Blood-nerve Barrier Research Articles

Netrin-1 as a Multitarget Barrier Stabilizer in the Peripheral Nerve after Injury

The blood–nerve barrier and myelin barrier normally shield peripheral nerves from potentially harmful insults. They are broken down during nerve injury, which contributes to neuronal damage. Netrin-1 is a neuronal guidance protein with various established functions in the peripheral and central nervous systems; however, its role in regulating barrier integrity and pain processing after nerve injury is poorly understood. Here, we show that chronic constriction injury (CCI) in Wistar rats reduced netrin-1 protein and the netrin-1 receptor neogenin-1 (Neo1) in the sciatic nerve. Replacement of netrin-1 via systemic or local administration of the recombinant protein rescued injury-induced nociceptive hypersensitivity. This was prevented by siRNA-mediated knockdown of Neo1 in the sciatic nerve. Mechanistically, netrin-1 restored endothelial and myelin, but not perineural, barrier function as measured by fluorescent dye or fibrinogen penetration. Netrin-1 also reversed the decline in the tight junction proteins claudin-5 and claudin-19 in the sciatic nerve caused by CCI. Our findings emphasize the role of the endothelial and myelin barriers in pain processing after nerve damage and reveal that exogenous netrin-1 restores their function to mitigate CCI-induced hypersensitivity via Neo1. The netrin-1-neogenin-1 signaling pathway may thus represent a multi-target barrier protector for the treatment of neuropathic pain.

Guillain-Barre Syndrome: Review and Summary

uillain-Barré Syndrome is a life-threatening, demyelinating, autoimmune condition in which the body’s immune system attacks the myelin of the peripheral nervous system. Guillain-Barré Syndrome is characterized by ascending motor weakness and acute flaccid paralysis. Demyelination results in nerve inflammation, numbness, tingling, muscle weakness, structural damage to the myelin sheath, and possible respiratory system complications. The annual incidence rate is 1.1 to 1.8 per 100,000 persons worldwide. Guillain-Barré Syndrome is thought to be triggered by an antecedent infection such as a viral, gastrointestinal, or bacterial infection, food poisoning, or reaction to a vaccine. Approximately 9-11% of cases result in severe disability or death. The acute phase can vary in length from a few days to several months, although over 90% of patients begin rehabilitation within four weeks. Patient care involves a team of neurologists, physiatrist, internist, nurses, physical, occupational, and speech therapists, social worker, psychologist and family physician. Elevated cerebrospinal fluid protein, symmetrical muscle weakness, the rate and order at which symptoms appear, and the absence or prolonged latency of reflexes are hallmarks for diagnosing Guillain-Barré Syndrome. A lumbar puncture to test for protein levels in the brain and spinal cord, and nerve conduction velocity test may aid in proper diagnosis, critical for optimizing treatment options and minimizing further progression. Although there is no cure, treatment may consist of plasmapheresis, typically performed four times during hospitalization, or intravenous immunoglobulin. Intravenous immunoglobulin combined with plasmapheresis should be avoided. Although glucocorticoids could repair damage to the blood-nerve barrier, oral corticosteroids could delay recovery.

SY7.2. Electrophysiological features in GBS and CIDP

GBS is currently classified into axonal and demyelinating categories. Acute motor axonal neuropathy (AMAN), an axonal subtype of GBS, was widely recognized in the 1990s. Whereas in Europe and North America, acute inflammatory demyelinating polyneuropathy (AIDP) is considered the major subtype of GBS, in East Asia, and Central and South America, AMAN is found for 30–80% of GBS cases. Over the past 20 years, major advances have been made in understanding the immunopathogenesis and pathophysiology of AMAN. Clinically, AMAN is characterized by pure motor involvement, frequent antecedent Campylobacter jejuni enteritis, and serum anti-ganglioside antibodies. Electrophysiological studies frequently reveal, as well as axonal degeneration, rapidly reversible nerve conduction block/slowing (resolved within days to a few weeks); the time-course suggests functional or microstructural changes at the nodes of Ranvier. It is now established that disrupted nodal sodium channel clusters, and paranodal myelin detachment is responsible for conduction block in AMAN. CIDP is currently classified into “typical CIDP” and other variants such as “multifocal acquired demyelinating sensory and motor neuropathy (MADSAM)”. Typical CIDP is a classic form, clinically characterized by symmetric proximal and distal muscle weakness and motor- dominant manifestation. In typical CIDP, demyelination predominantly affects the distal nerve terminals and nerve roots, presumably because of the lack of the blood-nerve barrier in these regions, and this could be responsible for the “non-nerve length-dependent” distribution of muscle weakness. These findings suggest an importance of humoral immunity in typical CIDP. In contrast, MADSAM is characterized by multifocal demyelination in the intermediate nerve trunks. In MADSAM neuropathy, cellular immunity may be predominantly involved in breakdown of the blood-nerve barrier at the site of conduction block. Among the CIDP spectrum, typical CIDP and MADSAM are the major subtypes, and their pathophysiology appears to be distinct. The understanding of the pathophysiology of each CIDP subtype is important for appropriate immune treatments.

