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Axon-to-soma signaling events drive the changes in gene expression required for the injured axon to shift from non-elongating to growth-competent. Genetic reprogramming of adult neurons back to a growth-compatible state relies on the activation and coordinated actions of several transcription factors and epigenetic modifiers. Local translation supplies the injured axon with the necessary proteins to carry out the regenerative program. Neurons activate intrinsic energetic repair mechanisms to remobilize axonal mitochondria and meet the high energy demands of the regenerative process. Several intrinsic barriers to axonal regeneration have been identified, including the presence of functional presynaptic active zones, transcriptional repressors, and inhibitors of critical regenerative signaling pathways. Injury to the central nervous system (CNS) often results in permanent neurological impairments because axons fail to regenerate and re-establish lost synaptic contacts. By contrast, peripheral neurons can activate a pro-regenerative program and regenerate following a nerve lesion. This relies on an intricate intracellular communication system between the severed axon and the cell body. Locally activated signaling molecules are retrogradely transported to the soma to promote the epigenetic and transcriptional changes required for the injured neuron to regain growth competence. These signaling events rely heavily on intra-axonal translation and mitochondrial trafficking into the severed axon. Here, we discuss the interplay between these mechanisms and the main intrinsic barriers to axonal regeneration. We also examine the potential of manipulating these processes for driving CNS repair. [ABSTRACT FROM AUTHOR]

Retinal ganglion cells (RGCs), neurons transmitting visual information via the optic nerve, fail to regenerate their axons after injury. The progressive loss of RGC function underlies the pathophysiology of glaucoma and other optic neuropathies, often leading to irreversible blindness. Therefore, there is an urgent need to identify the regulators of RGC survival and the regenerative program. In this study, we investigated the role of the family of transcription factors known as nuclear factor of activated T cells (NFAT), which are expressed in the retina; however, their role in RGC survival after injury is unknown. Using the optic nerve crush (ONC) model, widely employed to study optic neuropathies and central nervous system axon injury, we found that NFATc4 is specifically but transiently up-regulated in response to mechanical injury. In the injured retina, NFATc4 immunolocalized primarily to the ganglionic cell layer. Utilizing NFATc4−/− and NFATc3−/− mice, we demonstrated that NFATc4, but not NFATc3, knockout increased RGC survival, improved retina function, and delayed axonal degeneration. Microarray screening data, along with decreased immunostaining of cleaved caspase-3, revealed that NFATc4 knockout was protective against ONC-induced degeneration by suppressing pro-apoptotic signaling. Finally, we used lentiviral-mediated NFATc4 delivery to the retina of NFATc4−/− mice and reversed the pro-survival effect of NFATc4 knockout, conclusively linking the enhanced survival of injured RGCs to NFATc4-dependent mechanisms. In summary, this study is the first to demonstrate that NFATc4 knockout may confer transient RGC neuroprotection and decelerate axonal degeneration after injury, providing a potent therapeutic strategy for optic neuropathies. [ABSTRACT FROM AUTHOR]

As the primary connection between the eye and brain, the optic nerve plays a pivotal role in visual information transmission. Injuries to the optic nerve can occur for various reasons, including trauma, glaucoma, and neurodegenerative diseases. Retinal ganglion cells (RGCs), a type of neurons that extend axons through the optic nerve, can rapidly respond to injury and initiate cell death. Additionally, following optic nerve injury microglia, which serve as markers of neuroinflammation, transition from a resting state to an activated state. The phosphorylation of collapsin response mediator protein2 (CRMP2) in the semaphorin 3A (Sema3A) signalling pathway affects several processes, including axon guidance and neuron regeneration. In this study, we used an optic nerve crush (ONC) mouse model to investigate the effects of suppressing CRMP2 phosphorylation on microglia activation. We found that CRMP2 phosphorylation inhibitor suppressed RGCs loss and promoted neuronal regeneration following ONC. In addition, CRMP2 S522A mutant (CRMP2 KI) mice exhibited decreased microglial activation in both the retina and optic nerve following ONC. These results suggest that inhibiting the phosphorylation of CRMP2 can alleviate the loss of RGCs and microglial activation after optic nerve injury, providing insight into the development of treatments for optical neuropathies and neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Objective To explore the relationship between phenotypic changes of retinal microglia and retinal ganglion cells (RGCs) death after optic nerve injury. Methods Male C57BL/6J mice (6 to 8 weeks old) were randomly divided into 1-, 3-, 7-, and 14-day injury groups and sham operation group, with 4 mice in each group. The eyes in the injured groups were inflicted with optic nerve crush (ONC), while the eyes of the sham operation group were treated with the same operation procedure but without optic nerve clamp. Flash visual evoked potential (fVEP) and immunofluorescence staining were employed to evaluate the impact of optic nerve injury on visual function and number of RGCs. RT-qPCR and immunofluorescence staining were applied to detect the effecy of optic nerve injury on phenotypic changes in retinal microglia. Results fVEP results showed that the visual conduction of the injured eye was gradually decreased over time when compared with that of the sham group (P < 0.01). Immunofluorescence staining revealed that the number of RGCs was lost mainly within 7 d after injury (P < 0.01). At the same time, the number of retinal microglia reached its peak at 7 d after injury (P < 0.01). RT-qPCR indicated that the expression of disease-associated microglia (DAM) and interferon-responsive microglia (IRM) specific genes were significantly increased when compared with the sham group at 7 d after ONC (P < 0.01). Immunofluorescence staining displayed that the number of DAM peaked at 3 d after ONC (P < 0.01), but the proportion was decreased gradually with the progress of time (P < 0.05). The number and proportion of IRM peaked 7 d after ONC (P < 0.01). Correlation analysis suggested that the number of IRM was strongly correlated with the loss of ganglion cells (P < 0.01). Conclusion The conversion of retinal microglia from DAM type to IRM type after optic nerve injury may be an important cause of ganglion cell loss.

