Optic Nerve Regeneration Research Articles

Intraocular BDNF promotes ectopic branching, alters motility and stimulates abnormal collaterals in regenerating optic fibers

A great deal of effort has been invested in using trophic factors and other bioactive molecules to promote cell survival and axonal regeneration in the adult central nervous system. Far less attention has been paid to investigating potential effects that trophic factors may have that might interfere with recovery. In the visual system, BDNF has been previously reported to prevent regeneration. To test if BDNF is inherently incompatible with regeneration, BDNF was given intraocularly during optic nerve regeneration in the adult goldfish. In vivo imaging and anatomical analysis of selectively labeled axons were used as a sensitive assay for effects on regeneration within the tectum. BDNF had no detectable inhibitory effect on the ability of axons to regenerate. Normal numbers of axons regenerated into the tectum, exhibited dynamic growth and retractions similar to controls, and were able to navigate to their correct target zone in the tectum. However, BDNF was found to have additional effects that adversely affected the quality of regeneration. It promoted premature branching at ectopic locations, diminished the growth rate of axons through the tectum, and resulted in the formation of ectopic collaterals. Thus, although BDNF has robust effects on axonal behavior, it is, nevertheless, compatible with axonal regeneration, axon navigation and the formation of terminal arbors.

Ultrastructural Changes in the Optic Nerve After Injury and Neurotrophic Factor Treatment

We have shown that ciliary neurotrophic factor (CNTF) and fibroblast growth factor (FGF‐2) have strong facilitatory effects on axon regeneration in the adult frog optic nerve after injury. In these nerves, bundles of regenerating axons were associated with astrocytes and macrophage‐like cells. The objective of the present study is to characterize the identity of these cells, and to determine the changes that occur after CNTF or FGF‐2 application. We performed optic nerve crush and applied into the nerve either saline solution or neurotrophic factors. We examined the optic nerves at different timepoints: 48h, one week, and two weeks after axotomy. Electron microscopy was used to characterize the ultrastructure and localization of the macrophages/microglia after injury and neurotrophic treatment. Antibodies against specific macrophage subtypes were used to label these cells in confocal images of different regions of the nerve. We found a large number of macrophage‐like cells at the lesion site, and distally in close proximity to regenerating axons in CNTF and FGF‐2 treated nerves. Significantly fewer cells were present proximal to the lesion. Many of these macrophage‐like cells at, and distal to, the lesion were ED‐1‐positive in both CNTF and FGF‐2 treated nerves. Both M1 (Arginase‐positive) and M2 (CD‐86‐positive) subtypes were identified. We are currently quantifying the distribution of these cell subtypes at different timepoints and nerve regions after injury. In conclusion, the application of CNTF and FGF‐2 affects the number and the distribution of macrophage subtypes after optic nerve injury and during optic nerve regeneration.

Spermidine promotes retinal ganglion cell survival and optic nerve regeneration in adult mice following optic nerve injury.

Spermidine acts as an endogenous free radical scavenger and inhibits the action of reactive oxygen species. In this study, we examined the effects of spermidine on retinal ganglion cell (RGC) death in a mouse model of optic nerve injury (ONI). Daily ingestion of spermidine reduced RGC death following ONI and sequential in vivo retinal imaging revealed that spermidine effectively prevented retinal degeneration. Apoptosis signal-regulating kinase-1 (ASK1) is an evolutionarily conserved mitogen-activated protein kinase kinase kinase and has an important role in ONI-induced RGC apoptosis. We demonstrated that spermidine suppresses ONI-induced activation of the ASK1-p38 mitogen-activated protein kinase pathway. Moreover, production of chemokines important for microglia recruitment was decreased with spermidine treatment and, consequently, accumulation of retinal microglia is reduced. In addition, the ONI-induced expression of inducible nitric oxide synthase in the retina was inhibited with spermidine treatment, particularly in microglia. Furthermore, daily spermidine intake enhanced optic nerve regeneration in vivo. Our findings indicate that spermidine stimulates neuroprotection as well as neuroregeneration, and may be useful for treatment of various neurodegenerative diseases including glaucoma.

