Optic Nerve Regeneration Research Articles

Optic nerve damage model: A preliminary study to determine injury duration and degree of gliosis

Aims/Purpose: The aim of this study was to investigate the effects of varying durations of optic nerve compression on retinal function and morphology in an adult DA/HanR rat with optic nerve crush model.Methods: In the study, adult DA/HanR rats (4‐8 mo) were divided into 5 experimental groups. Lateral canthotomy and lateral bulbar conjunctiva incision were performed to reach the area. The optic nerve was held 2‐3 mm posterior to the globe with the help of calibrated forceps and compressed for four different periods of time: 10 seconds, 15 seconds, 30 seconds and 2 minutes. During the injury, retinal fundus observation of rats was checked with a 90‐diopter fundus lens. To evaluate changes in vision after optic nerve damage, in vivo electrophysiological tests (VEP, EEG and ERG) with daylight stimulator, a light intensity of 500 μW/cm2, was studied. Changes in optic nerve and retina morphology after injury were evaluated by hematoxylin‐eosin (H&E), TUNEL assay, immunofluorescence staining of gliosis and retina cell markers.Results: It was observed that the response to light was reduced in both the retina (ERG) and visual cortex (VEP‐EEG) in the damaged eyes compared to the control group. Retina cell survival showed decrease in injured groups by TUNEL assay. In immunofluorescence staining, an increase in the severity of gliosis with activation of the microglia and Müller cells in the retina and optic nerve depending on the duration of damage was shown by the expressions of GFAP, Glutamine Synthetase and Vimentin. It was observed that the expression of the neural marker NeuN and the photoreceptor marker Rhodopsin decreased upon injury.Conclusions: Our study provided preliminary results to further optic nerve regeneration studies to select optimum time points for improve axonal healing in retina and optic nerve injuries.Funding Information: This work is supported by the Scientific and Technological Research Council of Turkey (TÜBİTAK) under Grant ARDEB‐121S762

Tppp3 is a novel molecule for retinal ganglion cell identification and optic nerve regeneration

Mammalian central nervous system (CNS) axons cannot spontaneously regenerate after injury, creating an unmet need to identify molecular regulators to promote axon regeneration and reduce the lasting impact of CNS injuries. While tubulin polymerization promoting protein family member 3 (Tppp3) is known to promote axon outgrowth in amphibians, its role in mammalian axon regeneration remains unknown. Here we investigated Tppp3 in retinal ganglion cells (RGCs) neuroprotection and axonal regeneration using an optic nerve crush (ONC) model in the rodent. Single-cell RNA sequencing identified the expression of Tppp3 in RGCs of mice, macaques, and humans. Tppp3 overexpression enhanced neurite outgrowth in mouse primary RGCs in vitro, promoted axon regeneration, and improved RGC survival after ONC. Bulk RNA sequencing indicated that Tppp3 overexpression upregulates axon regeneration genes such as Bmp4 and neuroinflammatory pathways. Our findings advance regenerative medicine by developing a new therapeutic strategy for RGC neuroprotection and axon regeneration.

Marcks overexpression in retinal ganglion cells promotes optic nerve regeneration

Regeneration of injured central nervous system (CNS) axons is highly restricted, leading to permanent neurological deficits. The myristoylated alanine-rich C-kinase substrate (MARCKS) is a membrane-associated protein kinase C (PKC) substrate ubiquitously expressed in eukaryotic cells, plays critical roles in development, brain plasticity, and tissues regeneration. However, little is known about the role of Marcks in CNS axon regeneration. Here we show that Marcks overexpression promotes robust axon regeneration either before or after optic nerve crush, but insignificantly impacts neuronal survival. Notably, immunostaining and RNA sequencing demonstrate that Marcks overexpression does not affect known regeneration-associated genes and pathways. Furthermore, combining CNTF which activates the JAK-STAT3 pathway and Marcks overexpression further enhances axon regeneration. Finally, we demonstrate functionally essential effector domain (ED) of MARCKS has similar effects on inducing axon regeneration in RGCs. These results suggest that manipulating Marcks and its ED may become a therapeutic approach to promote axon regeneration after CNS injury.

Engineered bio-functional material-based nerve guide conduits for optic nerve regeneration: a view from the cellular perspective, challenges and the future outlook.