421-P: Genetically Reduced Chondroitin Sulfate Prevents the Progression of Diabetic Neuropathy via Pericyte Functions

Background: The extracellular matrix is associated with diabetic complications; however, chondroitin sulfate (CS) role remains unclear. Herein, genetically engineered mice lacking the rate-limiting CS-synthesizing enzyme, CS N-acetylgalactosaminyltransferase-1 (T1), were used to clarify CS effects on diabetic neuropathy. Diabetes was induced by streptozotocin injection in 6-week-old male T1 knockout (T1KO) and wild-type (WT) mice. Results: Previously reported preliminary data at the former ADA meeting revealed that thermal nociception and the number of plantar peripheral nerve fibers were disrupted in diabetic WT mice, whereas in diabetic T1KO were preserved. Moreover, conduction velocity in the sciatic nerve was significantly declined in diabetic WT than in T1KO mice. [A1] Immunohistochemical data revealed loss of calcitonin gene-related peptide-positive neurons in the dorsal root ganglia (DRG) in diabetic WT mice, whereas those neurons were protected in diabetic T1KO mice. Moreover, DRG gene expression analysis showed that caspase-3 and -9 were reduced in T1KO compared with WT mice. To investigate the mechanisms underlying these events, the role of pericytes, which are important CS-expressing components of the blood-nerve barrier (BNB), was explored. Assessment of the retinal vessels, which represent a good model to evaluate pericyte functions and easier to access than peripheral nerves, revealed a higher proportion of pericyte-deficient retina blood vessels in diabetic WT than in T1KO mice upon administration of a platelet-derived growth factor receptor (PDGFR) β antibody. Therefore, pericytes in T1KO mice were more resistant against PDGFRβ antibody than those of WT mice. Thus, it is possible that the BNB in T1KO mice may be more resistant against external stress, including diabetes. Conclusions: Reduced CS production may induce beneficial effects to prevent diabetic neuropathy by improving pericyte function. Disclosure H. Ishiguro: None. T. Ushiki: None. A. Honda: None. T. Mikami: None. H. Kitagawa: None. K. Sango: None. M. Masuko: None. M. Igarashi: None. H. Sone: Research Support; Self; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co.

Selective blood-nerve barrier leakiness with claudin-1 and vessel-associated macrophage loss in diabetic polyneuropathy

Diabetic polyneuropathy (DPN) is the most common complication in diabetes and can be painful in up to 26% of all diabetic patients. Peripheral nerves are shielded by the blood-nerve barrier (BNB) consisting of the perineurium and endoneurial vessels. So far, there are conflicting results regarding the role and function of the BNB in the pathophysiology of DPN. In this study, we analyzed the spatiotemporal tight junction protein profile, barrier permeability, and vessel-associated macrophages in Wistar rats with streptozotocin-induced DPN. In these rats, mechanical hypersensitivity developed after 2 weeks and loss of motor function after 8 weeks, while the BNB and the blood-DRG barrier were leakier for small, but not for large molecules after 8 weeks only. The blood-spinal cord barrier remained sealed throughout the observation period. No gross changes in tight junction protein or cytokine expression were observed in all barriers to blood. However, expression of Cldn1 mRNA in perineurium was specifically downregulated in conjunction with weaker vessel-associated macrophage shielding of the BNB. Our results underline the role of specific tight junction proteins and BNB breakdown in DPN maintenance and differentiate DPN from traumatic nerve injury. Targeting claudins and sealing the BNB could stabilize pain and prevent further nerve damage.Key messages• In diabetic painful neuropathy in rats:• Blood nerve barrier and blood DRG barrier are leaky for micromolecules.• Perineurial Cldn1 sealing the blood nerve barrier is specifically downregulated.• Endoneurial vessel-associated macrophages are also decreased.• These changes occur after onset of hyperalgesia thereby maintaining rather than inducing pain.Graphical abstract

Morpho-Functional Consequences of Swiss Cheese Knockdown in Glia of Drosophila melanogaster.

