1:7). The motor branches (FDP and FCU) showed that sensory axons outnumber motor axons by a ratio of 10:1. Knowledge of the detailed axonal architecture of the motor and sensory components of the human ulnar nerve is of the utmost importance for surgeons considering fascicular grafting or nerve transfer surgery. The low number of efferent axons in motor branches of the ulnar nerve and their distinct topographical distribution along the distal course of the nerve is indispensable information for modern nerve surgery.

Alterations of the nervous system in patients with vibration disease

Introduction. An important aspect of prevention is the dynamic monitoring of workers exposed to the vibration in the workplace, which not only forms the basis for the diagnosis of occupational intoxication, but also ensures timely resolution of issues of examination of working capacity.&#x0D; Materials and methods. Twenty one male patient with an established diagnosis of vibration disease (VD) associated with exposure to local vibration. A dynamic survey was conducted, 3 observation periods were studied.&#x0D; Results. Over the 3rd period of the examination, the latency of N10 and N30 increased when compared with the 1st period. In periods 2 and 3, the duration of N13–N18 increased compared to period 1. The rate of pulse conduction (RPC) along the ulnar nerve decreased during period 2 when compared with period 1. Over the period 3, a decrease in RPC along the tibial nerve was revealed when compared with periods 1 and 2. During periods 2 and 3, the amplitude of the ulnar nerve action potential decreased when compared with period 1, along the afferent axons of the ulnar nerve the RPC decreased during period 2 when compared with 1. In period 3, the RPC along the median nerve decreased when compared with period 1.&#x0D; Limitations. The limitation of this study is that the dynamics of changes depending on the degree of vibration disease has not been analyzed. This task was not implemented due to the small number of observations in the sample. &#x0D; Conclusion. The progression of vibration disease syndromes and the degree of severity of vibration disease in dynamics were noted. The time of activation of neurons of the somatosensory zone of the cerebral cortex and the time of passage of the pulse from neurons of the cervical thickening to the thalamic structures in dynamics was found to slow down. There were increased disturbances in the conduction of the pulse along the axons at the level of the brachial plexus and from the brachial plexus to the lower parts of the brain stem. Demyelinating changes in the motor component of the peripheral nerves of the upper and lower extremities were aggravated in patients.

Serum neurofilament light chain – A potential biomarker for polyneuropathy in type 2 diabetes?

AimsTo investigate the relationship between neurofilament light chain (NfL) and the presence and severity of diabetic polyneuropathy (DPN). MethodsWe performed cross-sectional analysis of data from 178 participants of the ADDITION-Denmark cohort of people with screen-detected type 2 diabetes and 32 healthy controls. Biobank serum samples were analyzed for NfL using single-molecule array. DPN was defined by Toronto criteria for confirmed DPN. Original and axonal nerve conduction study (NCS) sum z-scores were used as indicators of the severity of DPN and peripheral nerve damage. Results39 (21.9%) participants had DPN. Serum NfL (s-NfL) was significantly higher in participants with DPN (18.8 ng/L [IQR 14.4; 27.9]) than in participants without DPN (15.4 ng/L [IQR 11.7; 20.1]). There were no unadjusted s-NfL differences between controls (17.6 ng/L [IQR 12.7; 19.8]) and participants with or without DPN. Higher original and axonal NCS sum z-scores were associated with 10% higher s-NfL (10.2 and 12.1% [95% CI’s 4.0; 16.8 and 6.6; 17.9] per 1 SD). The AUC of s-NfL for DPN was 0.63 (95% CI 0.52; 0.73). ConclusionsS-NfL is unlikely to be a reliable biomarker for the presence of DPN. S-NfL is however associated tothe severity of the nerve damage underlying DPN.