Background: Activated microglia release harmful substances to retinal ganglion cells (RGCs), but may also benefit by removing cellular debris and secreting neurotrophic factors. These paradoxical roles remain controversial because the nature and time-course of the injury that defines their role is unknown. The aim of this study was to determine if pharmacological manipulation of microglia to acquire a pro-inflammatory or pro-survival phenotype will exacerbate or enhance neuronal survival after injury.Material and methods: Treated HAP I (highly aggressively proliferating immortalized) microglia were injected into the vitreous or tail vein (T V) of female Sprague-Dawley rats. Retinas were examined at 4-14 days following optic nerve crush (ONC) and the number of surviving RGCs was determined.Results: Injection of untreated HAP I cells resulted in the greater loss of RGCs early after ONC when injected into the vitreous and later after ONC when injected into the T V. LP S activated HAP I cells injected into the vitreous resulted in greater RGC loss with and without injury. When injected into the T V with ONC there was no loss of RGCs 4 days after ONC but greater loss afterwards. Minocycline treated HAP I cells injected into the vitreous resulted in greater RGC survival than untreated HAP I cells. However, when injected into the T V with ONC there was greater loss of RGCs. These results suggest that optic nerve signals attract extrinsic microglia to the retina, resulting in a proinflammatory response.Conclusion: Neuroprotection or cytotoxicity of microglia depends on the type of activation, time course of the injury, and if they act on the axon or cell body. HAPI microglia migrate to the retina or optic nerve following optic nerve injury when injected into the vitreous or tail vein, respectively. Pretreatment with LPS or minocycline differentially effects retinal ganglion cell survival. In most cases, the result late in the injury process is greater retinal ganglion cell loss. We show here that neuroprotection is not solely determined by the microglial activation state but factors such as the environment and time-course of the injury. Culture microglia can be treated in vitro and then injected in vivo. The cells migrate to the site of injury, cell body of retinal ganglion cells if in the vitreous or to the optic nerve if injected in the tail vein. Retinal ganglion cell death is dependent on the location the microglia act, time-course of injury, and activation state. Proinflammatory microglia can be neuroprotective early in the injury when the primary site of action is on the axons whereas hypoactivated microglia are neuroprotective early in injury when they act on the soma. Later in the injury, both become detrimental. [ABSTRACT FROM AUTHOR]

Visual field defects are commonly present in patients with brain tumors, particularly due to direct compression on the optic apparatus. However, there are instances where brain tumors, despite not directly compressing the optic pathway, can still cause visual symptoms, albeit rarely reported but not uncommonly observed. These mechanisms are thought to be associated with increased intracranial pressure (IICP). We report a case of a 32-year-old man who presented with right blurred vision and was diagnosed with a right convexity meningioma. Upon reviewing his magnetic resonance images, we hypothesized that the indentation of the pituitary stalk on the optic chiasm and the stretching of the optic nerve, combined with a focal effect of IICP, could be responsible for his atypical visual field defect.

Glaucomatous optic neuropathy(GON)is the difficulty of glaucoma treatment. In recent years, a variety of theories have been put forward about the pathogenesis of GON, but none of them can explain the principle of optic neuropathy caused by all types of glaucoma, which makes the disease difficult to treat in clinical treatment and is not conducive to early intervention. The latest research found that the transient receptor potential channel vanillic acid subfamily 4(TRPV4)in the retina plays an important role in various pathogenesis of GON. This article will review TRPV4 and its role in the occurrence and development of GON in order to find a common “connection point” for the multiple mechanism theories of GON, which will contribute to further understanding and clinical treatment of the disease.

Activated astrocytes are a primary source of inflammatory factors following traumatic optic neuropathy (TON). Accumulation of inflammatory factors in this context leads to increased axonal damage and loss of retinal ganglion cells (RGCs). Therefore, in the present study, we explored the role of the astrocyte G protein-coupled estrogen receptor (GPER) in regulating inflammatory factors following optic nerve crush (ONC), and analyzed its potential regulatory mechanisms. Overall, our results showed that GPER was abundantly expressed in the optic nerve, and co-localized with glial fibrillary acidic proteins (GFAP). Exogenous administration of G-1 led to a significant reduction in astrocyte activation and expression of inflammation-related factors (including IL-1β, TNF-α, NFκB, and p-NFκB). Additionally, it dramatically increased the survival of RGCs. In contrast, astrocytes were activated to a greater extent by exogenous G15 administration; however, RGCs survival was significantly reduced. In vitro, GPER activation significantly reduced astrocyte activation and the release of inflammation-related factors. In conclusion, activation of astrocyte GPER significantly reduced ONC inflammation levels, and should be explored as a potential target pathway for protecting the optic nerve and RGCs after TON.

Objective To investigate the characteristics and objective assessment method of visual field defects caused by optic chiasm and its posterior visual pathway injury. Methods Typical cases of visual field defects caused by injuries to the optic chiasm, optic tracts, optic radiations, and visual cortex were selected. Visual field examinations, visual evoked potential （VEP） and multifocal visual evolved potential （mfVEP） measurements, craniocerebral CT/MRI, and retinal optical coherence tomography （OCT） were performed, respectively, and the aforementioned visual electrophysiological and neuroimaging indicators were analyzed comprehensively. Results The electrophysiological manifestations of visual field defects caused by optic chiasm injuries were bitemporal hemianopsia mfVEP abnormalities. The visual field defects caused by optic tract, optic radiation, and visual cortex injuries were all manifested homonymous hemianopsia mfVEP abnormalities contralateral to the lesion. Mild relative afferent pupil disorder （RAPD） and characteristic optic nerve atrophy were observed in hemianopsia patients with optic tract injuries, but not in patients with optic radiation or visual cortex injuries. Neuroimaging could provide morphological evidence of damages to the optic chiasm and its posterior visual pathway. Conclusion Visual field defects caused by optic chiasm, optic tract, optic radiation, and visual cortex injuries have their respective characteristics. The combined application of mfVEP and static visual field measurements, in combination with neuroimaging, can maximize the assessment of the location and degree of visual pathway damage, providing an effective scheme for the identification of such injuries.

