Nerve Degeneration Research Articles

Histological changes in the olfactory bulb and rostral migratory stream due to interruption of olfactory input

ObjectivePeriglomerular and granule cells in the adult mammalian olfactory bulb modulate olfactory signal transmission. These cells originate from the subventricular zone, migrate to the olfactory bulb via the Rostral Migratory Stream (RMS), and differentiate into mature cells within the olfactory bulb throughout postnatal life. While the regulation of neuroblast development is known to be affected by external stimuli, there is a lack of information concerning changes that occur during the recovery process after injury caused by external stimuli. To address this gap in research, the present study conducted histological observations to investigate changes in the olfactory bulb and RMS occurring after the degeneration and regeneration of olfactory neurons. MethodsTo create a model of olfactory neurodegeneration, adult mice were administered methimazole intraperitoneally. Nasal tissue and whole brains were removed 3, 7, 14 and 28 days after methimazole administration, and EdU was administered 2 and 4 h before removal of these tissues to monitor dividing cells in the RMS. Methimazole-untreated mice were used as controls. Olfactory nerve fibers entering the olfactory glomerulus were observed immunohistochemically using anti-olfactory marker protein. In the brain tissue, the entire RMS was observed and the volume and total number of cells in the RMS were measured. In addition, the number of neuroblasts and dividing neuroblasts passing through the RMS were measured using anti-doublecortin and anti-EdU antibodies, respectively. Statistical analysis was performed using the Tukey test. ResultsOlfactory epithelium degenerated was observed after methimazole administration, and recovered after 28 days. In the olfactory glomeruli, degeneration of OMP fibers began after methimazole administration, and after day 14, OMP fibers were reduced or absent by day 28, and overall OMP positive fibers were less than 20%. Glomerular volume tended to decrease after methimazole administration and did not appear to recover, even 28 days after recovery of the olfactory epithelium. In the RMS, EdU-positive cells decreased on day 3 and began to increase on day 7. However, they did not recover to the same levels as the control methimazole-untreated mice even after 28 days. ConclusionThese results suggest that the division and maturation of neuroblasts migrating from the RMS was suppressed by olfactory nerve degeneration or the disruption of olfactory input.

The Optic Nerve at Stake: Update on Environmental Factors Modulating Expression of Leber's Hereditary Optic Neuropathy.

Optic neuropathies are characterized by the degeneration of the optic nerves and represent a considerable individual and societal burden. Notably, Leber's hereditary optic neuropathy (LHON) is a devastating vision disease caused by mitochondrial gene mutations that hinder oxidative phosphorylation and increase oxidative stress, leading to the loss of retinal ganglion neurons and axons. Loss of vision is rapid and severe, predominantly in young adults. Penetrance is incomplete, and the time of onset is unpredictable. Recent findings revealed that the incidence of genetic LHON susceptibility is around 1 in 1000, much higher than believed till now. Environmental factors are critical in LHON triggering or severity. Families at risk have a very strong demand for how to prevent the onset or limit the severity of the disease. Here, we review recent knowledge of the extrinsic determinants of LHON expression, including lifestyle, dietary supplements, common chemicals, and drugs.

Phytic Acid Maintains Peripheral Neuron Integrity and Enhances Survivability against Platinum-Induced Degeneration via Reducing Reactive Oxygen Species and Enhancing Mitochondrial Membrane Potential.