Repairing Injured Optic Nerve of Rat with Several Therapies

Optic nerve of mammalian, as brain and spinal cord, is difficult to regenerate successfully after injury. It is one of research focuses and difficult projects how to promote regeneration of injured optic nerve in the neuroscience and ophthalmology. We have explored to repair the injured optic nerve of rat with several therapeutic strategies in the recent years. (1)Physical therapy: In a rat model of optic nerve crush, hyperbaric oxygen preconditioning or hydrogen‐rich saline administered intraperitoneally could decrease apoptosis of retinal ganglion cells, promote their survival, and improve visual functional restoration as pupillary light reflex and visual evoked potential. (2)Cell therapy: Rat amniotic epithelial cells (AECs) with some characteristics of stem cells, AECs transfected by basic fibroblast growth factor gene, or AECs seeded in the collagen sponge was implanted into the injured region of rat optic nerve transected. These three therapies could increase the survival of retinal ganglion cells after injury of rat optic nerve. The cells could guide the regenerating axon to extend into the injured region, and promote a few of axons to cross the injured region into 1‐2 mm in the distal optic nerve. (3)Gene therapy: After neuritin lentivirus infection of rat retina, the number of retinal ganglion cells and optic nerve axons were increased significantly after optic nerve crush, this protective effects was further confirmed by the functional tests as pupillary light reflex and visual evoked potential. After RGC5 damage in vitro, neuritin overexpression promoted neurite outgrowth which might be through the upregulation of phosphorylation of Akt and Erk, and reduced cell apoptosis which might be through the inhibition of caspase 3 activation.

MicroRNA-30b promotes axon outgrowth of retinal ganglion cells by inhibiting Semaphorin3A expression

Semaphorin3A (Sema3A) is a major inhibitory factor of optic nerve (ON) regeneration post-injury. Many microRNAs (miRNAs) are expressed specifically in the mammalian brain and retina and are dynamically regulated during development, suggesting that this group of miRNAs may be associated with neural development. We found that microRNA-30b (miR-30b) bound to the three prime untranslated region (3′ UTR) of Sema3A and inhibited the expression of Sema3A mRNA. The mRNA expression level of miR-30b and the protein expression levels of Sema3A, Neuropilin1 (NRP1), PlexinA1 (PlexA1), phosphorylated p38MAPK (p-p38MAPK), and active caspase-3 were all upregulated in retinas from rats with a damaged ON relative to those with an intact ON. Transfection of cultured retinal ganglion cells (RGCs) with an miR-30b mimic led to decreased levels of Sema3A, NRP1, PlexA1, p-p38MAPK, and active caspase-3 protein expression, as well as axon elongation and reduced levels of apoptosis. These findings provide evidence that miR-30b inhibits Sema3A expression. Decreased Sema3A expression promotes axon outgrowth in RGCs due to reduced levels of Sema3A binding to NRP1 and PlexA1 and simultaneously reduces apoptosis by inhibiting the p38MAPK and caspase-3 pathways. Our findings provide the first evidence that miR-30b-mediated Sema3A downregulation may serve as a new strategy for the clinical treatment of ON injury.

Atoh7 promotes the differentiation of Müller cells-derived retinal stem cells into retinal ganglion cells in a rat model of glaucoma.