Nerve injuries can be tantamount to severe impairment, standard treatment such as the use of autograft or surgery comes with complications and confers a shortened relief. The mechanism relevant to the regeneration of the optic nerve seems yet to be fully uncovered. The prevailing rate of vision loss as a result of direct or indirect insult on the optic nerve is alarming. Currently, the use of nerve guide conduits (NGC) to some extent has proven reliable especially in rodents and among the peripheral nervous system, a promising ground for regeneration and functional recovery, however in the optic nerve, this NGC function seems quite unfamous. The insufficient NGC application and the unabridged regeneration of the optic nerve could be a result of the limited information on cellular and molecular activities. This review seeks to tackle two major factors (i) the cellular and molecular activity involved in traumatic optic neuropathy and (ii) the NGC application for the optic nerve regeneration. The understanding of cellular and molecular concepts encompassed, ocular inflammation, extrinsic signaling and intrinsic signaling for axon growth, mobile zinc role, Ca2+ factor associated with the optic nerve, alternative therapies from nanotechnology based on the molecular information and finally the nanotechnological outlook encompassing applicable biomaterials and the use of NGC for regeneration. The challenges and future outlook regarding optic nerve regenerations are also discussed. Upon the many approaches used, the comprehensive role of the cellular and molecular mechanism may set grounds for the efficient application of the NGC for optic nerve regeneration.

Novel laser model of optic nerve transection provides valuable insights about the dynamics of optic nerve regeneration

Optic nerve (ON) injury causes blindness in adult mammals as their retinal ganglion cells (RGCs) cannot regenerate axons. However, amphibian RGC axons do not experience the same regenerative failure. Studying the regeneration process of the ON in amphibians holds profound implications for regenerative medicine and human health. Using transgenic tadpoles and laser micro-optics, we developed a reproducible ON transection and regeneration model. Through microscopy of axon dynamics, functional testing to assess visual pathway recovery, TUNEL cell death and EdU cell proliferation assays, and RNA-seq of the retina and optic nerve, we characterized the optic nerve injury response and subsequent recovery. Our model suggests no chemoattractant gradient exists early in regeneration, with defasciculated axons sprouting in random directions from the globe-proximal cut end. Once individual axons reach the appropriate targets in the brain, their tract is reinforced by other regenerating axons, restoring normal ON morphology. Thus, guidance cues or scaffolding from brain-innervating axons likely support later stages of regeneration. After 14 days, the regenerated ON is morphologically indistinguishable from the naïve ON, and visual function is restored. We found no evidence of RGC death or new RGC formation in the model, suggesting that ON regeneration involves remodeling of injured axons of pre-existing RGCs.

Implantation of biomimetic polydopamine nanocomposite scaffold promotes optic nerve regeneration through modulating inhibitory microenvironment

Optic nerve regeneration remains challenging worldwide due to the limited intrinsic regenerative capacity of retinal ganglion cells (RGCs) and the inhibitory microenvironment. Oxidative stress, induced by excessive reactive oxygen species (ROS) following optic nerve injury, is associated with prolonged neuroinflammation, resulting in a secondary injury of RGCs and the impairment of axon regeneration. Herein, we developed a bionic nanocomposite scaffold (GA@PDA) with immunoregulatory ability for enhanced optic nerve regeneration. The ice-templating method was employed to fabricate biopolymer-based scaffolds with a directional porous structure, mimicking the optic nerve, which effectively guided the oriented growth of neuronal cells. The incorporation of bioinspired polydopamine nanoparticles (PDA NPs) further confers excellent ROS scavenging ability, thereby modulating the phenotype transformation of microglia/macrophages from pro-inflammatory M1 to anti-inflammatory M2. In a rat optic nerve crush model, the implantation of GA@PDA scaffold enhanced survival of RGCs and promoted axonal regeneration. Our study offers novel insights and holds promising potential for the advancement of engineered biomaterials in facilitating optic nerve regeneration.

Novel laser model of optic nerve transection provides valuable insights about the dynamics of optic nerve regeneration.