AIM: To evaluate the changes of retinal microvascular density in patients with sellar region tumor, and its correlation with the damage to visual field, and to explore its application value in evaluating optic nerve injury of those patients.METHODS: Cross-sectional study. A total of 157 patients(292 eyes)with sellar region tumor, including 82 cases(152 eyes)of pituitary adenoma and 75 cases(140 eyes)of craniopharyngioma, were selected from neurosurgery department and ophthalmology department of Beijing Tiantan Hospital, Capital Medical University between October 2018 and May 2022. A total of 90 people(180 eyes)during the same period, including the family members of patients, students and staff in Beijing Tiantan Hospital, Capital Medical University were collected as control group. All participants underwent optical coherence tomography angiography(OCTA)examination. The changes of retinal microvascular density and its correlation with visual field parameters were compared between the two groups.RESULTS: In patients with sellar region tumor, the radial peripapillary capillary(RPC)and superficial retinal capillary plexus(SRCP)density were significantly lower than that in the control group [50.81%(46.49%, 53.49%)vs. 52.78%(50.73%, 54.51%)and 50.57%(48.13%, 52.73%)vs. 51.63%(49.78%, 53.02%), all P

Injured axons in the central nervous system (CNS) usually fail to regenerate, causing permanent disabilities. However, the knockdown of Pten knockout or treatment of neurons with hyper-IL-6 (hIL-6) transforms neurons into a regenerative state, allowing them to regenerate axons in the injured optic nerve and spinal cord. Transneuronal delivery of hIL-6 to the injured brain stem neurons enables functional recovery after severe spinal cord injury. Here we demonstrate that the beneficial hIL-6 and Pten knockout effects on axon growth are limited by the induction of tubulin detyrosination in axonal growth cones. Hence, cotreatment with parthenolide, a compound blocking microtubule detyrosination, synergistically accelerates neurite growth of cultured murine CNS neurons and primary RGCs isolated from adult human eyes. Systemic application of the prodrug dimethylamino-parthenolide (DMAPT) facilitates axon regeneration in the injured optic nerve and spinal cord. Moreover, combinatorial treatment further improves hIL-6-induced axon regeneration and locomotor recovery after severe SCI. Thus, DMAPT facilitates functional CNS regeneration and reduces the limiting effects of pro-regenerative treatments, making it a promising drug candidate for treating CNS injuries.

The retinal ganglion cells (RGCs) are the sole output neurons that connect information from the retina to the brain. Optic neuropathies such as glaucoma, trauma, inflammation, ischemia and hereditary optic neuropathy can cause RGC loss and axon damage, and lead to partial or total loss of vision, which is an irreversible process in mammals. The accurate diagnoses of optic neuropathies are crucial for timely treatments to prevent irrevocable RGCs loss. After severe ON damage in optic neuropathies, promoting RGC axon regeneration is vital for restoring vision. Clearance of neuronal debris, decreased intrinsic growth capacity, and the presence of inhibitory factors have been shown to contribute to the failure of post‐traumatic CNS regeneration. Here, we review the current understanding of manifestations and treatments of various common optic neuropathies. We also summarise the current known mechanisms of RGC survival and axon regeneration in mammals, including specific intrinsic signalling pathways, key transcription factors, reprogramming genes, inflammation‐related regeneration factors, stem cell therapy, and combination therapies. Significant differences in RGC subtypes in survival and regenerative capacity after injury have also been found. Finally, we highlight the developmental states and non‐mammalian species that are capable of regenerating RGC axons after injury, and cellular state reprogramming for neural repair. [ABSTRACT FROM AUTHOR]

Optic nerve injury is a type of neurodegenerative disease. Physcion is an anthraquinone that exerts a protective role against various diseases. However, its function in regulating optic nerve injury remains largely unknown. An in vitro model of optic nerve injury was established in HAPI cells treated with IFN-ß. Functional assays were used to detect HAPI cell viability and apoptosis. The levels of inflammation and the expression levels of oxidative stress-related genes were measured in HAPI cells. In addition, western blot analysis was used to detect the expression levels of Janus kinase 2 (JAK2)/STAT3-linked genes in HAPI cells. Treatment of the cells with physcion prevented cells against IFN-ß-induced neuronal injury. Physcion restrained IFN-ß-induced inflammatory response and oxidative stress in HAPI cells. In addition, it improved IFN-ß-induced injury in HAPI cells by suppressing the JAK2/STAT3 pathway. In conclusion, the present study revealed that physcion improved optic nerve injury in vitro by inhibiting the JAK2/STAT3 pathway. Physcion may be a promising therapeutic target for the treatment of this disease. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Forensic Medicine / Fayixue Zazhi is the property of Journal of Forensic Medicine Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Introduction: Optic nerve injury is a leading cause of irreversible blindness worldwide. The retinal ganglion cells (RGCs) and their axons cannot be regenerated once damaged. Therefore, reducing RGC damage is crucial to prevent blindness. Accordingly, we aimed to investigate the potential influence of the gut microbiota on RGC survival, as well as the associated action mechanisms. Methods: We evaluated the effects of microbiota, specifically Bifidobacterium, on RGC. Optic nerve crush (ONC) was used as a model of optic nerve injury. Vancomycin and Bifidobacterium were orally administered to specific pathogen‐free (SPF) mice. Results: Bifidobacterium promoted RGC survival and optic nerve regeneration. The administration of Bifidobacterium inhibited microglia activation but promoted Müller cell activation, which was accompanied by the downregulation of inflammatory cytokines and upregulation of neurotrophic factors and retinal ERK/Fos signaling pathway activation. Conclusions: Our study demonstrates that Bifidobacterium‐induced changes in intestinal flora promote RGC survival. The protective effect of Bifidobacterium on RGC can be attributed to the inhibition of microglia activation and promotion of Müller cell activation and the secondary regulation of inflammatory and neurotrophic factors. [ABSTRACT FROM AUTHOR]