Glaucoma is one of the leading eye diseases resulting in blindness due to the death of retinal ganglion cells. This study aimed to develop novel protocol to promote the differentiation of retinal Müller cells into ganglion cells in vivo in a rat model of glaucoma. The stem cells dedifferentiated from rat retinal Müller cells were randomized to receive transfection with empty lentivirus PGC-FU-GFP or lentivirus PGC-FU-Atoh7-GFP, or no transfection. The stem cells were induced further to differentiate. Ocular hypertension was induced using laser photocoagulation. The eyes were injected with Atoh7 expression vector lentivirus PGC-FU-Atoh7-GFP. Eyeball frozen sections, immunohistochemistry, RT-PCR, Western bolt, and apoptosis assay were performed. We found that the proportion of ganglion cells differentiated from Atoh7-tranfected stem cells was significantly higher than that of the other two groups. The mean intraocular pressure of glaucomatous eyes was elevated significantly compared with those of contralateral eyes. Some retinal Müller cells in the inner nuclear layer entered the mitotic cell cycle in rat chronic ocular hypertension glaucoma model. Atoh7 contributes to the differentiation of retinal Müller cells into retinal ganglion cells in rat model of glaucoma. In conclusion, Atoh7 promotes the differentiation of Müller cells-derived retinal stem cells into retinal ganglion cells in a rat model of glaucoma, thus opening up a new avenue for gene therapy and optic nerve regeneration in glaucoma.

Neuroinflammation triggered by β-glucan/dectin-1 signaling enables CNS axon regeneration

Innate immunity can facilitate nervous system regeneration, yet the underlying cellular and molecular mechanisms are not well understood. Here we show that intraocular injection of lipopolysaccharide (LPS), a bacterial cell wall component, or the fungal cell wall extract zymosan both lead to rapid and comparable intravitreal accumulation of blood-derived myeloid cells. However, when combined with retro-orbital optic nerve crush injury, lengthy growth of severed retinal ganglion cell (RGC) axons occurs only in zymosan-injected mice, and not in LPS-injected mice. In mice deficient for the pattern recognition receptor dectin-1 but not Toll-like receptor-2 (TLR2), zymosan-mediated RGC regeneration is greatly reduced. The combined loss of dectin-1 and TLR2 completely blocks the proregenerative effects of zymosan. In the retina, dectin-1 is expressed by microglia and dendritic cells, but not by RGCs. Dectin-1 is also present on blood-derived myeloid cells that accumulate in the vitreous. Intraocular injection of the dectin-1 ligand curdlan [a particulate form of β(1, 3)-glucan] promotes optic nerve regeneration comparable to zymosan in WT mice, but not in dectin-1(-/-) mice. Particulate β(1, 3)-glucan leads to increased Erk1/2 MAP-kinase signaling and cAMP response element-binding protein (CREB) activation in myeloid cells in vivo. Loss of the dectin-1 downstream effector caspase recruitment domain 9 (CARD9) blocks CREB activation and attenuates the axon-regenerative effects of β(1, 3)-glucan. Studies with dectin-1(-/-)/WT reciprocal bone marrow chimeric mice revealed a requirement for dectin-1 in both retina-resident immune cells and bone marrow-derived cells for β(1, 3)-glucan-elicited optic nerve regeneration. Collectively, these studies identify a molecular framework of how innate immunity enables repair of injured central nervous system neurons.

Amino-Nogo Inhibits Optic Nerve Regeneration and Functional Recovery via the Integrin αv Signaling Pathway in Rats

Background: Nogo-A, a major myelin-associated inhibitor, can inhibit injured optic nerve regeneration. However, whether Amino-Nogo is the most important functional domain of Nogo-A remains unknown. This study aimed to identify the role of Amino-Nogo following optic nerve injury, and the mechanism of the Amino-Nogo-integrin αv signaling pathway in vivo. Methods: Sprague-Dawley rats with optic nerve crush injury were injected with Nogo-A siRNA (Nogo-A-siRNA), the Nogo-66 functional domain antagonist peptide of Nogo-A (Nep1-40) or a recombinant rat Amino-Nogo-A protein (∆20) into the vitreous cavity to knock down Nogo-A, inhibit Nogo-66 or activate the Amino-Nogo, resparately. Retinal ganglion cell (RGC) density, axon regeneration and the pattern of NPN of visual electrophysiology (flash visual evoked potentials [F-VEP]) at different times post-injury were investigated. Results: Our study revealed a lower RGC survival rate; shorter axonal outgrowth; longer N1, P1 and N2 waves latencies; and lower N1-P1 and P1-N2 amplitudes in the Δ20 group, and Δ20 treatment significantly attenuated integrin αv expression and phosphorylated focal adhesion kinase (p-FAK) levels. In the Nep1-40 and Nogo-A siRNA groups, there were higher RGC survival rates, longer axonal outgrowth, shorter N1 and P1 wave latencies, and higher N1-P1 and P1-N2amplitudes. Nogo-A siRNA treatment significantly increased integrin αv expression and p-FAK levels. Nepl-40 treatment did not alter integrin αv expression. In addition, there was no significant change in integrin α5 in any group. Conclusion: These results suggest that the integrin signaling pathway is regulated by Amino-Nogo, which inhibits optic nerve regeneration and functional recovery, and that the integrin subunit involved might be integrin αv but not integrin α5.