Optic nerve (ON) injury causes blindness in adult mammals as their retinal ganglion cells (RGCs) cannot regenerate axons. However, amphibian RGC axons do not experience the same regenerative failure. Studying the regeneration process of the ON in amphibians holds profound implications for regenerative medicine and human health. Using transgenic tadpoles and laser micro-optics, we developed a reproducible ON transection and regeneration model. Through microscopy, functional testing, TUNEL, EdU assays, and RNA-seq, we characterized the ON injury response and recovery. Our model suggests no chemoattractant gradient exists early in regeneration, with defasciculated axons sprouting in random directions from the globe-proximal cut end. Once individual axons reach the appropriate anatomical insertion point in the brain, their tract is reinforced by other regenerating axons, restoring normal ON morphology. Thus, guidance cues or scaffolding from brain-innervating axons likely support later stages of regeneration. After 14 days, the regenerated ON is morphologically indistinguishable from the naïve ON, and visual function is restored. We found no evidence of RGC death or new RGC formation in the model, suggesting that only pre-existing RGCs are involved in ON regeneration.

Immunomodulation by the combination of statin and matrix-bound nanovesicle enhances optic nerve regeneration

Modulating inflammation is critical to enhance nerve regeneration after injury. However, clinically applicable regenerative therapies that modulate inflammation have not yet been established. Here, we demonstrate synergistic effects of the combination of an HMG-CoA reductase inhibitor, statin/fluvastatin and critical components of the extracellular matrix, Matrix-Bound Nanovesicles (MBV) to enhance axon regeneration and neuroprotection after mouse optic nerve injury. Mechanistically, co-intravitreal injections of fluvastatin and MBV robustly promote infiltration of monocytes and neutrophils, which lead to RGC protection and axon regeneration. Furthermore, monocyte infiltration is triggered by elevated expression of CCL2, a chemokine, in the superficial layer of the retina after treatment with a combination of fluvastatin and MBV or IL-33, a cytokine contained within MBV. Finally, this therapy can be further combined with AAV-based gene therapy blocking anti-regenerative pathways in RGCs to extend regenerated axons. These data highlight novel molecular insights into the development of immunomodulatory regenerative therapy.

In Vitro and In Vivo Methods for Studying Retinal Ganglion Cell Survival and Optic Nerve Regeneration.

Glaucoma is marked by a progressive degeneration of the optic nerve and delayed loss of retinal ganglion cells (RGCs), the projection neurons of the eye. Because RGCs are not replaced and because surviving RGCs cannot regenerate their axons, the visual loss in glaucoma is largely irreversible. Here we describe methods to evaluate treatments that may be beneficial for treating glaucoma using in vitro cell culture models (immunopanning to isolate neonatal RGCs, dissociated mature retinal neurons, retinal explants) and in vivo models that test potential treatments or investigate underlying molecular mechanisms in an intact system. Potentially, the use of these models can help investigators continue to improve treatments to preserve RGCs and restore visual function in patients with glaucoma.

Zebrafish optic nerve regeneration involves resident and retinal oligodendrocytes.

The visual system of teleost fish grows continuously, which is a useful model for studying regeneration of the central nervous system. Glial cells are key for this process, but their contribution is still not well defined. We followed oligodendrocytes in the visual system of adult zebrafish during regeneration of the optic nerve at 6, 24, and 72 hours post-lesion and at 7 and 14 days post-lesion via the sox10:tagRFP transgenic line and confocal microscopy. To understand the changes that these oligodendrocytes undergo during regeneration, we used Sox2 immunohistochemistry, a stem cell marker involved in oligodendrocyte differentiation. We also used the Click-iTTM Plus TUNEL assay to study cell death and a BrdU assay to determine cell proliferation. Before optic nerve crush, sox10:tagRFP oligodendrocytes are located in the retina, in the optic nerve head, and through all the entire optic nerve. Sox2-positive cells are present in the peripheral germinal zone, the mature retina, and the optic nerve. After optic nerve crush, sox10:tagRFP cells disappeared from the optic nerve crush zone, suggesting that they died, although they were not TUNEL positive. Concomitantly, the number of Sox2-positive cells increased around the crushed area, the optic nerve head, and the retina. Then, between 24 hours post-lesion and 14 days post-lesion, double sox10:tagRFP/Sox2-positive cells were detected in the retina, optic nerve head, and whole optic nerve, together with a proliferation response at 72 hours post-lesion. Our results confirm that a degenerating process may occur prior to regeneration. First, sox10:tagRFP oligodendrocytes that surround the degenerated axons stop wrapping them, change their "myelinating oligodendrocyte" morphology to a "nonmyelinating oligodendrocyte" morphology, and die. Then, residual oligodendrocyte progenitor cells in the optic nerve and retina proliferate and differentiate for the purpose of remyelination. As new axons arise from the surviving retinal ganglion cells, new sox10:tagRFP oligodendrocytes arise from residual oligodendrocyte progenitor cells to guide, nourish and myelinate them. Thus, oligodendrocytes play an active role in zebrafish axon regeneration and remyelination.