Phytic acid (PA) has been reported to possess anti-inflammatory and antioxidant properties that are critical for neuroprotection in neuronal disorders. This raises the question of whether PA can effectively protect sensory neurons against chemotherapy-induced peripheral neuropathy (CIPN). Peripheral neuropathy is a dose-limiting side effect of chemotherapy treatment often characterized by severe and abnormal pain in hands and feet resulting from peripheral nerve degeneration. Currently, there are no effective treatments available that can prevent or cure peripheral neuropathies other than symptomatic management. Herein, we aim to demonstrate the neuroprotective effects of PA against the neurodegeneration induced by the chemotherapeutics cisplatin (CDDP) and oxaliplatin. Further aims of this study are to provide the proposed mechanism of PA-mediated neuroprotection. The neuronal protection and survivability against CDDP were characterized by axon length measurements and cell body counting of the dorsal root ganglia (DRG) neurons. A cellular phenotype study was conducted microscopically. Intracellular reactive oxygen species (ROS) was estimated by fluorogenic probe dichlorofluorescein. Likewise, mitochondrial membrane potential (MMP) was assessed by fluorescent MitoTracker Orange CMTMRos. Similarly, the mitochondria-localized superoxide anion radical in response to CDDP with and without PA was evaluated. The culture of primary DRG neurons with CDDP reduced axon length and overall neuronal survival. However, cotreatment with PA demonstrated that axons were completely protected and showed increased stability up to the 45-day test duration, which is comparable to samples treated with PA alone and control. Notably, PA treatment scavenged the mitochondria-specific superoxide radicals and overall intracellular ROS that were largely induced by CDDP and simultaneously restored MMP. These results are credited to the underlying neuroprotection of PA in a platinum-treated condition. The results also exhibited that PA had a synergistic anticancer effect with CDDP in ovarian cancer in vitro models. For the first time, PA's potency against CDDP-induced PN is demonstrated systematically. The overall findings of this study suggest the application of PA in CIPN prevention and therapeutic purposes.

Detection of Reduced Diameter of the Cochlear Nerve in Long-term Deaf Patients Quantified With Semiautomatic Measurement of Nerve Cross-sectional Area Using 3T MRI Data.

High-resolution parallel transmit T2 sampling perfection with application optimized contrast using different flip angle evolution sequence with improved edge discrimination and semiautomatic determination of nerve cross-sectional area (CSA) can be used to evaluate nerve degeneration in the inner auditory canal (IAC) in long-term deaf patients. In patients with hearing loss, temporal bone MRI is routinely acquired to evaluate the morphology of the nerves within the IAC. Earlier studies have shown that the diameter of the cochlear nerve can be used as prognostic marker for the auditory performance after cochlear implantation in postlingually deaf patients. Eighty-two consecutive MRI scans were analyzed using a semiautomatic tool to measure CSA of cranial nerves in the IAC. Results were correlated with patient history and audiology testing as well as with age and gender. There was a significant reduced CSA of the cochlear nerve in ears with moderate-to-profound hearing loss and deafness compared with ears with normal hearing, but no significant difference in ears with mild-to-moderate hearing loss compared with normal hearing. In detail, normal hearing ears had a CSA of 1.23 ± 0.11 mm2, whereas ears with pantonal hearing loss of more than 40 dB had 1.02 ± 0.05 mm2 (P = 0.026). Maximal CSA of the facial nerve was not different among all groups (average, 1.04 mm2 ± 0.03; linear regression, P = 0.001) and stable with age. However, vestibular nerve CSA decreased significantly with age (average, 1.78 ± 0.05 mm2; linear regression, P = 0.128). In long-term deaf patients, smaller the diameter of cochlear nerve is the more severe the hearing loss is. The new semiautomatic tool can primarily be used to assess nerve diameter and possibly determine ears with nerve degeneration.