Development of a Stem Cell Therapy for Glaucoma

Glaucoma is the most common form of optic neuropathy and a major cause of blindness worldwide. Currently, there is no cure for glaucoma. Damage to retinal ganglion cells and optic nerve caused by the diseases is permanent. Stem cells, which can divide indefinitely and differentiate into various cell types, offer a great premise for cell-replacement therapy. Recent breakthroughs in stem cell research that enable generation of pluripotent stem cells from adult somatic cells by reprogramming technology have opened new therapeutic possibilities. However, besides the common factors in inducing directed and homogenous cell differentiation and integration into the host tissue and establishing functionality, stem cell therapy for glaucoma is especially challenged by difficulties in driving optic nerve regeneration or repair. On the contrary, stem cell transplantation may still gain functional benefits by secreting neurotrophic factors and promoting neural plasticity. This review will discuss these advances and challenges in stem cell therapy.

RAFting the rapids of axon regeneration signaling.

The functional regeneration of damaged axons and severed connections in the mature central nervous system (CNS) remains a challenging goal of neurological research. Mature CNS neurons are refractory to axon regeneration for two major reasons, one, because the activity of cell-intrinsic mechanisms that drive axon growth during development is low – and often further suppressed after an injury – and two, because certain molecules that are part of mature extracellular matrix and myelin act as strong inhibitors of axon growth. Genetic removal of growth inhibitory molecules can increase axon sprouting, but is not sufficient to enable long-range axon growth. Since axon growth is robust during early developmental stages, it has long been hypothesized that mature injured neurons may be “reprogrammed” to the earlier growth state by re-activation of the intracellular growth signaling cascades that drive axon elongation in the developing fetus.

Acute neuroinflammation mediates optic nerve regeneration in adult zebrafish

Acute neuroinflammation mediates optic nerve regeneration in adult zebrafish

Restoring Vision to the Blind: Concluding Remarks.

When we conceived of this initiative to study the progress made so far of restoring vision to the blind, we recognized the enormous diversity of approaches already underway and their complexity. An immediate concern was whether we could get our hands around the topic and present a reasonably comprehensive and useful report; a report that would be helpful to the research community, funding agencies, and foundations. I believe we have succeeded in doing this, thanks to the hard work and time of all the participants who contributed to the project, especially the Chairs and Scribes of the Targeted Sessions who formulated the report chapters. The success of the report, on the other hand, will be determined largely by you, its readers, and by its impact on the field. This area of research is exceptionally fast moving with new findings and ideas appearing all the time. Let me mention two such examples. The first is a new experimental finding mentioned in the report, but which has received much attention and further development even during the course of the initiative. I am referring to the three-dimensional culture systems using stem cells that result in the formation of eye cups that contain laminated retinal tissue (see Fig. 4.3 and cover micrograph). So far these eye cups are tiny, but that they form retinal tissue much as happens during normal eye development suggests it may be possible eventually to grow eye cups and entire retinas large enough to be useful for transplantation purposes. The second example is just an idea at present, but is being given serious consideration by a number of clinicians and scientists. This is to transplant whole adult human eyes. The eye surgeons say that this is possible technically, but the biggest obstacle at present is the regeneration of the optic nerve. Whereas we have known for many years that regeneration of axons in the central nervous system including the optic nerve can occur under the right conditions, the number of axons that regenerate is only a few percent of the total number of axons. Which ganglion cells they derive from is not known nor is whether regenerating axons make the correct connections centrally. These are critical questions to answer if the possibility of transplanting an adult human eye is ever to become a reality. Another obvious question is whether there would be enough healthy human eyes available for transplantation purposes. These two examples undoubtedly represent only the tip of the iceberg of the ongoing experiments and ideas being generated all over the world to conquer blindness. For example, in the United States the National Eye Institute has recently announced an Audacious Goals Initiative that will focus on the regeneration of photoreceptors and ganglion cells in diseased retinas, including optic nerve regeneration. We applaud all of these efforts and are confident that restoring vision to the blind is a reasonable and realistic goal. This chapter is part of the Restoring Vision to the Blind report by the Lasker/IRRF Initiative for Innovation in Vision Science. The full report, Restoring Vision to the Blind, including a complete list of contributors, is available in the Supplementary Material.