Sphingosine-1-phosphate receptor (S1PR) signaling regulates diverse pathophysiological processes in the central nervous system. The role of S1PR signaling in neurodegenerative conditions is still largely unidentified. Siponimod is a specific modulator of S1P1 and S1P5 receptors, an immunosuppressant drug for managing secondary progressive multiple sclerosis. We investigated its neuroprotective properties in vivo on the retina and the brain in an optic nerve injury model induced by a chronic increase in intraocular pressure or acute N-methyl-D-aspartate excitotoxicity. Neuronal-specific deletion of sphingosine-1-phosphate receptor (S1PR1) was carried out by expressing AAV-PHP.eB-Cre recombinase under Syn1 promoter in S1PR1flox/flox mice to define the role of S1PR1 in neurons. Inner retinal electrophysiological responses, along with histological and immunofluorescence analysis of the retina and optic nerve tissues, indicated significant neuroprotective effects of siponimod when administered orally via diet in chronic and acute optic nerve injury models. Further, siponimod treatment showed significant protection against trans-neuronal degenerative changes in the higher visual center of the brain induced by optic nerve injury. Siponimod treatment also reduced microglial activation and reactive gliosis along the visual pathway. Our results showed that siponimod markedly upregulated neuroprotective Akt and Erk1/2 activation in the retina and the brain. Neuronal-specific deletion of S1PR1 enhanced retinal and dorsolateral geniculate nucleus degenerative changes in a chronic optic nerve injury condition and attenuated protective effects of siponimod. In summary, our data demonstrated that S1PR1 signaling plays a vital role in the retinal ganglion cell and dorsolateral geniculate nucleus neuronal survival in experimental glaucoma, and siponimod exerts direct neuroprotective effects through S1PR1 in neurons in the central nervous system independent of its peripheral immuno-modulatory effects. Our findings suggest that neuronal S1PR1 is a neuroprotective therapeutic target and its modulation by siponimod has positive implications in glaucoma conditions.

Glaucoma is a leading cause of irreversible blindness in the world and its specific pathogenesis is not clear. More attention has been paid to intraocular pressure and aqueous outflow channel. In recent years, scholars began to attach more importance to the role of non-pressure dependent factors, such as corneal hysteresis(CH), in glaucoma. CH is a biomechanical parameter of cornea, which reflects the viscous resistance of cornea, i.e., the ability to absorb and disperse energy. CH can be easily acquired clinically and may serve as surrogate markers for biomechanical properties of tissues in the back of the eye, like the lamina cribrosa and peripapillary sclera, which may be related to the susceptibility of glaucomatous damage. Several studies have provided evidence of the associations between CH and clinically relevant outcomes in glaucoma. This article reviews the latest findings on CH and summarizes the measurement methods of CH, relations between CH and central corneal thickness, glaucomatous visual field progress, optic disc damage, retinal nerve fiber layer loss, etc.

Failure of central nervous system projection neurons to spontaneously regenerate long-distance axons underlies irreversibility of white matter pathologies. A barrier to axonal regenerative research is that the axons regenerating in response to experimental treatments stall growth before reaching postsynaptic targets. Here, we test the hypothesis that the interaction of regenerating axons with live oligodendrocytes, which were absent during developmental axon growth, contributes to stalling axonal growth. To test this hypothesis, first, we used single cell RNA-seq (scRNA-seq) and immunohistology to investigate whether post-injury born oligodendrocytes incorporate into the glial scar after optic nerve injury. Then, we administered demyelinationinducing cuprizone and stimulated axon regeneration by Pten knockdown (KD) after optic nerve crush. We found that postinjury born oligodendrocyte lineage cells incorporate into the glial scar, where they are susceptible to the demyelination diet, which reduced their presence in the glial scar. We further found that the demyelination diet enhanced Pten KD-stimulated axon regeneration and that localized cuprizone injection promoted axon regeneration. We also present a resource for comparing the gene expression of scRNA-seq-profiled normal and injured optic nerve oligodendrocyte lineage cells. [ABSTRACT FROM AUTHOR]

Optic nerve damage is a common cause of blindness. Optic nerve injury is often accompanied by fundus vascular disease, retinal ganglion cell apoptosis, and changes in retinal thickness. These changes can cause alterations in protein expression within neurons in the retina. Proteomics analysis offers conclusive evidence to decode a biological system. Furthermore, animal models of optic nerve injury made it possible to gain insight into pathological mechanisms, therapeutic targets, and effective treatment of such injuries. Proteomics takes the proteome as the research object and studies protein changes in cells and tissues. At present, a variety of proteomic analysis methods have been widely used in the research of optic nerve injury diseases. This review summarizes the application of proteomic research in optic nerve injury diseases and animal models of optic nerve injury. Additionally, differentially expressed proteins are summarized and analyzed. Various optic nerve injuries, including those associated with different etiologies, are discussed along with their potential therapeutic targets and future directions. [ABSTRACT FROM AUTHOR]

AIM: To investigate the expression changes of Toll like recepter 9(TLR-9)and myeloid differentiation factor 88(MyD88)in retina of mice following optic nerve injury(ONI).METHODS: There were 36 male 8-week-old C57BL/6J mice randomly divided into 6 groups: blank control(no treatment), ONI 1d group(materials were taken at 1d after optic nerve injury), ONI 3d group(materials were taken at 3d after optic nerve injury), ONI 5d group(materials were taken at 5d after optic nerve injury), ONI 7d group(materials were taken at 7d after optic nerve injury), ONI 14d group(materials were taken at 14d after optic nerve injury). The mice optic nerve model was made by optic nerve gripping, and the mRNA and protein levels of Toll like recepter 9 and myeloid differentiation factor 88 in each retinal were measured by RT-qPCR and Western-blot.RESULTS: The mRNA and protein levels of Toll like recepter 9 and myeloid differentiation factor 88 in the retina of ONI 1d group were not significantly different from those of the blank control group(P>0.05), the mRNA and protein levels of TLR-9 and MyD88 in the retina of ONI 3d group, ONI 5d group, ONI 7d group and ONI 14d group were significantly increased compared with the blank control group, and the differences were statistically significant(P