Tear metabolomics for the diagnosis of primary open-angle glaucoma

Primary Open-Angle Glaucoma (POAG) is the most prevalent glaucoma type, and the leading cause of irreversible visual impairment and blindness worldwide. Identification of early POAG biomarkers is of enormous value, as there is not an effective treatment for the glaucomatous optic nerve degeneration (OND). In this pilot study, a metabolomic analysis, by using proton (1H) nuclear magnetic resonance (NMR) spectroscopy was conducted in tears, in order to determine the changes of specific metabolites in the initial glaucoma eyes and to discover potential diagnostic biomarkers. A classification model, based on the metabolomic fingerprint in tears was generated as a non-invasive tool to support the preclinical and clinical POAG diagnosis. 1H NMR spectra were acquired from 30 tear samples corresponding to the POAG group (n = 11) and the control group (n = 19). Data were analysed by multivariate statistics (partial least squares-discriminant analysis: PLS-DA) to determine a model capable of differentiating between groups. The whole data set was split into calibration (65%)/validation (35%), to test the performance and the ability for glaucoma discrimination. The calculated PLS-DA model showed an area under the curve (AUC) of 1, as well as a sensitivity of 100% and a specificity of 83.3% to distinguish POAG group versus control group tear data. This model included 11 metabolites, potential biomarkers of the disease. When comparing the study groups, a decrease in the tear concentration of phenylalanine, phenylacetate, leucine, n-acetylated compounds, formic acid, and uridine, was found in the POAG group. Moreover, an increase in the tear concentration of taurine, glycine, urea, glucose, and unsaturated fatty acids was observed in the POAG group. These results highlight the potential of tear metabolomics by 1H NMR spectroscopy as a non-invasive approach to support early POAG diagnosis and in order to prevent visual loss.

Chemical (Alkali) Burn-Induced Neurotrophic Keratitis Model in New Zealand Rabbit Investigated Using Medical Clinical Readouts and In Vivo Confocal Microscopy (IVCM).

Chemical eye injury is an acute emergency that can result in vision loss. Neurotrophic keratitis (NK) is the most common long-term manifestation of chemical injury. NK due to alkali burn affects ocular surface health and is one of its most common causes. Here, we established a rabbit model of corneal alkali burns to evaluate the severity of NK-associated changes. Alkali burns were induced in NZ rabbits by treating the cornea with (i) a 5 mm circular filter paper soaked in 0.75 N NaOH for 10 s (Mild NK) and (ii) trephination using a guarded trephine (5 mm diameter and 150-micron depth), followed by alkali burn, with a 5 mm circular filter paper soaked in 0.75 N NaOH for 10 s (a severe form of NK). Immediately after, the cornea was rinsed with 10 mL of normal saline to remove traces of NaOH. Clinical features were evaluated on Day 0, Day 1, Day 7, Day 15, and Day 21 post-alkali burn using a slit lamp, Pentacam, and anterior segment optical coherence tomography (AS-OCT). NK-like changes in epithelium, sub-basal nerve plexus, and stroma were observed using in vivo confocal microscopy (IVCM), and corneal sensation were measured using an aesthesiometer post alkali injury. After 21 days, pro-inflammatory cytokines were evaluated for inflammation through ELISA. Trephination followed by alkali burn resulted in the loss of epithelial layers (manifested using fluorescein stain), extensive edema, and increased corneal thickness (550 µm compared to 380 µm thickness of control) evaluated through AS-OCT and increased opacity score in alkali-treated rabbit (80 compared to 16 controls). IVCM images showed complete loss of nerve fibers, which failed to regenerate over 30 days, and loss of corneal sensation-conditions associated with NK. Cytokines evaluation of IL6, VEGF, and MMP9 indicated an increased angiogenic and pro-inflammatory milieu compared to the milder form of NK and the control. Using clinical parameters, we demonstrated that the alkali-treated rabbit model depicts features of NK. Using IVCM in the NaOH burn animal model, we demonstrated a complete loss of nerve fibers with poor self-healing capability associated with sub-basal nerve degeneration and compromised corneal sensation. This pre-clinical rabbit model has implications for future pre-clinical research in neurotrophic keratitis.

