Wallerian Degeneration Research Articles

Fine‐grained ordering of white matter degeneration in the Alzheimer’s disease pathophysiological cascade

AbstractBackgroundThe role of white matter (WM) neurodegeneration in Alzheimer’s disease (AD) is poorly understood. Fine‐grained sequencing of WM neurodegeneration could provide new avenues for early diagnosis and novel disease‐modifying therapies to slow or halt AD progression. Previous approaches are limited by their coarse granularity and incomplete disease coverage. In this study, we apply event‐based disease progression modelling (DPM) (Fonteijn et al, Neuroimage, 2012), which can provide fine‐grained ordering, to estimate progression of regional WM abnormality in AD.MethodDiffusion tensor imaging (DTI) markers of WM abnormality and Freesurfer volumetric markers of grey matter (GM) atrophy were obtained from ADNI. DTI markers were hemisphere‐averaged and GM volumes were normalised by head size. Eleven WM ROIs with reported AD abnormality and 4 reference GM ROIs were selected for sequencing (abbreviations in Table 1), yielding complete data for 83 cognitively normal subjects, 40 AD patients and 102 MCI subjects. Event‐based DPM (github.com/ucl‐pond/kde_ebm) was used to estimate a data‐driven sequence of neurodegeneration and its uncertainty (positional variance), and individuals were assigned to their most likely stage (Young et al., Brain, 2014). Resampling analysis assessed the robustness of the estimated sequence.ResultFig. 1 shows the first data‐driven sequence of WM abnormalities in AD, including positional variance, with GM abnormality events for reference. The earliest WM events are increases in mean diffusivity (MD) in CGH and axial diffusivity (AxD) in FX and BCC. Subsequently, a cascade of AxD events in corpus callosum regions precedes abnormality in other medial temporal lobe WM structures.Fig. 2 shows the sequence is relatively robust under resampling, with low positional variance and similar median positions for most ROIs. Subject staging (Fig. 3, 4) shows that the fine‐grained approach splits MCI subjects with hippocampal atrophy into those with hippocampal atrophy and those with additional increased MD in CGH.ConclusionThis study finds WM microstructural abnormality among the earliest events in AD. Early hippocampal WM abnormality and corpus callosum ordering are consistent with early memory deficits in AD and inferences from cruder group‐based comparisons. The order suggests Wallerian degeneration rather than retrogenesis is the primary driver of WM neurodegeneration in AD.

Next-generation RNA sequencing elucidates transcriptomic signatures of pathophysiologic nerve regeneration

The cellular and molecular underpinnings of Wallerian degeneration have been robustly explored in laboratory models of successful nerve regeneration. In contrast, there is limited interrogation of failed regeneration, which is the challenge facing clinical practice. Specifically, we lack insight on the pathophysiologic mechanisms that lead to the formation of neuromas-in-continuity (NIC). To address this knowledge gap, we have developed and validated a novel basic science model of rapid-stretch nerve injury, which provides a biofidelic injury with NIC development and incomplete neurologic recovery. In this study, we applied next-generation RNA sequencing to elucidate the temporal transcriptional landscape of pathophysiologic nerve regeneration. To corroborate genetic analysis, nerves were subject to immunofluorescent staining for transcripts representative of the prominent biological pathways identified. Pathophysiologic nerve regeneration produces substantially altered genetic profiles both temporally and in the mature neuroma microenvironment, in contrast to the coordinated genetic signatures of Wallerian degeneration and successful regeneration. To our knowledge, this study presents as the first transcriptional study of NIC pathophysiology and has identified cellular death, fibrosis, neurodegeneration, metabolism, and unresolved inflammatory signatures that diverge from pathways elaborated by traditional models of successful nerve regeneration.

Detection and verification of neurodegeneration after traumatic brain injury in the mouse: Immunohistochemical staining for amyloid precursor protein.