Gene therapy has become an essential treatment for optic nerve injury (ONI) in recent years, and great strides have been made using animal models. ONI, which is characterized by the loss of retinal ganglion cells (RGCs) and axons, can induce abnormalities in the pupil light reflex, visual field defects, and even vision loss. The eye is a natural organ to target with gene therapy because of its high accessibility and certain immune privilege. As such, numerous gene therapy trials are underway for treating eye diseases such as glaucoma. The aim of this review was to cover research progress made in gene therapy for ONI. Specifically, we focus on the potential of gene therapy to prevent the progression of neurodegenerative diseases and protect both RGCs and axons. We cover the basic information of gene therapy, including the classification of gene therapy, especially focusing on genome editing therapy, and then we introduce common editing tools and vector tools such as Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) -Cas9 and adeno-associated virus (AAV). We also summarize the progress made on understanding the roles of brain derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), phosphatase-tensin homolog (PTEN), suppressor of cytokine signal transduction 3 (SOCS3), histone acetyltransferases (HATs), and other important molecules in optic nerve protection. However, gene therapy still has many challenges, such as misalignment and mutations, immunogenicity of AAV, time it takes and economic cost involved, which means that these issues need to be addressed before clinical trials can be considered.

Optic nerve injury causes secondary degeneration, a sequela that spreads damage from the primary injury to adjacent tissue, through mechanisms such as oxidative stress, apoptosis, and blood-brain barrier (BBB) dysfunction. Oligodendrocyte precursor cells (OPCs), a key component of the BBB and oligodendrogenesis, are vulnerable to oxidative deoxyribonucleic acid (DNA) damage by 3 days post-injury. However, it is unclear whether oxidative damage in OPCs occurs earlier at 1 day post-injury, or whether a critical 'window-of-opportunity' exists for therapeutic intervention. Here, a partial optic nerve transection rat model of secondary degeneration was used with immunohistochemistry to assess BBB dysfunction, oxidative stress, and proliferation in OPCs vulnerable to secondary degeneration. At 1 day post-injury, BBB breach and oxidative DNA damage were observed, alongside increased density of DNA-damaged proliferating cells. DNA-damaged cells underwent apoptosis (cleaved caspase3+), and apoptosis was associated with BBB breach. OPCs experienced DNA damage and apoptosis and were the major proliferating cell type with DNA damage. However, the majority of caspase3+ cells were not OPCs. These results provide novel insights into acute secondary degeneration mechanisms in the optic nerve, highlighting the need to consider early oxidative damage to OPCs in therapeutic efforts to limit degeneration following optic nerve injury. [ABSTRACT FROM AUTHOR]

Copyright of Journal of China Medical University is the property of Journal of China Medical University Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objective: Any damage to the optic nerve can potentially lead to degeneration of non-regenerating axons and ultimately death of retinal ganglion cells (RGCs) that in most cases, are not curable by surgery or medication. Neuroprotective functions of different types of stem cells in the nervous system have been evaluated in many studies investigating the effectiveness of these cells in various retinal disease models. Neural progenitor cells (NPCs) secrete an assortment of trophic factors that are vital to the protection of the visual system. We aimed to assess the therapeutic potentials of NPCs in an ONC mouse model. Materials and Methods: In this experimental study, NPCs were produced using noggin and retinoic acid from human embryonic stem cells (hESCs). Fifty mice were divided into the following three groups: i. Intact , ii. Vehicle [optic nerve crush+Hank’s balanced salt solution (HBSS)], and iii. Treatment (optic nerve crush+NPCs). The visual behavior of the mice was examined using the Visual Cliff test, and in terms of RGC numbers, they were assessed by Brn3a immunostaining and retrograde tracing using DiI injection. Results: Intravenous injection of 50,000 NPCs through visual cliff did not produce any visual improvement. However, our data suggest that the RGCs protection was more than two-times in NPCs compared to the vehicle group as examined by Brn3a staining and retrograde tracing. Conclusion: Our study indicated that intravenous injection of NPCs could protect RGCs probably mediated by trophic factors. Due to this ability and good manufacturing practices (GMP) grade production feasibility, NPCs may be used for optic nerve protection.

Purpose: There are no effective treatments currently available for optic nerve transection injuries. Stem cell therapy represents a feasible future treatment option. This study investigated the therapeutic potential of human umbilical cord–derived mesenchymal stem cell (hUC-MSC) transplantation in rats with optic nerve injury. Methods: Sprague–Dawley (SD) rats were divided into three groups: a no-treatment control group (n = 6), balanced salt solution (BSS) treatment group (n = 6), and hUC-MSCs treatment group (n = 6). Visual functions were assessed by flash visual evoked potential (fVEP) at baseline, Week 3, and Week 6 after optic nerve crush injury. Right eyes were enucleated after 6 weeks for histology. Results: The fVEP showed shortened latency delay and increased amplitude in the hUC-MSCs treated group compared with control and BSS groups. Higher cellular density was detected in the hUC-MSC treated group compared with the BSS and control groups. Co-localized expression of STEM 121 and anti-S100B antibody was observed in areas of higher nuclear density, both in the central and peripheral regions. Conclusion: Peribulbar transplantation of hUC-MSCs demonstrated cellular integration that can potentially preserve the optic nerve function with a significant shorter latency delay in fVEP and higher nuclear density on histology, and immunohistochemical studies observed cell migration particularly to the peripheral regions of the optic nerve.