Bioengineering strategy to promote CNS nerve growth and regeneration via chronic glutamate signaling

Being part of the mature mammalian central nervous system, impairments of the retina and optic nerves caused by trauma or diseases often cannot be restored. Progressive degeneration of retinal ganglion cells (RGCs) in glaucoma and other optic neuropathies gradually leads to permanent vision loss, which currently has no cure. The purpose of this study is to develop a biocompatible scaffold to support RGC survival and guide axon growth, facilitating optic nerve repair and regeneration. We here report that electrical stimulation (ES) significantly promoted neurite outgrowth and elongation from primary RGCs, mediated through glutamate receptor signaling. To mimic prolonged glutamate stimulation and facilitate sustained nerve growth, we fabricated biocompatible poly-γ-benzyl-L-glutamate (PBG) scaffolds for controlled glutamate release. These PBG scaffolds supported RGC survival and robust long-distance nerve growth in both retinal explants and isolated RGC cultures. In contrast, control polycaprolactone (PCL) scaffolds with similar physical structures showed little benefits on RGC survival or nerve growth. Moreover, PBG scaffolds promoted the differentiation and neurite outgrowth from embryonic stem cell-derived RGC progenitors. The aligned PBG scaffold drove directed nerve elongation along the fiber alignment. Transplantation of PBG-coated biocompatible conduits induced robust optic nerve regeneration in adult mice following nerve transection. Together, the findings present the exciting possibility of driving optic nerve regeneration and RGC progenitor cell differentiation by imitating ES or glutamate signaling. PBG presents a permissive biomaterial in supporting robust and directed axon growth with promising clinical applications in the future. Statement of SignificanceWe here reported compelling findings that demonstrate the potent regenerative effects of a bioengineered scaffold incorporating poly-γ-benzyl-L-glutamate (PBG) on the optic nerve. Retinal ganglion cell (RGC) axons, which form the optic nerve, are incapable of regenerating in adulthood, posing a significant hurdle in restoring vision for patients with optic nerve diseases or injuries. Built upon the finding that electrical stimulation promotes RGC axonal growth through glutamate signaling, we developed PBG scaffolds to provide sustained glutamate stimulation and showed their exceptional effects on driving directed axonal elongation in cultured RGCs and neural progenitors, as well as supporting robust optic nerve regeneration after transection in vivo. The findings hold great promise for reversing vision loss in patients with optic nerve conditions.

Roles of Kdm6a and Kdm6b in regulation of mammalian neural regeneration.

Epigenetic regulation of neuronal transcriptomic landscape is emerging to be a key coordinator of mammalian neural regeneration. Here we investigated roles of two histone 3 lysine 27 (H3K27) demethylases Kdm6a/b in controlling neuroprotection and axon regeneration. Deleting either Kdm6a or Kdm6b led to enhanced sensory axon regeneration in PNS, whereas in the CNS only deleting Kdm6a in retinal ganglion cells (RGCs) significantly enhanced optic nerve regeneration. Moreover, both Kdm6a and Kdm6b functioned to regulate RGC survival but with different mechanisms. Mechanistically, Kdm6a regulates RGC regeneration via distinct pathway from that of Pten and co-deleting Kdm6a and Pten resulted in long distance optic nerve regeneration passing the optic chiasm. In addition, RNA-seq profiling revealed that Kdm6a deletion switched the RGC transcriptomics into a developmental-like state and suppressed several known repressors of neural regeneration. Klf4 was identified as a direct downstream target of Kdm6a-H3K27me3 signaling in both sensory neurons and RGCs to regulate axon regeneration. These findings not only revealed different roles of Kdm6a and Kdm6b in regulation of neural regeneration and their underlying mechanisms, but also identified Kdm6a-mediated histone demethylation signaling as a novel epigenetic target for supporting CNS neural regeneration.

Inhibition of CRMP2 Phosphorylation Suppresses Microglia Activation in the Retina and Optic Nerve and Promotes Optic Nerve Regeneration After Optic Nerve Injury

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.