Previous studies of human traumatic brain injury (TBI) have shown diffuse axonal injury as varicosities or spheroids in white matter (WM) bundles when using immunoperoxidase-ABC staining with 22C11, a mouse monoclonal antibody against amyloid precursor protein (APP). These findings have been interpreted as TBI-induced axonal pathology. In a mouse model of TBI however, when we used immunofluorescent staining with 22C11, as opposed to immunoperoxidase staining, we did not observe varicosities or spheroids. To explore this discrepancy, we performed immunofluorescent staining with Y188, an APP knockout-validated rabbit monoclonal that shows baseline immunoreactivity in neurons and oligodendrocytes of non-injured mice, with some arranged-like varicosities. In gray matter after injury, Y188 intensely stained axonal blebs. In WM, we encountered large patches of heavily stained puncta, heterogeneous in size. Scattered axonal blebs were also identified among these Y188-stained puncta. To assess the neuronal origin of Y188 staining after TBI we made use of transgenic mice with fluorescently labeled neurons and axons. A close correlation was observed between Y188-stained axonal blebs and fluorescently labeled neuronal cell bodies/axons. By contrast, no correlation was observed between Y188-stained puncta and fluorescent axons in WM, suggesting that these puncta in WM did not originate from axons, and casting further doubt on the nature of previous reports with 22C11. As such, we strongly recommend Y188 as a biomarker for detecting damaged neurons and axons after TBI. With Y188, stained axonal blebs likely represent acute axonal truncations that may lead to death of the parent neurons. Y188-stained puncta in WM may indicate damaged oligodendrocytes, whose death and clearance can result in secondary demyelination and Wallerian degeneration of axons. We also provide evidence suggesting that 22C11-stained varicosities or spheroids previously reported in TBI patients might be showing damaged oligodendrocytes, due to a cross-reaction between the ABC kit and upregulated endogenous biotin.

The Axon Initial Segment Plays a Dynamic Role in Peripheral Motor Neuron Synapse Regeneration following Injury.

Unlike axons of the central nervous system, which have limited ability to regenerate, axons of the peripheral nervous system (PNS) die back and can then reform in response to injury, through a process called Wallerian degeneration ([Huebner and Strittmatter, 2009][1]). However, severe peripheral

Super-resolution imaging pinpoints the periodic ultrastructure at the human node of Ranvier and its disruption in patients with polyneuropathy

The node of Ranvier is the key element in saltatory conduction along myelinated axons, but its specific protein organization remains elusive in the human species. To shed light on nanoscale anatomy of the human node of Ranvier in health and disease, we assessed human nerve biopsies of patients with polyneuropathy by super-resolution fluorescence microscopy. We applied direct stochastic optical reconstruction microscopy (dSTORM) and supported our data by high-content confocal imaging combined with deep learning-based analysis. As a result, we revealed a ∼ 190 nm periodic protein arrangement of cytoskeletal proteins and axoglial cell adhesion molecules in human peripheral nerves. In patients with polyneuropathy, periodic distances increased at the paranodal region of the node of Ranvier, both at the axonal cytoskeleton and at the axoglial junction. In-depth image analysis revealed a partial loss of proteins of the axoglial complex (Caspr-1, neurofascin-155) in combination with detachment from the cytoskeletal anchor protein ß2-spectrin. High content analysis showed that such paranodal disorganization occurred especially in acute and severe axonal neuropathy with ongoing Wallerian degeneration and related cytoskeletal damage. We provide nanoscale and protein-specific evidence for the prominent, but vulnerable role of the node of Ranvier for axonal integrity. Furthermore, we show that super-resolution imaging can identify, quantify and map elongated periodic protein distances and protein interaction in histopathological tissue samples. We thus introduce a promising tool for further translational applications of super resolution microscopy.

Disseminated Intracranial Germinoma Presenting with Wallerian Degeneration.

Disseminated Intracranial Germinoma Presenting with Wallerian Degeneration.

Degeneration specific NF-L immunoreactivity in spinal cord and brainstem 10 days post-cervical spinal cord contusion