Abstract Background Because some of its CNS neurons (e.g., retinal ganglion cells after optic nerve crush (ONC)) regenerate axons throughout life, whereas others (e.g., hindbrain neurons after spinal cord injury (SCI)) lose this capacity as tadpoles metamorphose into frogs, the South African claw-toed frog, Xenopus laevis, offers unique opportunities for exploring differences between regenerative and non-regenerative responses to CNS injury within the same organism. An earlier, three-way RNA-seq study (frog ONC eye, tadpole SCI hindbrain, frog SCI hindbrain) identified genes that regulate chromatin accessibility among those that were differentially expressed in regenerative vs non-regenerative CNS [11]. The current study used whole genome bisulfite sequencing (WGBS) of DNA collected from these same animals at the peak period of axon regeneration to study the extent to which DNA methylation could potentially underlie differences in chromatin accessibility between regenerative and non-regenerative CNS. Results Consistent with the hypothesis that DNA of regenerative CNS is more accessible than that of non-regenerative CNS, DNA from both the regenerative tadpole hindbrain and frog eye was less methylated than that of the non-regenerative frog hindbrain. Also, consistent with observations of CNS injury in mammals, DNA methylation in non-regenerative frog hindbrain decreased after SCI. However, contrary to expectations that the level of DNA methylation would decrease even further with axotomy in regenerative CNS, DNA methylation in these regions instead increased with injury. Injury-induced differences in CpG methylation in regenerative CNS became especially enriched in gene promoter regions, whereas non-CpG methylation differences were more evenly distributed across promoter regions, intergenic, and intragenic regions. In non-regenerative CNS, tissue-related (i.e., regenerative vs. non-regenerative CNS) and injury-induced decreases in promoter region CpG methylation were significantly correlated with increased RNA expression, but the injury-induced, increased CpG methylation seen in regenerative CNS across promoter regions was not, suggesting it was associated with increased rather than decreased chromatin accessibility. This hypothesis received support from observations that in regenerative CNS, many genes exhibiting increased, injury-induced, promoter-associated CpG-methylation also exhibited increased RNA expression and association with histone markers for active promoters and enhancers. DNA immunoprecipitation for 5hmC in optic nerve regeneration found that the promoter-associated increases seen in CpG methylation were distinct from those exhibiting changes in 5hmC. Conclusions Although seemingly paradoxical, the increased injury-associated DNA methylation seen in regenerative CNS has many parallels in stem cells and cancer. Thus, these axotomy-induced changes in DNA methylation in regenerative CNS provide evidence for a novel epigenetic state favoring successful over unsuccessful CNS axon regeneration. The datasets described in this study should help lay the foundations for future studies of the molecular and cellular mechanisms involved. The insights gained should, in turn, help point the way to novel therapeutic approaches for treating CNS injury in mammals.

Both inflammation and anti-inflammation are involved in the protection of retinal cells. Antagonists of the hypothalamic growth hormone-releasing hormone receptor (GHRHR) have been shown to possess potent anti-inflammatory properties in experimental disease models of various organs, some with systemic complications. Such effects are also found in ocular inflammatory and neurologic injury studies. In experimental models of mice and rats, both growth hormone-releasing hormone receptor agonists and antagonists may alleviate death of ocular neural cells under certain experimental conditions. This review explores the properties of growth hormone-releasing hormone receptor agonists and antagonists that lead to its protection against inflammatory responses induced by extrinsic agents or neurologic injures in ocular animal models.

Qianxue Mou,1 Ke Yao,1 Meng Ye,1 Bowen Zhao,1 Yuanyuan Hu,1 Xiaotong Lou,1 Huixia Li,2 Hong Zhang,1 Yin Zhao1 1Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China; 2Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, People’s Republic of ChinaCorrespondence: Hong ZhangDepartment of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of ChinaEmail tjyksys@163.comCorrespondence: Yin ZhaoDepartment of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of ChinaEmail zhaoyin85@hust.edu.cnPurpose: Optic nerve injury (ONI) causes neuroinflammation and neurodegeneration leading to visual deficits. The response of microglia has emerged as an impactful component of etiology in neurodegeneration. This study aimed to investigate the effect of SIRT1-mTORC1 signaling pathway in microglia regulation after ONI.Methods: Cx3Cr1-CreERT2/RaptorF/F and Cx3Cr1-CreERT2/Sirt1F/F mice were used to delete Raptor and Sirt1 in microglia, respectively. Optic nerve crush (ONC) model was established to mimic ONI. PLX5622, a highly specific inhibitor of the colony-stimulating factor 1 receptor (CSF1R), is used to eliminate microglia in optic nerve. Ionized calcium binding adaptor molecule 1 (Iba1) immunostaining was used to detect microglial activation. Retinal ganglion cells (RGCs) were quantified by Nissl staining and retinal whole-mount immunostaining with RNA-binding protein with multiple splicing (RBPMS). Axonal damage was valued by transmission electron microscopy (TEM).Results: Microglial activation emerged on day 3 post ONC and was earlier than RGCs loss which occurred at day 5 after injury. Depleting microglia with PLX5622 could attenuate the loss of RGCs and axon damage after ONC. Gain- and loss-of-function studies revealed that SIRT1 determined the activation of microglia in optic nerve. In addition, microglia-specific deletion of Raptor resulted in decreased microglial activation. Interestingly, activating mTORC1 with CCT007093 could reverse the function of SIRT1 in regulating the process of microglial activation mediated RGCs loss.Conclusion: Our study reveals a potential novel mechanism of SIRT1-mTORC1 pathway in microglia regulation, and indicates a therapeutic potential for the protection of RGCs in ONI.Keywords: microglia, retinal ganglion cells, optic nerve injury, SIRT1, mTORC1

Abstract Background Oxidative stress contributes to retina ganglion cells (RGCs) loss in variety of ocular diseases, including ocular trauma, ocular vein occlusion, and glaucoma. Scavenging the excessed reactive oxygen species (ROS) in retinal neurovascular unit could be beneficial to RGCs survival. In this study, a polydopamine (PDA)-based nanoplatform is developed to protect RGCs. Results The PDA nanoparticles efficiently eliminate multi-types of ROS, protect endothelia and neuronal cells from oxidative damage, and inhibit microglia activation in retinas. In an optic nerve crush (ONC) model, single intravitreal injection of PDA nanoparticles could significantly attenuate RGCs loss via eliminating ROS in retinas, reducing the inflammatory response and maintaining barrier function of retinal vascular endothelia. Comparative transcriptome analysis of the retina implied that PDA nanoparticles improve RGCs survival probably by altering the expression of genes involved in inflammation and ROS production. Importantly, as a versatile drug carrier, PDA nanoparticles could deliver brimonidine (a neuroprotection drug) to synergistically attenuate RGCs loss and promote axon regeneration, thus restore visual function. Conclusions The PDA nanoparticle-based therapeutic nanoplatform displayed excellent performance in ROS elimination, providing a promising probability for treating retinal degeneration diseases. Graphical Abstract