Anosmia due to bilateral papillary atrophy : a case report

Abstract
 Introduction : Papillary atrophy refers to degeneration of the optic nerve, which occurs as an end result of a pathological process that damages the axons, with ophthalmoscopic observation showing pallor of the optic nerve papillae which generally accompanies permanent damage to the optic nerve.
 Case Illustration : It was reported that a 36 year old woman came to the polyclinic with complaints of not being able to see in both eyes since 8 months ago. Complaints of blurred vision in both eyes are followed by smell that cannot smell. This complaint has been getting worse for the past 2 weeks. On brain MRI examination, results were obtained with SOL impressions in the midline frontalis area with perifocal edema ec, suspected olfactory groove meningioma.
 Discussion : In this case SOL is located in the midline frontal area so that the patient complains of loss of smell sensation (anosmia). The presence of a frontal or subfrontal tumor can compress the optic tract and optic nerve together. Optic tract compression will cause anosmia. Olfactory disturbances are strongly associated with anterior cerebral fossa tumors.
 Conclusion : Secondary papillary atrophy is caused by increased intracranial pressure caused by a mass tumor which is preceded by papilledema signs and eventually becomes papillary atrophy, and gives a pale optic papillae with blurred boundaries. Brain CT scan examinations are important to estimate the location of the lesion.

Transient Receptor Potential Vanilloid-1 Channels Facilitate Axonal Degeneration of Corneal Sensory Nerves in Dry Eye

Corneal nerve impairment contributes significantly to dry eye disease (DED) symptoms and is thought to be secondary to corneal epithelial damage. Transient receptor potential vanilloid-1 (TRPV1) channels abound in corneal nerve fibers and respond to inflammation-derived ligands, which increase in DED. TRPV1 overactivation promotes axonal degeneration invitro, but whether it participates in DED-associated corneal nerve dysfunction is unknown. To explore this, DED was surgically induced in wild-type and TRPV1-knockout mice, which developed comparable corneal epithelial damage and reduced tear secretion. However, corneal mechanosensitivity decreased progressively only in wild-type DED mice. Sensitivity to capsaicin (TRPV1 agonist) increased in wild-type DED mice, and consistently, only this strain displayed DED-induced pain signs. Wild-type DED mice exhibited nerve degeneration throughout the corneal epithelium, whereas TRPV1-knockout DED mice only developed a reduction in the most superficial nerve endings that failed to propagate to the deeper subbasal corneal nerves. Pharmacologic TRPV1 blockade reproduced these findings in wild-type DED mice, whereas CD4+ T cells from both strains were equally pathogenic when transferred, ruling out a T-cell-mediated effect of TRPV1 deficiency. These data show that ocular desiccation triggers superficial corneal nerve damage in DED, but proximal propagation of axonal degeneration requires TRPV1 expression. Local inflammation sensitized TRPV1 channels, which increased ocular pain. Thus, ocular TRPV1 overactivation drives DED-associated corneal nerve impairment.

Regulation and function of endoplasmic reticulum autophagy in neurodegenerative diseases.

The endoplasmic reticulum, a key cellular organelle, regulates a wide variety of cellular activities. Endoplasmic reticulum autophagy, one of the quality control systems of the endoplasmic reticulum, plays a pivotal role in maintaining endoplasmic reticulum homeostasis by controlling endoplasmic reticulum turnover, remodeling, and proteostasis. In this review, we briefly describe the endoplasmic reticulum quality control system, and subsequently focus on the role of endoplasmic reticulum autophagy, emphasizing the spatial and temporal mechanisms underlying the regulation of endoplasmic reticulum autophagy according to cellular requirements. We also summarize the evidence relating to how defective or abnormal endoplasmic reticulum autophagy contributes to the pathogenesis of neurodegenerative diseases. In summary, this review highlights the mechanisms associated with the regulation of endoplasmic reticulum autophagy and how they influence the pathophysiology of degenerative nerve disorders. This review would help researchers to understand the roles and regulatory mechanisms of endoplasmic reticulum-phagy in neurodegenerative disorders.