Distribution of mesenchymal stem cells and effects on neuronal survival and axon regeneration after optic nerve crush and cell therapy.

Bone marrow-derived cells have been used in different animal models of neurological diseases. We investigated the therapeutic potential of mesenchymal stem cells (MSC) injected into the vitreous body in a model of optic nerve injury. Adult (3–5 months old) Lister Hooded rats underwent unilateral optic nerve crush followed by injection of MSC or the vehicle into the vitreous body. Before they were injected, MSC were labeled with a fluorescent dye or with superparamagnetic iron oxide nanoparticles, which allowed us to track the cells in vivo by magnetic resonance imaging. Sixteen and 28 days after injury, the survival of retinal ganglion cells was evaluated by assessing the number of Tuj1- or Brn3a-positive cells in flat-mounted retinas, and optic nerve regeneration was investigated after anterograde labeling of the optic axons with cholera toxin B conjugated to Alexa 488. Transplanted MSC remained in the vitreous body and were found in the eye for several weeks. Cell therapy significantly increased the number of Tuj1- and Brn3a-positive cells in the retina and the number of axons distal to the crush site at 16 and 28 days after optic nerve crush, although the RGC number decreased over time. MSC therapy was associated with an increase in the FGF-2 expression in the retinal ganglion cells layer, suggesting a beneficial outcome mediated by trophic factors. Interleukin-1β expression was also increased by MSC transplantation. In summary, MSC protected RGC and stimulated axon regeneration after optic nerve crush. The long period when the transplanted cells remained in the eye may account for the effect observed. However, further studies are needed to overcome eventually undesirable consequences of MSC transplantation and to potentiate the beneficial ones in order to sustain the neuroprotective effect overtime.

The role of Sodium valproate in the regeneration of injured optic nerve in rats

Objective To study the role of Sodium valproate in the regeneration of injured optic nerve in rats.Methods 60 clean grade healthy male SD rats were divided into 3 groups randomly:normal group with 12 rats (24 eyes),saline treatment group (control group) and valproate treatment group (treatment group) with 24 rats (24 eyes) in each group.No treatment was performed in normal group and the right optic nerve injury models were established by using nerve crush method in two experimental groups.The 300 mg/kg Sodium valproate was injected intraperitoneally in the treatment group,and the same volume of balance normal saline was injected intraperitoneally in control group respectively.The eyeball was enucleated at 3,7,14 and 21 days after injury,and the retinal slice were prepared.The pathological changes of retinal ganglion cell (RGC) were observed under light microscope,the expression of brain derived neurotrophic factor (BDNF) was studied through immunohistochemistry,and the average optical density (AOD) value of BDNF was tested by computer image analysis.Results Compared with the control group,the edema and vacuolization degree of ganglion cell layer cells were lighter.The nucleus of RGC were arranged neatly in treatment group after Sodium valproate injection.At the same time,the AOD value and positive cell count of BDNF in treatment group was higher than control and normal group.Conclusion Sodium valproate can promote the BDNF expression after optic nerve injury,reduce RGC damage and has a protective effect on injured optic nerve. Key words: Sodium valproate; Injury, nerve, optical; Cell, ganglion, retinal; Factor, neurotrophic, brain derived (BDNF)

Upregulation of leukemia inhibitory factor (LIF) during the early stage of optic nerve regeneration in zebrafish.