We recently described a panel of novel antibodies to epitopes on the neurofilament light chain (NF-L) which are hidden in healthy neurons and their processes but specifically exposed during neurodegeneration ( doi.org/10.1101/2022.08.27.504533 ). We saw widespread immunopositivity for such antibodies in degenerating and degenerated processes in the rat spinal cord 1-5 days following cervical spinal cord injury (cSCI). Here we aimed to determine if such immunopositivity would persist at 10 days following cSCI. Male Sprague Dawley rats received laminectomy (n=3) or right unilateral contusion at C4 (n=3; 150kdyn; Infinite Horizon Impactor). Tissue was harvested 10 days post-SCI and stained with either Cresyl Violet for routine histology or for immunohistochemistry using mouse monoclonal antibody MCA-6H63, one of several novel antibodies binding to degeneration specific NF-L epitopes (EnCor Biotechnology Inc.). Spinal cord MCA-6H63 immunopositivity was not detected in spinal cords from the laminectomy group. Contusion produced the expected histopathology with ipsilateral grey and white matter disruption and some damage to the contralateral dorsal columns. Punctate labeling for MCA-6H63 was prominent at the lesion epicenter, as well as in the ipsilateral cord rostral and caudal to the injury, consistent with axonal degeneration. Sparse, punctate MCA-6H63 positivity was observed in the contralateral cervical white matter. Qualitatively, MCA-6H63 staining was most robust in the ventral and lateral white matter ipsilateral and caudal to the lesion. This location was consistent with ongoing Wallerian degeneration in prominent spinal tracts including spinothalamic, spinocerebellar, reticulospinal, vestibulospinal and raphespinal. Bilateral MCA-6H63 staining in the dorsal columns was present mostly rostral to the injury. Some MCA-6H63 staining was noted in the medulla, most prominently ipsilateral to the lesion. We conclude that at 10 days post-cSCI this novel NF-L antibody specifically identifies degenerating and degenerated axonal profiles. This is a promising technique in assessing neurodegeneration following SCI and other neurodegenerative diseases. R01HL139708-01A1 (DDF), R01 HL153140-01 (DDF), and EnCor Biotechnology Inc. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Progressive Longitudinally Extensive Myelopathy following Stroke in a Patient later found to have m.14484T>C Mutation in Leber’s Hereditary Optic Neuropathy (LHON) gene. (P5-8.008)

<h3>Objective:</h3> To present a unique case of progressive myelopathy following stroke and its relationship to subsequently revealed LHON gene mutation (m.14484T&gt;C). <h3>Background:</h3> Leber’s Hereditary Optic Neuropathy (LHON) is a maternally inherited mitochondrial disease associated with acute or subacute bilateral painless vision loss. LHON can also present with non-optic nerve disorders, including longitudinal myelopathy and increased risk of multiple sclerosis, known as LHON plus or LHON-MS. LHON plus presenting as longitudinal myelopathy without preceding optic neuropathy has been rarely reported. <h3>Design/Methods:</h3> N/A <h3>Results:</h3> A 66-year-old woman with history of hypertension suffered an acute right hemispheric subcortical stroke at age 63 with resultant left sided hemiparesis. Months afterwards she began to experience progressive bilateral sensory symptoms and worsening hemiparesis, initially resembling Brown-Sequard syndrome. MRI demonstrated exuberant Wallerian degeneration of the corticospinal tract from the site of her stroke, extending through the brainstem to contralateral spinal cord. Extensive autoimmune, neoplastic, ischemic, and metabolic workups were largely unrevealing, aside from elevated ANA and vitamin B12 deficiency. Over the ensuing two years symptoms progressed to near-complete sensory loss of the lower extremities, right sided weakness, and ultimately development of orthopnea, intermittent diplopia, and dysphagia. This continued despite trials of high dose steroids and IVIG. MRI demonstrated new lesions in the contralateral medulla, bilateral posterior and lateral columns, and atrophy in previously affected areas. Whole exome sequencing revealed pathogenic homoplasmic m.14484T&gt;C mutation in the MT-ND6 gene. Patient has never endorsed visual loss. <h3>Conclusions:</h3> This case adds to the few reports of myelopathy as the presenting feature of LHON. Unique in our patient is the absence of visual symptomatology after three years of disease onset, possibly expanding the spectrum of pathology resulting from MT-ND6 mutation. <b>Disclosure:</b> Dr. Eszes has nothing to disclose. Dr. Samkoff has nothing to disclose. Ms. Bontrager has received personal compensation in the range of $500-$4,999 for serving as a Speaker with Muscular Dystrophy Association.