Glia are crucial for the normal development and functioning of the nervous system in many animals. Insects are widely used for studies of glia genetics and physiology. Drosophila melanogaster surface glia (perineurial and subperineurial) form a blood–brain barrier in the central nervous system and blood–nerve barrier in the peripheral nervous system. Under the subperineurial glia layer, in the cortical region of the central nervous system, cortex glia encapsulate neuronal cell bodies, whilst in the peripheral nervous system, wrapping glia ensheath axons of peripheral nerves. Here, we show that the expression of the evolutionarily conserved swiss cheese gene is important in several types of glia. swiss cheese knockdown in subperineurial glia leads to morphological abnormalities of these cells. We found that the number of subperineurial glia nuclei is reduced under swiss cheese knockdown, possibly due to apoptosis. In addition, the downregulation of swiss cheese in wrapping glia causes a loss of its integrity. We reveal transcriptome changes under swiss cheese knockdown in subperineurial glia and in cortex + wrapping glia and show that the downregulation of swiss cheese in these types of glia provokes reactive oxygen species acceleration. These results are accompanied by a decline in animal mobility measured by the negative geotaxis performance assay.

From the low-density lipoprotein receptor–related protein 1 to neuropathic pain: a potentially novel target

This review describes the roles of the low-density lipoprotein receptor-related protein 1 (LRP-1) in inflammatory pathways, nerve nerve degeneration and -regeneration and in neuropathic pain. Induction of LRP-1 is able to reduce the activation of the proinflammatory NFκB-mediated pathway and the mitogen-activated protein kinase (MAPK) c-Jun N-terminal kinase and p38 signaling pathways, in turn decreasing the production of inflammatory mediators. Low-density lipoprotein receptor-related protein 1 activation also decreases reactive astrogliosis and polarizes microglial cells and macrophages from a proinflammatory phenotype (M1) to an anti-inflammatory phenotype (M2), attenuating the neuroinflammatory environment. Low-density lipoprotein receptor-related protein 1 can also modulate the permeability of the blood-brain barrier and the blood-nerve barrier, thus regulating the infiltration of systemic insults and cells into the central and the peripheral nervous system, respectively. Furthermore, LRP-1 is involved in the maturation of oligodendrocytes and in the activation, migration, and repair phenotype of Schwann cells, therefore suggesting a major role in restoring the myelin sheaths upon injury. Low-density lipoprotein receptor-related protein 1 activation can indirectly decrease neurodegeneration and neuropathic pain by attenuation of the inflammatory environment. Moreover, LRP-1 agonists can directly promote neural cell survival and neurite sprouting, decrease cell death, and attenuate pain and neurological disorders by the inhibition of MAPK c-Jun N-terminal kinase and p38-pathway and activation of MAPK extracellular signal-regulated kinase pathway. In addition, activation of LRP-1 resulted in better outcomes for neuropathies such as Alzheimer disease, nerve injury, or diabetic peripheral neuropathy, attenuating neuropathic pain and improving cognitive functions. To summarize, LRP-1 plays an important role in the development of different experimental diseases of the nervous system, and it is emerging as a very interesting therapeutic target.

Blood-Nerve Barrier (BNB) Pathology in Diabetic Peripheral Neuropathy and In Vitro Human BNB Model.