Fish retinal ganglion cells (RGCs) can regenerate their axons after optic nerve injury, whereas mammalian RGCs normally fail to do so. Interleukin 6 (IL-6)-type cytokines are involved in cell differentiation, proliferation, survival, and axon regrowth; thus, they may play a role in the regeneration of zebrafish RGCs after injury. In this study, we assessed the expression of IL-6-type cytokines and found that one of them, leukemia inhibitory factor (LIF), is upregulated in zebrafish RGCs at 3 days post-injury (dpi). We then demonstrated the activation of signal transducer and activator of transcription 3 (STAT3), a downstream target of LIF, at 3–5 dpi. To determine the function of LIF, we performed a LIF knockdown experiment using LIF-specific antisense morpholino oligonucleotides (LIF MOs). LIF MOs, which were introduced into zebrafish RGCs via a severed optic nerve, reduced the expression of LIF and abrogated the activation of STAT3 in RGCs after injury. These results suggest that upregulated LIF drives Janus kinase (Jak)/STAT3 signaling in zebrafish RGCs after nerve injury. In addition, the LIF knockdown impaired axon sprouting in retinal explant culture in vitro; reduced the expression of a regeneration-associated molecule, growth-associated protein 43 (GAP-43); and delayed functional recovery after optic nerve injury in vivo. In this study, we comprehensively demonstrate the beneficial role of LIF in optic nerve regeneration and functional recovery in adult zebrafish.

Dock3 overexpression and p38 MAPK inhibition synergistically stimulate neuroprotection and axon regeneration after optic nerve injury

The dedicator of cytokinesis 3 (Dock3) is an atypical guanine nucleotide exchange factor that is predominantly expressed in the CNS. Dock3 exerts neuroprotective effects and stimulates optic nerve regeneration. The p38 mitogen-activated protein kinase acts downstream of apoptosis signal-regulating kinase 1 (ASK1) signaling and plays an important role in neural cell death. We assessed a therapeutic efficacy of Dock3 stimulation and p38 inhibition in retinal degeneration induced by optic nerve injury (ONI). In vivo retinal imaging using optical coherence tomography revealed that ONI-induced retinal degeneration was ameliorated in SB203580 (a p38 inhibitor)-treated WT mice and PBS-treated Dock3 overexpressing (Dock3 Tg) mice, and SB203580 further stimulated retinal protection in Dock3 Tg mice. In addition, SB203580 increased the number of regenerating axons after ONI in both WT and Dock3 Tg mice. ONI-induced phosphorylation of ASK1, p38 and the N-methyl-d-aspartate receptor 2B subunit were suppressed in the retina of Dock3 Tg mice. Inhibition of the ASK1 pathway in Dock3 Tg mice suggests that Dock3 may have an antioxidant-like property. These results indicate that overexpression of Dock3 and pharmacological interruption of p38 have synergistic effects for both neuroprotection and axon regeneration, thus combined application may be beneficial for the treatment of ONI.

FRO 2014: MMP‐2 as a potential benefactor in zebrafish optic nerve regeneration

AbstractThe zebrafish retinotectal system proves to be a valuable research model to investigate regenerative strategies of damaged retinal ganglion cells (RGCs) and thus holds great promise towards identifying new regenerative molecules. Recent research performed in our lab shows that retinal broad‐spectrum MMP inhibition seriously reduces retinotectal regeneration after optic nerve crush (ONC) in the adult zebrafish. Based on preliminary results, we now intend to determine the exact role of MMP‐2 in zebrafish RGC axonal regrowth and identify underlying molecules, which might ultimately serve as new therapeutic targets for the injured mammalian CNS. Hereto, we will pursue the following goals: (1) Determination of the regenerative potential of RGCs after retinal MMP‐2 inhibition/knockdown in zebrafish subjected to ONC. (2) Proteomic identification of MMP‐2 regulated pathways underlying a successful regeneration in the zebrafish visual system.