Utilization of Lead citrate on the peripheral Nervous Systemin Rat (An Experimental and Histological Study)

administrated of lead citrate solution with phosphate buffer saline orally in a dose of 250 mg/kg for thirty days. Animais were divided into four groups. Group A survived for 30 days. Group B for 60 days. Group C fbr 90 days and Groupb tzO days. Twenty animals were administrated phosphate buffer saline for 30 clays and classified into four 4 groups and survived for 30,60,90 and 120 days afterthe last dose. Atthe end of eachperiod the animals were scarified and segments of the peripheral nerve (Sciatic nerve) were removed and fixed in osmic acid 1o/o , then processed in graded glycerin 500/o , pure glycerin for obtaining teased nerve fibers . Specimens tbr miiror"opi" examination were done by application of the histological technique for obtaining transverse and longitudinal sections of the 6um thickness. The results of the present itr,iy d"*onstrated that the peripheral nerve fibers were affected after the 30,and 60 days mostly reflected by the presence of the wallerian degeneration ( destrr-rction of the myelin sheath ancl axon) of the most nerve fibers and at the period of 90 days after the last dose was indicated a regeneration of the most nerve fibers , but still there cerlain percentage of the degeneratecl nerve f-rbers and irregular outlines of its myelin sheath. After 120 days, Remyelination of most nerve fibers were detected associated with short internodes in between other intact nodes of Ranvier .

Zebrafish cutaneous injury models reveal that Langerhans cells engulf axonal debris in adult epidermis.

Somatosensory neurons extend enormous peripheral axons to the skin, where they detect diverse environmental stimuli. Somatosensory peripheral axons are easily damaged due to their small caliber and superficial location. Axonal damage results in Wallerian degeneration, creating vast quantities of cellular debris that phagocytes must remove to maintain organ homeostasis. The cellular mechanisms that ensure efficient clearance of axon debris from stratified adult skin are unknown. Here, we established zebrafish scales as a tractable model to study axon degeneration in the adult epidermis. Using this system, we demonstrated that skin-resident immune cells known as Langerhans cells engulf the majority of axon debris. In contrast to immature skin, adult keratinocytes did not significantly contribute to debris removal, even in animals lacking Langerhans cells. Our study establishes a powerful new model for studying Wallerian degeneration and identifies a new function for Langerhans cells in maintenance of adult skin homeostasis following injury. These findings have important implications for pathologies that trigger somatosensory axon degeneration.

Immunohistochemical Study of Macrophages of Sciatic Rat Nerve after Damage and Subperineural Injection of Mesenchymal Stem Cells

The dynamics of the processes of Wallerian degeneration in the Wistar-Kyoto rat sciatic nerve after injury (ligation, 40 s) was studied.The density of Iba-1+ macrophages and the state of myelin fibers stained with Luxol strong blue in the distal segment of the nerve at different times after injury were studied. Parts of rats were subperineurally transplanted with MSCs from the bone marrow of Wistar-Kyoto rats. It was shown that the highest distribution density of macrophages in the distal segment of the nerve was observed 7 days after surgery. The use of cell therapy leads to a decrease in the number of macrophages during this period and to a delay in the demyelination of damaged nerve fibers. Sixty days after the operation, the macrophage population density and the number of remyelinated regenerating nerve fibers of the distal nerve segment did not differ in control (ligature) and experimental (ligature and MSC injection) animals. The molecular mechanisms of the noted changes in the early stages after injury require further research.

Relative Effects of Various Factors on Ice Ball Formation and Ablation Zone Size During Ultrasound-Guided Percutaneous Cryoneurolysis: A Laboratory Investigation to Inform Clinical Practice and Future Research.