Uveitic glaucoma-like features in Yap conditional knockout mice

Glaucoma is a multifactorial neurodegenerative disease characterized by the progressive and irreversible degeneration of the optic nerve and retinal ganglion cells. Despite medical advances aiming at slowing degeneration, around 40% of treated glaucomatous patients will undergo vision loss. It is thus of utmost importance to have a better understanding of the disease and to investigate more deeply its early causes. The transcriptional coactivator YAP, an important regulator of eye homeostasis, has recently drawn attention in the glaucoma research field. Here we show that Yap conditional knockout mice (Yap cKO), in which the deletion of Yap is induced in both Müller glia (i.e. the only retinal YAP-expressing cells) and the non-pigmented epithelial cells of the ciliary body, exhibit a breakdown of the aqueous-blood barrier, accompanied by a progressive collapse of the ciliary body. A similar phenotype is observed in human samples that we obtained from patients presenting with uveitis. In addition, aged Yap cKO mice harbor glaucoma-like features, including deregulation of key homeostatic Müller-derived proteins, retinal vascular defects, optic nerve degeneration and retinal ganglion cell death. Finally, transcriptomic analysis of Yap cKO retinas pointed to early-deregulated genes involved in extracellular matrix organization potentially underlying the onset and/or progression of the observed phenotype. Together, our findings reveal the essential role of YAP in preserving the integrity of the ciliary body and retinal ganglion cells, thereby preventing the onset of uveitic glaucoma-like features.

A Comparison of the Effectiveness Between Trabeculectomy and Minimally Invasive Glaucoma Surgeries

Background and Hypothesis: Glaucoma affects 3 million Americans and is the second most common cause of blindness globally, after cataracts. It involves the degeneration of the optic nerve, often associated with increased eye pressure, leading to vision loss. Trabeculectomy was traditionally the standard surgical approach for managing glaucoma progression once medication and laser had failed. Recently, minimally invasive glaucoma surgeries (MIGS) have gained FDA approval for mild and moderate cases and are being implemented in practice. We hypothesize that MIGS procedures are just as effective as trabeculectomy in mild, moderate, and severe cases of glaucoma.
 Experimental Design or Project Methods: Using data from IU Health, patients that underwent either a MIGS procedure or a trabeculectomy for open-angle glaucoma at least a year ago were identified. Visual field data was used to stage their glaucoma. Any future glaucoma surgery was noted. Using this information, three separate Kaplan-Meier curves at 95% confidence intervals were created corresponding to each stage of glaucoma with a second surgery defined as a failure and a survival analysis was done to visualize the difference between these surgical approaches.
 Results: The sample included 119 patients and 179 eyes with a mean age of 80 and 57% females. The study had 80% power at a two-sided 5% significance level. Based on the survival analysis, there were no significant differences between trabeculectomy and MIGS in mild and moderate glaucoma (p=0.69 and 0.97 respectively). In severe glaucoma, MIGS had a lower failure rate compared to trabeculectomy (p=0.026).
 Conclusion and Potential Impact: The research comparing trabeculectomy to MIGS is still relatively new and this study shows the safety and efficacy of MIGS procedures. If confirmed, this study could potentially change the standard of care to MIGS for all stages of open-angle glaucoma.

Aldose reductase is a potential therapeutic target for neurodegeneration

Neurodegeneration is a complex process involving various inflammatory mediators and cellular responses. Aldose reductase (AR) is a key enzyme in the polyol pathway, which converts glucose to sorbitol. Beyond its metabolic role, AR has also been found to play a significant role in modulating neuroinflammation. This review aims to provide an overview of the current knowledge regarding the involvement of AR inhibition in attenuating neuroinflammation and complications from diabetic neuropathies. Here, we review the literature regarding AR and neuropathy/neurodegeneration. We discuss the mechanisms underlying the influence of AR inhibitors on ocular inflammation, beta-amyloid-induced neurodegeneration, and optic nerve degeneration. Furthermore, potential therapeutic strategies targeting AR in neurodegeneration are explored. The understanding of AR's role in neurodegeneration may lead to the development of novel therapeutic interventions for other neuroinflammatory disorders.

Iron role paradox in nerve degeneration and regeneration.