In diabetic peripheral neuropathy (DPN), metabolic disorder by hyperglycemia progresses in peripheral nerves. In addition to the direct damage to peripheral neural axons, the homeostatic mechanism of peripheral nerves is disrupted by dysfunction of the blood–nerve barrier (BNB) and Schwann cells. The disruption of the BNB, which is a crucial factor in DPN development and exacerbation, causes axonal degeneration via various pathways. Although many reports revealed that hyperglycemia and other important factors, such as dyslipidemia-induced dysfunction of Schwann cells, contributed to DPN, the molecular mechanisms underlying BNB disruption have not been sufficiently elucidated, mainly because of the lack of in vitro studies owing to difficulties in establishing human cell lines from vascular endothelial cells and pericytes that form the BNB. We have developed, for the first time, temperature-sensitive immortalized cell lines of vascular endothelial cells and pericytes originating from the BNB of human sciatic nerves, and we have elucidated the disruption to the BNB mainly in response to advanced glycation end products in DPN. Recently, we succeeded in developing an in vitro BNB model to reflect the anatomical characteristics of the BNB using cell sheet engineering, and we established immortalized cell lines originating from the human BNB. In this article, we review the pathologic evidence of the pathology of DPN in terms of BNB disruption, and we introduce the current in vitro BNB models.

Glial derived neurotrophic factor: a sufficient essential molecular regulator of mammalian blood-nerve barrier tight junction formation.

Glial derived neurotrophic factor: a sufficient essential molecular regulator of mammalian blood-nerve barrier tight junction formation.

Increased Cerebrospinal Fluid Uric Acid Levels in Guillain-Barré Syndrome.

Uric acid (UA) is a natural scavenger for peroxynitrite and can reflect antioxidant activity and oxidative stress in several neurological disorders. Changes in serum and cerebrospinal fluid (CSF) levels of UA have been reported in patients with multiple sclerosis and neuromyelitis optica spectrum disorders. The levels of UA in CSF are relatively poorly understood in patients with Guillain–Barré syndrome (GBS). It remains unclear whether UA can play an antioxidant role and reflect oxidative stress in GBS. The purpose of this study is to investigate CSF and serum UA levels in patients with GBS and their relationship with clinical characteristics. The CSF and serum UA levels were detected in 43 patients with GBS, including 14 acute inflammatory demyelinating polyneuropathy (AIDP), 6 acute motor axonal neuropathy (AMAN), 13 with acute motor and sensory axonal neuropathy (AMSAN), 7 Miller Fisher syndrome (MFS), and 3 unclassified, and 25 patients with non-inflammatory neurological disorders (NIND) as controls. Moreover, serum UA levels were also detected in 30 healthy controls. The levels of UA were measured using uricase-based methods with an automatic biochemical analyzer. CSF UA levels were significantly increased in patients with GBS (p = 0.011), particularly in patients with AIDP (p = 0.004) when compared with NIND. Among patients with GBS, CSF UA levels were higher in those with demyelination (p = 0.022), although the difference was not significant after multiple testing correction. CSF UA levels in GBS were positively correlated with serum UA levels (r = 0.455, p = 0.022) and CSF lactate (r = 0.499, p = 0.011). However, no significant correlations were found between CSF UA levels and GBS disability scores. There were no significant differences in serum UA levels among GBS, NIND, and healthy controls. These results suggest that CSF UA may be related to the pathogenesis of demyelination in patients with GBS and may be partially determined by serum UA and the impaired blood–nerve barrier.

Porphyric Neuropathy: Pathophysiology, Diagnosis, and Updated Management.

To review the peripheral neurological complications of the acute hepatic porphyrias, as well as the latest advances in their pathophysiology and management. The diagnosis of porphyric neuropathy remains challenging as varying neuropathic patterns are encountered depending on disease stage, including a non-length-dependent distribution pattern. The major pathophysiologic mechanism is δ-aminolevulinic acid (ALA)-induced neurotoxicity. The less restrictive blood-nerve barrier in the autonomic ganglia and myenteric plexus may explain the frequency of dysautonomic manifestations. Recently, a prophylactic small interfering RNA (siRNA)-based therapy that reduces hepatic ALA Synthase-1 mRNA was approved for patients with recurrent neuro-visceral attacks. Neurologists should appreciate the varying patterns of porphyric neuropathy. As with most toxin-induced axonopathies, long-term outcomes depend on early diagnosis and treatment. While the short-term clinical and biochemical benefits of siRNA-based therapy are known, its long-term effects on motor recovery, chronic pain, and dysautonomic manifestations are yet to be determined.

A low amyloidogenic E61K transthyretin mutation may cause familial amyloid polyneuropathy.