Transglutaminase 2 Regulates HSF1 Gene Expression in the Acute Phase of Fish Optic Nerve Regeneration.

Fish retinal ganglion cells (RGCs) can regenerate after optic nerve lesions (ONLs). We previously reported that heat shock factor 1 (HSF1) and Yamanaka factors increased in the zebrafish retina 0.5-24 h after ONLs, and they led to cell survival and the transformation of neuro-stem cells. We also showed that retinoic acid (RA) signaling and transglutaminase 2 (TG2) were activated in the fish retina, performing neurite outgrowth 5-30 days after ONLs. In this study, we found that RA signaling and TG2 increased within 0.5 h in the zebrafish retina after ONLs. We examined their interaction with the TG2-specific morpholino and inhibitor due to the significantly close initiation time of TG2 and HSF1. The inhibition of TG2 led to the complete suppression of HSF1 expression. Furthermore, the results of a ChIP assay with an anti-TG2 antibody evidenced significant anti-TG2 immunoprecipitation of HSF1 genome DNA after ONLs. The inhibition of TG2 also suppressed Yamanaka factors' gene expression. This rapid increase in TG2 expression occurred 30 min after the ONLs, and RA signaling occurred 15 min before this change. The present study demonstrates that TG2 regulates Yamanaka factors via HSF1 signals in the acute phase of fish optic nerve regeneration.

Modulating amacrine cell-derived dopamine signaling promotes optic nerve regeneration and preserves visual function.

As part of the central nervous system, the optic nerve, composed of axons from retinal ganglion cells (RGCs), generally fails to regenerate on its own when injured in adult mammals. An innovative approach to promoting optic nerve regeneration involves manipulating the interactions between amacrine cells (ACs) and RGCs. Here, we identified a unique AC subtype, dopaminergic ACs (DACs), that responded early after optic nerve crush by down-regulating neuronal activity and reducing retinal dopamine (DA) release. Activating DACs or augmenting DA release with levodopa demonstrated neuroprotective effects and modestly enhanced axon regeneration. Within this context, we pinpointed the DA receptor D1 (DRD1) as a critical mediator of DAC-derived DA and showed that RGC-specific Drd1 overexpression effectively overcame subtype-specific barriers to regeneration. This strategy markedly boosted RGC survival and axon regeneration after crush and preserved vision in a glaucoma model. This study unveils the crucial role of DAC-derived DA signaling in optic nerve regeneration, holding promise for therapeutic insights into neural repair.

Develop Targeted Protein Drug Carriers through a High-Throughput Screening Platform and Rational Design.

Protein-based drugs offer advantages, such as high specificity, low toxicity, and minimal side effects compared to small molecule drugs. However, delivery of proteins to target tissues or cells remains challenging due to the instability, diverse structures, charges, and molecular weights of proteins. Polymers have emerged as a leading choice for designing effective protein delivery systems, but identifying a suitable polymer for a given protein is complicated by the complexity of both proteins and polymers. To address this challenge, a fluorescence-based high-throughput screening platform called ProMatch to efficiently collect data on protein-polymer interactions, followed by in vivo and in vitro experiments with rational design is developed. Using this approach to streamline polymer selection for targeted protein delivery, candidate polymers from commercially available options are identified and a polyhexamethylene biguanide (PHMB)-based system for delivering proteins to white adipose tissue as a treatment for obesity is developed. A branched polyethylenimine (bPEI)-based system for neuron-specific protein delivery to stimulate optic nerve regeneration is also developed. The high-throughput screening methodology expedites identification of promising polymer candidates for tissue-specific protein delivery systems, thereby providing a platform to develop innovative protein-based therapeutics.

Problems and prospects for restoration of the optic nerve

Restoring visual function after damage or complete destruction of the optic nerve in adult patients has many natural barriers to neuroregeneration. Research to restore vision has focused on maintaining retinal ganglion cells (RGCs), stimulating axonal growth toward the brain, and restoring their proper synaptic connections. Unfortunately, mammalian RGC axons under normal conditions do not regenerate after injury and ultimately die. In this review, we summarize the currently known mechanisms of RGC survival and axonal regeneration in mammals, including specific intrinsic signaling pathways, key transcription factors, reprogramming genes, inflammation-related regeneration factors, and stem cell therapy. We also review the current understanding of the phenomena impeding optic nerve regeneration and possible ways to overcome these obstacles. The most important research results obtained in recent decades may be informative for the development of methods for treating the damaged visual system.