Retinal ganglion cells (RGCs), the projection neurons of the eye, are irreversibly lost once the optic nerve is injured, which is a critical mechanism of glaucoma. Mobile zinc (Zn2+) levels rapidly increase in retinal interneuron amacrine cells and Zn2+ is then transferred to RGCs via the Zn2+ transporter protein ZnT-3, triggering RGC loss in optic nerve injury. Zn2+ chelation and ZnT-3 deletion promote long-term RGC survival. However, the downstream signaling pathways of Zn2+ in RGCs remains unknown. Here, we show that increased levels of Zn2+ upregulate the expression and activity of mitochondrial zinc metallopeptidase OMA1 in the retina, leading to the cleavage of DELE1 and activation of cytosolic eIF2α kinase PKR, triggering the integrated stress response (ISR) in RGCs. Our study identified OMA1 and ISR as the downstream molecular mechanisms of retinal Zn2+ and potential targets for preventing the progression of Zn2+-associated neuronal damage. [ABSTRACT FROM AUTHOR]

Reconstructing functional neuronal circuits is one major challenge of central nervous system repair. Through activation of pro-growth signaling pathways, some neurons achieve long-distance axon regrowth. Yet, functional reconnection has hardly been obtained, as these regenerating axons fail to resume their initial trajectory and reinnervate their proper target. Axon guidance is considered to be active only during development. Here, using the mouse visual system, we show that axon guidance is still active in the adult brain in regenerative conditions. We highlight that regenerating retinal ganglion cell axons avoid one of their primary targets, the suprachiasmatic nucleus (SCN), due to Slit/Robo repulsive signaling. Together with promoting regeneration, silencing Slit/Robo in vivo enables regenerating axons to enter the SCN and form active synapses. The newly formed circuit is associated with neuronal activation and functional recovery. Our results provide evidence that axon guidance mechanisms are required to reconnect regenerating axons to specific brain nuclei., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

ObjectiveTo study the quantitative and qualitative differences of visual evoked potential （VEP） in monocular visual impairment after different parts of visual pathway injury.MethodsA total of 91 subjects with monocular visual impairment caused by trauma were selected and divided into intraocular refractive media-injury group （eyeball injury group for short）, optic nerve injury group, central nervous system injury and intracranial combined injury group according to the injury cause and anatomical segment. Pattern Reversal visual evoked potential （PR-VEP） P100 peak time and amplitude, Flash visual evoked potential （F-VEP） P2 peak time and amplitude were recorded respectively. SPSS 26.0 software was used to analyze the differences of quantitative （peak time and amplitude） and qualitative indexes （spatial frequency sweep-VEP acuity threshold, and abnormal waveform category and frequency） of the four groups.ResultsCompared with healthy eyes, the PR-VEP P100 waveforms of the intraocular eyeball injury group and the F-VEP P2 waveforms of the optic nerve group showed significant differences in prolonged peak time and decreased amplitude in injured eyes （P

Glaucoma is an optic neuropathy and is currently one of the most common diseases that leads to irreversible blindness. The axonal degeneration that occurs before retinal ganglion neuronal loss is suggested to be involved in the pathogenesis of glaucoma. G protein-coupled receptor 3 (GPR3) belongs to the class A rhodopsin-type GPCR family and is highly expressed in various neurons. GPR3 is unique in its ability to constitutively activate the Gαs protein without a ligand, which elevates the basal intracellular cAMP level. Our earlier reports suggested that GPR3 enhances both neurite outgrowth and neuronal survival. However, the potential role of GPR3 in axonal regeneration after neuronal injury has not been elucidated. Herein, we investigated retinal GPR3 expression and its possible involvement in axonal regeneration after retinal injury in mice. GPR3 was relatively highly expressed in retinal ganglion cells (RGCs). Surprisingly, RGCs in GPR3 knockout mice were vulnerable to neural death during aging without affecting high intraocular pressure (IOP) and under ischemic conditions. Primary cultured neurons from the retina showed that GPR3 expression was correlated with neurite outgrowth and neuronal survival. Evaluation of the effect of GPR3 on axonal regeneration using GPR3 knockout mice revealed that GPR3 in RGCs participates in axonal regeneration after optic nerve crush (ONC) under zymosan stimulation. In addition, regenerating axons were further stimulated when GPR3 was upregulated in RGCs, and the effect was further augmented when combined with zymosan treatment. These results suggest that GPR3 expression in RGCs helps maintain neuronal survival and accelerates axonal regeneration after ONC in mice.

Retinal ganglion cells (RGCs) are a heterogeneous population of neurons that function synchronously to convey visual information through the optic nerve to retinorecipient target areas in the brain. Injury or disease to the optic nerve results in RGC degeneration and loss of visual function, as few RGCs survive, and even fewer can be provoked to regenerate their axons. Despite causative insults being broadly shared, regeneration studies demonstrate that RGC types exhibit differential resilience to injury and undergo selective survival and regeneration of their axons. While most early studies have identified these RGC types based their morphological and physiological characteristics, recent advances in transgenic and gene sequencing technologies have further enabled type identification based on unique molecular features. In this review, we provide an overview of the well characterized RGC types and identify those shown to preferentially survive and regenerate in various regeneration models. Furthermore, we discuss cellular characteristics of both the resilient and susceptible RGC types including the combinatorial expression of different molecular markers that identify these specific populations. Lastly, we discuss potential molecular mechanisms and genes found to be selectively expressed by specific types that may contribute to their reparative capacity. Together, we describe the studies that lay the important groundwork for identifying factors that promote neural regeneration and help advance the development of targeted therapy for the treatment of RGC degeneration as well as neurodegenerative diseases in general.