Ultrasound-guided percutaneous cryoneurolysis provides analgesia using cold temperatures to reversibly ablate peripheral nerves. Cryoneurolysis probes pass a gas through a small internal annulus, rapidly lowering the pressure and temperature, forming an ice ball to envelope the target nerve. Analgesia is compromised if a nerve is inadequately frozen, and laboratory studies suggest that pain may be paradoxically induced with a magnitude and duration in proportion with the incomplete ablation. We therefore investigated the relative effects of various factors that may contribute to the size of the ice ball and the effective cryoneurolysis zone. A cryoprobe was inserted into a piece of meat, a gas was passed through for 2min, and the resulting ice ball width (cross-section) and length (axis parallel to the probe) were measured using ultrasound, with the temperature evaluated in nine concentric locations concurrently. The factor with the greatest influence on ice ball size was probe gauge: in all probe types, a change from 18 to 14 increased ice ball width, length, and volume by up to 70%, 113%, and 512% respectively, with minimum internal temperature decreasing as much as from -5 to -32°C. In contrast, alternating the type of meat (chicken, beef, pork) and the shape of the probe tip (straight, coudé) affected ice ball dimensions to a negligible degree. The ice ball dimensions and the zone of adequate temperature drop were not always correlated, and, even within a visualized ice ball, the temperature was often inadequate to induce Wallerian degeneration. Percutaneous probe design can significantly influence the effective cryoneurolysis zone; visualizing a nerve fully encompassed in an ice ball does not guarantee adequate treatment to induce the desired Wallerian degeneration because ice forms at temperatures between 0 and -20°C, whereas only temperatures below -20°C induce Wallerian degeneration. The correlation between temperatures in isolated pieces of meat and perfused human tissue remains unknown, and further research to evaluate these findings in situ appears highly warranted.

Schwann cell-specific RhoA knockout accelerates peripheral nerve regeneration via promoting Schwann cell dedifferentiation.

Our previous studies indicated that RhoA knockdown or inhibition could alleviate the proliferation, migration, and differentiation of Schwann cells. However, the role of RhoA in Schwann cells during nerve injury and repair is still unknown. Herein, we developed two lines of Schwann cells conditional RhoA knockout (cKO) mice by breeding RhoAflox / flox mice with PlpCre -ERT2 or DhhCre mice. Our results indicate that RhoA cKO in Schwann cells accelerates axonal regrowth and remyelination after sciatic nerve injury, which enhances the recovery of nerve conduction and hindlimb gait, and alleviates the amyotrophy in gastrocnemius muscle. Mechanistic studies in both in vivo and in vitro models revealed that RhoA cKO could facilitate Schwann cell dedifferentiation via JNK pathway. Schwann cell dedifferentiation subsequently promotes Wallerian degeneration by enhancing phagocytosis and myelinophagy, as well as stimulating the production of neurotrophins (NT-3, NGF, BDNF, and GDNF). These findings shed light on the role of RhoA in Schwann cells during nerve injury and repair, indicating that cell type-specific RhoA targeting could serve as a promising molecular therapeutic strategy for peripheral nerve injury.

Molecular and morphological markers of neuronal death in acute cerebrovascular accidents

Acute cerebral circulation disorder is one of the most discussed issues in modern intensive care and neurology, as it is a severe condition, leading to disability or death of the patient, in the absence of immediate medical care. This review discusses general and specific biological markers of stroke, genetic markers of stroke, and current data on their diagnostic significance. The main mechanisms of brain tissue cell death in stroke, such as apoptosis, necrosis, ferroptosis, parthanatosis, sarmoptosis, autolysis, autophagy, oncosis, excitotoxic death are analyzed; the morphological features of the observed processes and their structural manifestations are reviewed. For each type of cell death in nervous tissue, the most frequently detected molecular markers are discussed: specific kinases, Toll-like receptors in the case of apoptosis; serine-threonine protein kinases, components of the polyubiquitin system detected in necrosis; transferrin 1 receptors, typical for ferroptosis; poly(ADP-ribose)-polymerase, whose activity increases in parthanatosis; slow Wallerian degeneration protein that accumulates during sarmoptosis; and other biomarkers characteristic of both individual types of nerve cell death and general pathological processes affecting the brain.

Traumatic Axonal Injury in the Optic Nerve: The Selective Role of SARM1 in the Evolution of Distal Axonopathy.