Iron accumulates in the neural tissue during peripheral nerve degeneration. Some studies have already been suggested that iron facilitates Wallerian degeneration (WD) events such as Schwann cell de-differentiation. On the other hand, intracellular iron levels remain elevated during nerve regeneration and gradually decrease. Iron enhances Schwann cell differentiation and axonal outgrowth. Therefore, there seems to be a paradox in the role of iron during nerve degeneration and regeneration. We explain this contradiction by suggesting that the increase in intracellular iron concentration during peripheral nerve degeneration is likely to prepare neural cells for the initiation of regeneration. Changes in iron levels are the result of changes in the expression of iron homeostasis proteins. In this review, we will first discuss the changes in the iron/iron homeostasis protein levels during peripheral nerve degeneration and regeneration and then explain how iron is related to nerve regeneration. This data may help better understand the mechanisms of peripheral nerve repair and find a solution to prevent or slow the progression of peripheral neuropathies.

Heterologous fibrin biopolymer as an emerging approach to peripheral nerve repair: a scoping review.

Nerve injuries present a substantial challenge within the medical domain due to their prevalent occurrence and significant impact. In nerve injuries, a range of physiopathological and metabolic responses come into play to stabilize and repair the resulting damage. A critical concern arises from the disruption of connections at neuromuscular junctions, leading to profound degeneration and substantial loss of muscle function, thereby hampering motor tasks. While end-to-end neurorrhaphy serves as the established technique for treating peripheral nerve injuries, achieving comprehensive morphofunctional recovery remains a formidable challenge. In pursuit of enhancing the repair process, alternative and supportive methods are being explored. A promising candidate is the utilization of heterologous fibrin biopolymer, a sealant devoid of human blood components. Notably, this biopolymer has showcased its prowess in establishing a stable and protective microenvironment at the site of use in multiple scenarios of regenerative medicine. Hence, this scoping review is directed towards assessing the effects of associating heterologous fibrin biopolymer with neurorrhaphy to treat nerve injuries, drawing upon findings from prior studies disseminated through PubMed/MEDLINE, Scopus, and Web of Science databases. Further discourse delves into the intricacies of the biology of neuromuscular junctions, nerve injury pathophysiology, and the broader utilization of fibrin sealants in conjunction with sutures for nerve reconstruction procedures. The association of the heterologous fibrin biopolymer with neurorrhaphy emerges as a potential avenue for surmounting the limitations associated with traditional sealants while also mitigating degeneration in nerves, muscles, and NMJs post-injury, thereby fostering a more conducive environment for subsequent regeneration. Indeed, queries arise regarding the long-term regenerative potential of this approach and its applicability in reconstructive surgeries for human nerve injuries.

RESTORE VISION: Novel advanced and repurposed therapeutics for vision restoration in a group of severe rare ocular diseases – Short introductory talk

Rare Eye Diseases (REDs) collectively represent a major cause of visual impairment and blindness for children and young adults in Europe. But importantly, REDs also affect adults and the aging population. Defective wound healing at the cornea and ocular surface, excessive inflammation, nerve degeneration, stem cell dysfunction, and aberrant vessel ingrowth are the common denominators in many REDs, representing a critical medical problem and an area of unmet medical need. The onset and progression of many REDs are characterized by common pathophysiologic mechanisms. The goal of many research groups is to disrupt these aberrant mechanisms with the aim of making therapy more effective. Current management is often prohibitively expensive, has low efficacy and leads to debilitating side effects, pointing to a critical medical problem and area of unmet medical need.Here, we will briefly introduce the RESTORE VISION project, which has been recently funded by the European Commission and brings together actors from across the full value chain: 6 leading research institutions, 3 SMEs and a European patient organization. The project will take a ground‐breaking approach to improve eye health by verifying disease pathomechanisms, using cutting‐edge models for each rare disease to test novel and repurposed compounds and determine drug mechanisms of action, formulating compounds as safe eye drop suspensions or subconjunctival drugs, and performing several first‐in‐human trials of novel therapies.

Chronic pain in the elderly: Exploring cellular and molecular mechanisms and therapeutic perspectives.