Whole-eye transplantation: Current challenges and future perspectives.

Whole-eye transplantation emerges as a frontier in ophthalmology, promising a transformative approach to irreversible blindness. Despite advancements, formidable challenges persist. Preservation of donor eye viability post-enucleation necessitates meticulous surgical techniques to optimize retinal integrity and ganglion cell survival. Overcoming the inhibitory milieu of the central nervous system for successful optic nerve regeneration remains elusive, prompting the exploration of neurotrophic support and immunomodulatory interventions. Immunological tolerance, paramount for graft acceptance, confronts the distinctive immunogenicity of ocular tissues, driving research into targeted immunosuppression strategies. Ethical and legal considerations underscore the necessity for stringent standards and ethical frameworks. Interdisciplinary collaboration and ongoing research endeavors are imperative to navigate these complexities. Biomaterials, stem cell therapies, and precision immunomodulation represent promising avenues in this pursuit. Ultimately, the aim of this review is to critically assess the current landscape of whole-eye transplantation, elucidating the challenges and advancements while delineating future directions for research and clinical practice. Through concerted efforts, whole-eye transplantation stands to revolutionize ophthalmic care, offering hope for restored vision and enhanced quality of life for those afflicted with blindness.

Harlequin mice exhibit cognitive impairment, severe loss of Purkinje cells and a compromised bioenergetic status due to the absence of Apoptosis Inducing Factor

The functional integrity of the central nervous system relies on complex mechanisms in which the mitochondria are crucial actors because of their involvement in a multitude of bioenergetics and biosynthetic pathways. Mitochondrial diseases are among the most prevalent groups of inherited neurological disorders, affecting up to 1 in 5000 adults and despite considerable efforts around the world there is still limited curative treatments.Harlequin mice correspond to a relevant model of recessive X-linked mitochondrial disease due to a proviral insertion in the first intron of the Apoptosis-inducing factor gene, resulting in an almost complete depletion of the corresponding protein. These mice exhibit progressive degeneration of the retina, optic nerve, cerebellum, and cortical regions leading to irremediable blindness and ataxia, reminiscent of what is observed in patients suffering from mitochondrial diseases.We evaluated the progression of cerebellar degeneration in Harlequin mice, especially for Purkinje cells and its relationship with bioenergetics failure and behavioral damage.For the first time to our knowledge, we demonstrated that Harlequin mice display cognitive and emotional impairments at early stage of the disease with further deteriorations as ataxia aggravates. These functions, corresponding to higher-order cognitive processing, have been assigned to a complex network of reciprocal connections between the cerebellum and many cortical areas which could be dysfunctional in these mice.Consequently, Harlequin mice become a suitable experimental model to test innovative therapeutics, via the targeting of mitochondria which can become available to a large spectrum of neurological diseases.

Application of electrostimulation and magnetic stimulation in patients with optic neuropathy: A mechanistic review.

Visual impairment caused by optic neuropathies is irreversible because retinal ganglion cells (RGCs), the specialized neurons of the retina, do not have the capacity for self-renewal and self-repair. Blindness caused by optic nerve neuropathies causes extensive physical, financial, and social consequences in human societies. Recent studies on different animal models and humans have established effective strategies to prevent further RGC degeneration and replace the cells that have deteriorated. In this review, we discuss the application of electrical stimulation (ES) and magnetic field stimulation (MFS) in optic neuropathies, their mechanisms of action, their advantages, and limitations. ES and MFS can be applied effectively in the field of neuroregeneration. Although stem cells are becoming a promising approach for regenerating RGCs, the inhibitory environment of the CNS and the long visual pathway from the optic nerve to the superior colliculus are critical barriers to overcome. Scientific evidence has shown that adjuvant treatments, such as the application of ES and MFS help direct thetransplanted RGCs to extend their axons and form new synapses in the central nervous system (CNS). In addition, these techniques improve CNS neuroplasticity and decrease the inhibitory effects of the CNS. Possible mechanisms mediating the effects of electrical current on biological tissues include the release of anti-inflammatory cytokines, improvement of microcirculation, stimulation of cell metabolism, and modification of stem cell function. ES and MFS have the potential to promote angiogenesis, direct axon growth toward the intended target, and enhance appropriate synaptogenesis in optic nerve regeneration.