Atoh7 promotes retinal Müller cell differentiation into retinal ganglion cells.

Glaucoma is one of the leading eye diseases due to the death of retinal ganglion cells. Increasing evidence suggests that retinal Müller cells exhibit the characteristics of retinal progenitor cells and can differentiate to neurons in injured retinas under certain conditions. However, the number of ganglion cells differentiated from retinal Müller cells falls far short of therapeutic needs. This study aimed to promote the differentiation of retinal Müller cells into ganglion cells by introducing Atoh7 into the stem cells dedifferentiated from retinal Müller cells. Rat retinal Müller cells were isolated and dedifferentiated into stem cells, which were transfected with PEGFP-N1 or PEGFP-N1-Atoh7 vector, and then further induced to differentiate into ganglion cells. The proportion of ganglion cells differentiated from Atoh7-tranfected stem cells was significantly higher than that of control transfected or untransfected cells. In summary, Atoh7 promotes the differentiation of retinal Müller cells into retinal ganglion cells. This may open a new avenue for gene therapy of glaucoma by promoting optic nerve regeneration.

Histopathological mechanism of optic nerves of rats after transverse sectioned

Objective To study the histopathological features and injured mechanism of optic nerves transaction of rats.Methods Twenty rats were divided into 2 groups randomly:normal group (n =4),no any interference; sectioned injured group(n =16),the optic nerve was completely sectioned 0.5 mm behind the eyeball.Animals were killed 4 weeks after treatment in both groups.The retinal ganglial cells were observed and counted.The regeneration of optic nerves was traced anterogrately with rhodamine-B.Results The structures of retina were clear in normal group,while that of sectioned injured group turn to thin.The number of peripheral retinal ganglial cells were 53.25 ± 1.96 in normal group and 4.06 ± 1.45 in sectioned injured group.The difference between the two groups was statistically significant (t =89.31,P ＜ 0.01).There were apparent clustered glial scar between the distal and proximal stumps of optic nerves in sectioned injured group,and fluorescence was blocked at the stumps.Conclusion There is no axon regeneration after suturing the sectioned optic nerves of rats.The most important factors that prevent the axon regeneration are the massive lose of retinal ganglial cells and the formation of the glial scars between the distal and proximal stumps of optic nerves. Key words: Injury, optic nerves; Regeneration, optic nerves; Histopathology; Mechanism

Dock GEFs and their therapeutic potential: neuroprotection and axon regeneration.

The dedicator of cytokinesis (Dock) family is composed of atypical guanine exchange factors (GEFs) that activate the Rho GTPases Rac1 and Cdc42. Rho GTPases are best documented for their roles in actin polymerization and they regulate important cellular functions, including morphogenesis, migration, neuronal development, and cell division and adhesion. To date, 11 Dock family members have been identified and their roles have been reported in diverse contexts. There has been increasing interest in elucidating the roles of Dock proteins in recent years and studies have revealed that they are potential therapeutic targets for various diseases, including glaucoma, Alzheimer's disease, cancer, attention deficit hyperactivity disorder and combined immunodeficiency. Among the Dock proteins, Dock3 is predominantly expressed in the central nervous system and recent studies have revealed that Dock3 plays a role in protecting retinal ganglion cells from neurotoxicity and oxidative stress as well as in promoting optic nerve regeneration. In this review, we discuss the current understanding of the 11 Dock GEFs and their therapeutic potential, with a particular focus on Dock3 as a novel target for the treatment of glaucoma and other neurodegenerative diseases.