Chronic pain is a debilitating condition frequently observed in the elderly, involving numerous pathological mechanisms within the nervous system. Diminished local blood flow, nerve degeneration, variations in fiber composition, alterations in ion channels and receptors, accompanied by the sustained activation of immune cells and release of pro-inflammatory cytokines, lead to overactivation of the peripheral nervous system. In the central nervous system, chronic pain is strongly associated with the activation of glial cells, which results in central sensitization and increased pain perception. Moreover, age-related alterations in neural plasticity and disruptions in pain inhibitory pathways can exacerbate chronic pain in older adults. Finally, the environmental influences on the development of chronic pain in the elderly must be considered. An understanding of these mechanisms is essential for developing novel treatments for chronic pain, which can significantly improve the quality of life for this vulnerable population.

Distinct metabolic profiles in ocular hypertensive individuals responding

Aims/Purpose: To determine the effect of hypoxia on the plasma metabolic signature of patients with normal‐tension glaucoma (NTG) and ocular hypertension (OHT), compared to healthy controls.Methods: Metabolomic profiles of plasma from patients with NTG (n = 10) and OHT (n = 10) were compared to age‐matched controls (n = 10) to investigate the signature of hypoxia. Participants underwent two hours of exposure to normobaric hypoxia, followed by a 30‐min recovery period in normobaric normoxia. Blood samples were collected at baseline, during hypoxia, and recovery. Plasma samples were analysed using a non‐targeted metabolomics approach based on liquid chromatography coupled with high‐resolution mass spectrometry (LC‐HRMS). Multivariate analyses were conducted using principal component analysis (PCA) and orthogonal partial least squares‐discriminant analysis (OPLS‐DA), as well as univariate analysis with Wilcoxon signed‐rank test and false discovery rate (FDR) correction.Results: Overall, controls, OHT, and NTG patients had similar regulatory patterns. Only few metabolites involved in fatty acid biosynthesis, ketone body metabolism and kynurenine pathway were affected in OHT patients exposed to hypoxia, whereas metabolites related to energy production were not modified in NTG and OHT patients. No differences were found when comparing them pairwise at baseline, or during hypoxia and recovery.Conclusions: OHT patients have altered regulation of ketogenesis and kynurenine pathway, that may explain why they do not suffer from degeneration of the optic nerve. The metabolomes of NTG and OHT patients are regulated differently from controls, and omit to regulate metabolites that are important for energy production. This can potentially contribute to neurodegeneration and ultimately cell death in retinal ganglion cells.

Zingerone attenuates sciatic nerve damage caused by sodium arsenite by inhibiting NF-κB, caspase-3, and ATF-6/CHOP pathways and activating the Akt2/FOXO1 pathway.

In the present study, the potential protective effects of zingerone (ZNG) against sciatic nerve damage caused by sodium arsenite (SA), a common environmental pollutant, were evaluated by various biochemical, molecular, and histological methods. In the study, SA and ZNG were given to 35 male Sprague Dawley rats for 14 days. At the end of the period, the sciatic nerve tissues were taken and the markers involved in oxidative stress, endoplasmic reticulum stress, inflammation, and apoptosis were analyzed. The data obtained showed that SA decreased glutathione (GSH) levels and increased malondialdehyde (MDA) levels in the sciatic nerve tissue. However, it was determined that these markers approached the control group levels due to the anti-oxidant properties of ZNG. While SA triggered endoplasmic reticulum stress and apoptosis pathways, ZNG suppressed them. Moreover, SA up-regulated inflammatory markers such as nuclear factor kappa-B (NF-κB), tumor necrosis factor-alpha (TNF-α), interleukin-1-beta (IL-1β), and neuronal nitric oxide synthases (nNOS) in the sciatic nerves and caused neuro-inflammation and inhibited cell survival by suppressing serine/threonine-protein kinase 2 (Akt2) and forkhead box protein O1 (FOXO1) genes. It has also been shown histopathologically that SA causes degeneration in the sciatic nerves. In contrast, ZNG suppressed neuro-inflammation, activated Akt2/FOXO1 signaling, and repaired histological irregularities. In general, SA caused oxidative stress, inflammation, ER stress, and apoptosis in the sciatic nerves of rats, causing damage to the tissues, however, ZNG suppressed these pathways and protected the sciatic nerves from the destructive effect of SA.