Traumatic axonal injury (TAI), thought to be caused by rotational acceleration of the head, is a prevalent neuropathology in traumatic brain injury (TBI). TAI in the optic nerve is a common finding in multiple blunt-force TBI models and hence a great model to study mechanisms and treatments for TAI, especially in view of the compartmentalized anatomy of the visual system. We have previously shown that the somata and the proximal, but not distal, axons of retinal ganglion cells (RGC) respond to DLK/LZK blockade after impact acceleration of the head (IA-TBI). Here, we explored the role of the sterile alpha and TIR-motif containing 1 (SARM1), the key driver of Wallerian degeneration (WD), in the progressive breakdown of distal and proximal segments of the optic nerve following IA-TBI with high-resolution morphological and classical neuropathological approaches. Wild type and Sarm1 knockout (KO) mice received IA-TBI or sham injury and were allowed to survive for 3, 7, 14, and 21 days. Ultrastructural and microscopic analyses revealed that TAI in the optic nerve is characterized by variable involvement of individual axons, ranging from apparent early disconnection of a subpopulation of axons to a range of ongoing axonal and myelin perturbations. Traumatic axonal injury resulted in the degeneration of a population of axons distal and proximal to the injury, along with retrograde death of a subpopulation of RGCs. Quantitative analyses on proximal and distal axons and RGC somata revealed that different neuronal domains exhibit differential vulnerability, with distal axon segments showing more severe degeneration compared with proximal segments and RGC somata. Importantly, we found that Sarm1 KO had a profound effect in the distal optic nerve by suppressing axonal degeneration by up to 50% in the first 2 weeks after IA-TBI, with a continued but lower effect at 3 weeks, while also suppressing microglial activation. Sarm1 KO had no evident effect on the initial traumatic disconnection and did not ameliorate the proximal optic axonopathy or the subsequent attrition of RGCs, indicating that the fate of different axonal segments in the course of TAI may depend on distinct molecular programs within axons.

Tau-mediated axonal degeneration is prevented by activation of the WldS pathway.

Tauopathy is characterized by neuronal dysfunction and degeneration occurring as a result of changes to the microtubule-associated protein tau. The neuronal changes evident in tauopathy bear striking morphological resemblance to those reported in models of Wallerian degeneration. The mechanisms underpinning Wallerian degeneration are not fully understood although it can be delayed by the expression of the slow Wallerian degeneration (WldS) protein, which has also been demonstrated to delay axonal degeneration in some models of neurodegenerative disease. Given the morphological similarities between tauopathy and Wallerian degeneration, this study investigated whether tau-mediated phenotypes can be modulated by co-expression of WldS. In a Drosophila model of tauopathy in which expression of human 0N3R tau protein leads to progressive age-dependent phenotypes, WldS was expressed with and without activation of the downstream pathway. The olfactory receptor neuron circuit OR47b was used for these studies in adults, and the larval motor neuron system was employed in larvae. Tau phenotypes studied included neurodegeneration, axonal transport, synaptic deficits and locomotor behaviour. Impact on total tau was ascertained by assessing total, phosphorylated and misfolded tau levels by immunohistochemistry. Activation of the pathway downstream of WldS completely suppressed tau-mediated degeneration. This protective effect was evident even if the pathway downstream of WldS was activated several weeks after tau-mediated degeneration had become established. Though total tau levels were not altered, the protected neurons displayed significantly reduced MC1 immunoreactivity suggestive of clearance of misfolded tau, as well as a trend for a decline in tau species phosphorylated at the AT8 and PHF1 epitopes. In contrast, WldS expression without activation of the downstream protective pathway did not rescue tau-mediated degeneration in adults or improve tau-mediated neuronal dysfunction including deficits in axonal transport, synaptic alterations and locomotor behaviour in tau-expressing larvae. This collectively implies that the pathway mediating the protective effect of WldS intersects with the mechanism(s) of degeneration initiated by tau and can effectively halt tau-mediated degeneration at both early and late stages. Understanding the mechanisms underpinning this protection could identify much-needed disease-modifying targets for tauopathies.

Glycolytic System in Axons Supplement Decreased ATP Levels after Axotomy of the Peripheral Nerve.