AIM: To explore the value of frequency threshold optical coherence tomography(OCT)in the diagnosis of primary open angle glaucoma optic nerve injury. METHODS: Eighty patients with early primary glaucoma who were admitted to the hospital between January 2018 and March 2020 and 100 healthy subjects were selected as the study subjects. Patients with primary open angle glaucoma were divided into early group, middle group and late group. OCT was used to measure the thicknesses of upper, lower, nasal, bitemporal peri-papillary retinal nerve fiber layer(pRNFL)and upper and lower macular ganglion cell complex(mGCC)in each group. The mean deviation(MD)of visual field was determined through perimetry. The OCT parameters and perimetry parameters were compared among groups. Spearman correlation analysis was performed to analyze the correlation between OCT parameters and visual field defects, and the receiver operating characteristic(ROC)curve was used to calculate the value of OCT parameters in diagnosing primary open angle glaucoma. RESULTS: There were 24 cases, 39 cases and 17 cases in the early group, middle group and late group, respectively. There were statistically significant differences in pRNFL and mGCC among 3 groups(P

Optic nerve injuries are severely disrupt the structural and functional integrity of the retina, often leading to visual impairment or blindness. Despite the profound impact of these injuries, the molecular mechanisms involved remain poorly understood. In this study, we performed a comprehensive whole-transcriptome analysis of mouse retina samples after optic nerve crush (ONC) to elucidate changes in gene expression and regulatory networks. Transcriptome analysis revealed a variety of molecular alterations, including 256 mRNAs, 530 lncRNAs, and 37 miRNAs, associated with metabolic, inflammatory, signaling, and biosynthetic pathways in the injured retina. The integrated analysis of co-expression and protein-protein interactions identified an active interconnected module comprising 5 co-expressed proteins (Fga, Serpina1a, Hpd, Slc38a4, and Ahsg) associated with the complement and coagulation cascades. Finally, 5 mRNAs (Fga, Serpinala, Hpd, Slc38a4, and Ahsg), 2 miRNAs (miR-671–5p and miR-3057–5p), and 6 lncRNAs (MSTRG. 1830.1, Gm10814, A530013C23Rik, Gm40634, MSTRG.9514.1, A330023F24Rik) were identified by qPCR in the injured retina, and some of them were validated as critical components of a ceRNA network active in 661W and HEK293T cells through dual-luciferase reporter assays. In conclusion, our study provides comprehensive insight into the complex and dynamic biological mechanisms involved in retinal injury responses and highlights promising potential targets to enhance neuroprotection and restore vision. • Whole transcriptome analysis in mRNA, lncRNA, and miRNA for an optic nerve injury model. • Key regulatory networks reveal crucial proteins linked to complement cascades. • A ceRNA network play critical roles in the post-injury retina. [ABSTRACT FROM AUTHOR]

A 59‐year‐old patient presented with 4‐day acute painless bilateral visual loss, MRI results showed dura enhancement of the frontal, anterior cranial fossa. The patient was considered to have idiopathic hypertrophic cranial pachymeningitis based on laboratory tests and MRI data. After treatment with hormones, the visual acuity obviously improved. [ABSTRACT FROM AUTHOR]

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As an important part of the central nervous system (CNS), the optic nerve usually cannot regenerate directly after injury. Therefore, treating the injury and restoring the function of the optic nerve are a historical problem in the medical field. Due to the special anatomical position of the optic nerve, the microenvironment needed for protection and regeneration after injury is lacking. Therefore, preventing the continued loss of neurons, protecting the functional nerves, and promoting the effective protection of nerves are the main ways to solve the problem. Exosomes are nano-sized vesicles with a diameter of 30–150 nm, composed of lipid bilayers, proteins, and genetic material. They have key functions in cell-to-cell communication, immune regulation, inflammation, and regeneration. More and more shreds of evidence show that exosomes not only play an important role in systemic diseases such as cancer, cardiovascular diseases, and brain diseases; they also play a key role in ophthalmological diseases. This article reviews the role of exosomes in the protection and regeneration of the optic nerve after optic nerve injury in related experimental studies and clinical treatment methods. Graphical abstarct: [ABSTRACT FROM AUTHOR]

Objective:: Any damage to the optic nerve can potentially lead to degeneration of non-regenerating axons and ultimately death of retinal ganglion cells (RGCs) that in most cases, are not curable by surgery or medication. Neuroprotective functions of different types of stem cells in the nervous system have been evaluated in many studies investigating the effectiveness of these cells in various retinal disease models. Neural progenitor cells (NPCs) secrete an assortment of trophic factors that are vital to the protection of the visual system. We aimed to assess the therapeutic potentials of NPCs in an ONC mouse model. MaterialsAndMethods: : In this experimental study, NPCs were produced using noggin and retinoic acid from human embryonic stem cells (hESCs). Fifty mice were divided into the following three groups: i. Intact, ii. Vehicle [optic nerve crush+Hank’s balanced salt solution (HBSS)], and iii. Treatment (optic nerve crush+NPCs). The visual behavior of the mice was examined using the Visual Cliff test, and in terms of RGC numbers, they were assessed by Brn3a immunostaining and retrograde tracing using DiI injection: Results Intravenous injection of 50,000 NPCs through visual cliff did not produce any visual improvement. However, our data suggest that the RGCs protection was more than two-times in NPCs compared to the vehicle group as examined by Brn3a staining and retrograde tracing. Conclusion: Our study indicated that intravenous injection of NPCs could protect RGCs probably mediated by trophic factors. Due to this ability and good manufacturing practices (GMP) grade production feasibility, NPCs may be used for optic nerve protection. [ABSTRACT FROM AUTHOR]