Glaucoma, More than Meets the Eye: Patterns of Demyelination Revealed in Human Postmortem Glaucomatous Optic Nerve.

Glaucoma is a neurodegenerative disease affecting millions worldwide, characterised by retinal ganglion cell (RGC) degeneration which leads to blindness in more advanced cases. Although the pathogenesis and underlying mechanisms of glaucoma are not fully understood, there are theories that hint at demyelination playing a role in the disease process. Demyelination, or the degeneration of the myelin sheath surrounding axons, has been found in previous studies using animal models of glaucoma and clinical assessments of glaucoma patients. However, this has not been fully realised or quantified in glaucoma patients. Utilising postmortem optic nerve samples from glaucoma and healthy subjects, various immunohistochemical and morphological assessments were performed to determine the extent, if any, of demyelination in glaucomatous optic nerves. Our findings revealed that alongside nerve shrinkage and degeneration of nerve tissue fascicles, there were significantly less myelin proteins, specifically myelin basic protein (MBP), in glaucoma optic nerves. Additionally, the loss of MBP was correlated with decreased oligodendrocyte (OLG) precursors and increasing glial activity. This further supports previous evidence that demyelination may be a secondary degenerative process associated with glaucoma disease progression. Not only do these results provide evidence for potential disease mechanisms, but this is also the first study to quantify optic nerve demyelination in glaucoma postmortem tissue.

Plasmacytoid dendritic cell‐derived secretome ameliorates neuropathic corneal pain

Aims/Purpose: Prior work from our group has demonstrated a role for plasmacytoid dendritic cells (pDCs) in corneal nerve homeostasis. Herein, we sought to determine if pDC‐derived secretome could be used for the treatment of neuropathic corneal pain.Methods: The BDCA2‐DTR transgenic mice, in which pDCs can be selectively depleted result in subsequent nerve degeneration, were utilized for ex vivo electrophysiology studies. Animals were treated with pDC secretome drops, beginning 1 day after initial depletion. Electrophysiologic recordings were taken at day 3 post‐depletion analysed. A ciliary nerve ligation model of neuropathic corneal pain (NCP), was used to assess the therapeutic potential of pDC secretome. Spontaneous and evoked pain responses were assessed by palpebral opening measurements and hyperosmolar saline, respectively.Results: There was a significant reduction in cooling threshold following pDC depletion, which was rescued by pDC secretome treatment (26.85 ± 0.65°C vs. 29.52 ± 0.42°C; p < 0.05), restoring the cooling threshold to control levels (29.21 ± 0.51). Furthermore, nerve terminal exhaustion was reduced following pDC depletion and rescued by pDC secretome treatment (0.55 ± 0.08 vs. 1.11 ± 0.10; p < 0.01). Spontaneous pain responses were worse in the vehicle‐treated compared to pDC secretome‐treated group (0.67 ± 0.03 vs. 0.85 ± 0.02; p < 0.001). Similarly, evoked pain responses were worse in the vehicle‐treated compared to pDC secretome‐treated group (30.25 ± 1.50 wipes/30 sec vs. 15.38 ± 1.29; p < 0.0001).Conclusions: Herein, we demonstrate that pDC secretome restores normal functioning of corneal cold receptors. Importantly, in a translational model of NCP, pDC secretome treatment improved both spontaneous and evoked pain responses. Thus, pDC secretome is a viable therapeutic modality for further development and may hold promise in treatment of NCP and other corneal nerve related diseases.Reference1. Jamali A, Kenyon B, Ortiz G, Abou‐Slaybi A, Sendra VG, Harris DL, Hamrah P. Plasmacytoid Dendritic Cells in the Eye. Prog Retin Eye Res 2021; 80: 100877.2. Jamali A, Hu K, Sendra VG, Blanco T, Qazi Y, Zheng L, Turhan A, Hamrah P. Characterization of Resident Corneal Plasmacytoid Dendritic Cells and Their Pivotal Role in Herpes Simplex Keratitis. Cell Rep 2020; 32: 108099.