Wallerian degeneration (WD) occurs in the early stages of numerous neurologic disorders, and clarifying WD pathology is crucial for the advancement of neurologic therapies. ATP is acknowledged as one of the key pathologic substances in WD. The ATP-related pathologic pathways that regulate WD have been defined. The elevation of ATP levels in axon contributes to delay WD and protects axons. However, ATP is necessary for the active processes to proceed WD, given that WD is stringently managed by auto-destruction programs. But little is known about the bioenergetics during WD. In this study, we made sciatic nerve transection models for GO-ATeam2 knock-in rats and mice. We presented the spatiotemporal ATP distribution in the injured axons with in vivo ATP imaging systems, and investigated the metabolic source of ATP in the distal nerve stump. A gradual decrease in ATP levels was observed before the progression of WD. In addition, the glycolytic system and monocarboxylate transporters (MCTs) were activated in Schwann cells following axotomy. Interestingly, in axons, we found the activation of glycolytic system and the inactivation of the tricarboxylic acid (TCA) cycle. Glycolytic inhibitors, 2-deoxyglucose (2-DG) and MCT inhibitors, a-cyano-4-hydroxycinnamic acid (4-CIN) decreased ATP and enhanced WD progression, whereas mitochondrial pyruvate carrier (MPC) inhibitors (MSDC-0160) did not change. Finally, ethyl pyruvate (EP) increased ATP levels and delayed WD. Together, our findings suggest that glycolytic system, both in Schwann cells and axons, is the main source of maintaining ATP levels in the distal nerve stump.

The Biology of Neuropathic Pain

Nerve injury or disease often leads to intractable neuropathic pain. Axons which are severed undergo Wallerian degeneration. This involves the activation of Schwann cells, mast cells, fibroblasts, keratinocytes and epithelial cells and the release of inflammatory cytokines, chemokines and growth factors. These primary mediators sensitize sensory nerve endings, attract macrophages, neutrophils and lymphocytes, alter gene expression, promote post-translational modification of proteins and alter ion channel function. This evokes spontaneous activity in primary afferent neurons that is crucial for the onset and maintenance of pain. In addition, secondary mediators such as colony stimulating factor 1 are generated and released from primary afferent terminals. These promote release of tertiary mediators such as brain-derived neurotrophic factor and interleukin 1b from spinal microglia and astrocytes. Tertiary mediators facilitate the generation and transmission of nociceptive information by facilitating excitatory transmission and attenuating inhibitory transmission in the dorsal horn. Transfer of information between neurons and immune cells is bidirectional. Neurons directly control immune cell function in a process termed neurogenic neuroinflammation. Increased permeability of the blood-brain barrier allows access of immune cells to neurons in central pain pathways. This, together with neurogenic neuroinflammation, increases activity throughout the pain sensory system. This review provides an overview of processes involved in the generation and persistence of peripherally generated neuropathic pain. Attention is drawn to the idea that pain etiology is dependent on the nature of the injury and different processes operate in males compared to females.

Assessment of Nerve Conduction in Patients With Lower Motor Neuron Facial Paralysis.

Introduction Bell's palsy (BP), a lower motor neuron facial paralysis, commonly causes dysfunction of muscles of facial expression. Nerve conduction electrodiagnostic studies differentiate early-stage minor conduction blocks from later-stage Wallerian degeneration. Nerve conduction studies (NCSs) assess facial nerve function by delivering supramaximal electrical stimulus at the stylomastoid foramen. The amplitude loss percentage of the affected side is calculated with reference to the normal side. Aim The study's aim was to characterize the ncs in BP cases and to evaluate the correlation between the Compound Muscle Action Potential (CMAP) of the muscles affected. Materials and methods One hundred and four NCS data of BP cases were retrospectively collected over the period of two years. Statistical analyses of variables were done using the Chi-square test, one-way ANOVA, and Pearson correlation coefficient. Result The greater amplitude loss was seen in the orbicularis oris muscle innervated by buccal and mandibular branches of the facial nerve. The bivariate correlation between the Right Nasalis versus Right Orbicularis Oculi and Left Orbicularis Oculi versus Left Nasalis showed a highly significant moderately Strong Positive Correlation with an R-value of 0.687 and 0.558, respectively. The amplitude drop percentage was statistically significant in the affected left and right sides with P values of 0.008 and 0.007 respectively (P value < 0.05). The amplitude drop between the nasalis, orbicularis oculi and orbicularis oris muscles of both sides was statistically significant with a P value of 0.001. Conclusion NCS should be mandatorily included as an assessment protocol in BP cases for quantification of nerve degeneration and as a prognostic tool during the course of treatment.

Delayed Diffusion Restriction of Wallerian Degeneration.

Delayed Diffusion Restriction of Wallerian Degeneration.