Patients with transthyretin (TTR)-type familial amyloid polyneuropathy (FAP) typically exhibit sensory dominant polyneuropathy and autonomic neuropathy. However, the molecular pathogenesis of the neuropathy remains unclear. In this study, we characterize the features of FAP TTR the substitution of lysine for glutamic acid at position 61 (E61K). This FAP was late-onset, with sensory dominant polyneuropathy, autonomic neuropathy, and cardiac amyloidosis. Interestingly, no amyloid deposits were found in the endoneurium of the four nerve specimens examined. Therefore, we examined the amyloidogenic properties of E61K TTR in vitro. Recombinant wild-type TTR, the substitution of methionine for valine at position 30 (V30M) TTR, and E61K TTR proteins were incubated at 37°C for 72hr, and amyloid fibril formation was assessed using the thioflavin-T binding assay. Amyloid fibril formation by E61K TTR was less than that by V30M TTR, and similar to that by wild-type TTR. E61K TTR did not have an inhibitory effect on neurite outgrowth from adult rat dorsal root ganglion (DRG) neurons, but V30M TTR did. Furthermore, we studied the sural nerve of our patient by terminal deoxynucleotidyl transferase dUTP nick end labeling and electron microscopy. A number of apoptotic cells were observed in the endoneurium of the nerve by transferase dUTP nick end labeling. Chromatin condensation was confirmed in the nucleus of non-myelinating Schwann cells by electron microscopy. These findings suggest that E61K TTR is low amyloidogenic, in vitro and in vivo. However, TTR aggregates and amyloid fibrils in the DRG may cause sensory impairments in FAP because the DRG has no blood-nerve barrier. Moreover, Schwann cell apoptosis may contribute to the neurodegeneration.

Missing perilymph but leaking blood-endolymph and vestibulocochlear nerve barriers in idiopathic sudden sensorineural hearing loss: A case study

ObjectivesTo evaluate the pathological changes in the blood-perilymph, blood-endolymph, and blood-nerve barriers of a patient with idiopathic sudden sensorineural hearing loss (SSNHL). MethodsPotential ossification or fibrosis in the inner ear was evaluated using temporal bone CT and MRI acquired using the 3-dimensional T2-weighted sampling perfection with application-optimized contrasts using a flip angle evolution sequence. Pathological changes in the barriers were analyzed by MRI obtained 4 h after a single-dose intravenous injection of gadolinium chelate using a medium inversion-time inversion recovery imaging with magnitude reconstruction sequence. ResultsThe perilymph was absent, while significant enhancements of the vestibulocochlear nerve and the endolymphatic compartments were detected. ConclusionSignificant injuries in the blood-endolymph and blood-vestibulocochlear nerve barriers and disabled perilymph production may contribute to the development of SSNHL with poor response to treatments.

Perineural Invasion in Adenoid Cystic Carcinoma of the Salivary Glands: Where We Are and Where We Need to Go.

Adenoid cystic carcinoma of the salivary gland (SACC) is a rare malignant tumors of the head and neck region, but it is one of the most common malignant tumors that are prone to perineural invasion (PNI) of the head and neck. The prognosis of patients with SACC is strongly associated with the presence of perineural spread (PNS). Although many contributing factors have been reported, the mechanisms underlying the preferential destruction of the blood-nerve barrier (BNB) by tumors and the infiltration of the tumor microenvironment by nerve fibers in SACC, have received little research attention. This review summarizes the current knowledge concerning the characteristics of SACC in relation to the PNI, and then highlights the interplay between components of the tumor microenvironment and perineural niche, as well as their contributions to the PNI. Finally, we provide new insights into the possible mechanisms underlying the pathogenesis of PNI, with particular emphasis on the role of extracellular vesicles that may serve as an attractive entry point in future studies.

Host tissue response to floating microelectrode arrays chronically implanted in the feline spinal nerve

Objective. Neural interfacing technologies could significantly improve quality of life for people living with the loss of a limb. Both motor commands and sensory feedback must be considered; these complementary systems are segregated from one another in the spinal nerve. Approach. The dorsal root ganglion-ventral root (DRG-VR) complex was targeted chronically with floating microelectrode arrays designed to record from motor neuron axons in the VR or stimulate sensory neurons in the DRG. Hematoxylin and eosin and Nissl/Luxol fast blue staining were performed. Characterization of the tissue response in regions of interest and pixel-based image analyses were used to quantify MAC387 (monocytes/macrophages), NF200 (axons), S100 (Schwann cells), vimentin (fibroblasts, endothelial cells, astrocytes), and GLUT1 (glucose transport proteins) reactivity. Implanted roots were compared to non-implanted roots and differences between the VR and DRG examined. Main results. The tissue response associated with chronic array implantation in this peripheral location is similar to that observed in central nervous system locations. Markers of inflammation were increased in implanted roots relative to control roots with MAC387 positive cells distributed throughout the region corresponding to the device footprint. Significant decreases in neuronal density and myelination were observed in both the VR, which contains only neuronal axons, and the DRG, which contains both neuronal axons and cell bodies. Notably, decreases in NF200 in the VR were observed only at implant times less than ten weeks. Observations related to the blood-nerve barrier and tissue integrity suggest that tissue remodeling occurs, particularly in the VR. Significance. This study was designed to assess the viability of the DRG-VR complex as a site for neural interfacing applications and suggests that continued efforts to mitigate the tissue response will be critical to achieve the overall goal of a long-term, reliable neural interface.

Inflammatory oedema of nerve trunks may be pathogenic in very early Guillain-Barré syndrome.

The aim of this paper is to analyse the pathological background of very early Guillain-Barré (VEGBS) (≤ 4days after onset) comparing it with initial stages of experimental autoimmune neuritis (EAN). The pathological hallmark of VEGBS is inflammatory oedema predominating in proximal nerve trunks. In EAN inflammatory oedema precedes the development of demyelination or axonal degeneration; such oedema may increase endoneurial fluid pressure (EFP) stretching the perineurium and constricting the transperineurial microcirculation. Centrofascicular or wedge-shaped areas of nerve ischemia have been reported in GBS and EAN. Additional support for proximal VEGBS pathology comes from electrophysiology showing alterations in late responses as the most frequent features, and ultrasonography illustrating that main changes rely on ventral rami of spinal nerves. Selective inefficiency of the blood-nerve barrier would explain the topography of changes in VEGBS. Increased serum neurofilament light chain concentration has recently been reported in VEGBS, with no difference between demyelinating and axonal subtypes. This is a marker of axonal damage, which could be correlated with endoneurial ischemia caused by increased EFP. Inflammatory oedema of proximal nerve trunks may be pathogenic in VEGBS, and consequently there is a pressing need for therapeutic strategies to stop its rapid impact on the axons.

Prox1 induces new lymphatic vessel formation and promotes nerve reconstruction in a mouse model of sciatic nerve crush injury.

The peripheral nervous system lacks lymphatic vessels and is protected by the blood–nerve barrier, which prevents lymphocytes and antibodies from entering the neural parenchyma. Peripheral nerve injury results in degeneration of the distal nerve and myelin degeneration causes macrophage aggregation, T lymphocyte infiltration, major histocompatibility complex class II antigen expression, and immunoglobulin G deposition in the nerve membrane, which together result in nerve edema and therefore affect nerve regeneration. In the present paper, we show myelin expression was absent from the sciatic nerve at 7 days after injury, and the expression levels of lymphatic vessel endothelial hyaluronan receptor 1 (LYVE‐1) and Prospero Homeobox 1 (Prox1) were significantly increased in the sciatic nerve at 7 days after injury. The lymphatic vessels were distributed around the myelin sheath and co‐localized with lymphatic endothelial cells. Prox1 induces the formation of new lymphatic vessels, which play important roles in the elimination of tissue edema as well as in morphological and functional restoration of the damaged nerve. This study provides evidence of the involvement of new lymphatic vessels in nerve repair after sciatic nerve injury.

Pathophysiology of Chronic Inflammatory Demyelinating Polyneuropathy: Insights into Classification and Therapeutic Strategy.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is classically defined as polyneuropathy with symmetric involvement of the proximal and distal portions of the limbs. In addition to this “typical CIDP”, the currently prevailing diagnostic criteria proposed by the European Federation of Neurological Societies and Peripheral Nerve Society (EFNS/PNS) define “atypical CIDP” as encompassing the multifocal acquired demyelinating sensory and motor (MADSAM), distal acquired demyelinating symmetric (DADS), pure sensory, pure motor, and focal subtypes. Although macrophage-induced demyelination is considered pivotal to the pathogenesis of CIDP, recent studies have indicated the presence of distinctive mechanisms initiated by autoantibodies against paranodal junction proteins, such as neurofascin 155 and contactin 1. These findings led to the emergence of the concept of nodopathy or paranodopathy. Patients with these antibodies tend to show clinical features compatible with typical CIDP or DADS, particularly the latter. In contrast, classical macrophage-induced demyelination is commonly found in some patients in each major subtype, including the typical CIDP, DADS, MADSAM, and pure sensory subtypes. Differences in the distribution of lesions and the repair processes underlying demyelination by Schwann cells may determine the differences among subtypes. In particular, the preferential involvement of proximal and distal nerve segments has been suggested to occur in typical CIDP, whereas the involvement of the middle nerve segments is conspicuous in MADSAM. These findings suggest that humoral rather than cellular immunity predominates in the former because nerve roots and neuromuscular junctions lack blood–nerve barriers. Treatment for CIDP consists of intravenous immunoglobulin (IVIg) therapy, steroids, and plasma exchange, either alone or in combination. However, patients with anti-neurofascin 155 and contactin 1 antibodies are refractory to IVIg. It has been suggested that rituximab, a monoclonal antibody to CD20, could have efficacy in these patients. Further studies are needed to validate the CIDP subtypes defined by the EFNS/PNS from the viewpoint of pathogenesis and establish therapeutic strategies based on the pathophysiologies specific to each subtype.

Impairment and restoration of the blood-nerve barrier and its correlation with pain following gradual nerve elongation of the rat sciatic nerve

Purpose: This study aimed to evaluate the time course of impairment and restoration of the blood-nerve barrier (BNB) following gradual elongation of the sciatic nerve and to clarify its association with nociception.Materials and Methods: The right femur was lengthened at a rate of 1.5 mm/day for 10 days. Von Frey tests were performed until 50 days after lengthening. Compound muscle action potentials (CMAPs) were measured to assess gross dysfunction of the elongated nerve. Evans blue-albumin tracing and immunohistochemistry for endothelial barrier antigen (EBA), rat endothelial cell antigen-1 (RECA-1), and CD68 for qualitative and quantitative analysis of the BNB and macrophage infiltration were performed for up to 50 days after cessation of lengthening in three segments of the sciatic nerves.Results: Paw-withdrawal threshold was significantly decreased at 7 days from initiation and began to recover from day 25 after lengthening. CMAPs showed delayed latency and attenuated amplitude but recovered at day 30 after cessation. On days 10 and 30 after cessation, spotted leakage of Evans blue-albumin in the endoneurium was observed, and the ratio of EBA/RECA-1-positive microvessels was significantly decreased, which subsequently recovered simultaneously in all segments on day 50 after cessation. Macrophages did not infiltrate the BNB at any time point.Conclusion: The restoration of BNB function following gradual nerve elongation was associated with the resolution of mechanical allodynia. Our findings provide insight into the association between nerve stretch injury and chronic nociception in adult male rats, which are potentially relevant to human orthopedic procedures and chronic neuropathic pain.

Pericytes of the Nervous System: Physiological and Pathological Role

Pericytes stabilize microvessels by wrapping them with their processes. They are located within the neurovascular unit between endothelial cells, astrocytes, and neurons, and interact with neighboring cells to generate diverse functional responses that are critical for central nerve system (CNS) function in health and disease. Recent evidence suggests that brain pericytes play crucial roles in regulating microvascular functions, such as blood-brain barrier properties, capillary blood flow, angiogenesis, and the entry of leukocytes into the brain. Pericytes also take part in tissue repair after CNS injury and may have stem cell-like properties. In addition, recent reports suggest that peripheral nerve pericytes, forming the blood-nerve barrier (BNB), regulate BNB function and basement membrane maintenance. Microvascular dysfunction due to pericyte degeneration initiates secondary neurodegenerative changes in the nervous system. In this review, we will first describe the origin, heterogeneity, and the physiological characteristics of pericytes. We next review possible pathological mechanisms and consequences of pericyte impairment in nervous system diseases including Alzheimer's diseases, diabetes, vascular dementia, and stroke. Finally, we will discuss how pericytes can be targeted for developing novel therapeutic approaches for treating patients with neurological disorders.