International Journal of Molecular Sciences

Editorial

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6 pages, 192 KiB

Open AccessEditorial

Optic Neuropathies: Current and Future Strategies for Optic Nerve Protection and Repair

by Neil R. Miller and Rong-Kung Tsai

Int. J. Mol. Sci. 2023, 24(8), 6977; https://doi.org/10.3390/ijms24086977 - 10 Apr 2023

Cited by 2 | Viewed by 3192

Abstract

Processes that damage the optic nerve, including elevated intraocular pressure, trauma, ischemia, and compression, often cause visual loss for which there is no current treatment [...] Full article

(This article belongs to the Special Issue Optic Neuropathies: Current and Future Strategies for Optic Nerve Protection and Repair)

Research

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13 pages, 2754 KiB

Open AccessArticle

Ligand-Induced Activation of GPR110 (ADGRF1) to Improve Visual Function Impaired by Optic Nerve Injury

by Heung-Sun Kwon, Karl Kevala, Haohua Qian, Mones Abu-Asab, Samarjit Patnaik, Juan Marugan and Hee-Yong Kim

Int. J. Mol. Sci. 2023, 24(6), 5340; https://doi.org/10.3390/ijms24065340 - 10 Mar 2023

Cited by 4 | Viewed by 1941

Abstract

It is extremely difficult to achieve functional recovery after axonal injury in the adult central nervous system. The activation of G-protein coupled receptor 110 (GPR110, ADGRF1) has been shown to stimulate neurite extension in developing neurons and after axonal injury in adult mice. [...] Read more.

It is extremely difficult to achieve functional recovery after axonal injury in the adult central nervous system. The activation of G-protein coupled receptor 110 (GPR110, ADGRF1) has been shown to stimulate neurite extension in developing neurons and after axonal injury in adult mice. Here, we demonstrate that GPR110 activation partially restores visual function impaired by optic nerve injury in adult mice. Intravitreal injection of GPR110 ligands, synaptamide and its stable analogue dimethylsynaptamide (A8) after optic nerve crush significantly reduced axonal degeneration and improved axonal integrity and visual function in wild-type but not gpr110 knockout mice. The retina obtained from the injured mice treated with GPR110 ligands also showed a significant reduction in the crush-induced loss of retinal ganglion cells. Our data suggest that targeting GPR110 may be a viable strategy for functional recovery after optic nerve injury. Full article

(This article belongs to the Special Issue Optic Neuropathies: Current and Future Strategies for Optic Nerve Protection and Repair)

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15 pages, 17136 KiB

Open AccessArticle

Secondary Degeneration of Oligodendrocyte Precursor Cells Occurs as Early as 24 h after Optic Nerve Injury in Rats

by Lillian M. Toomey, Melissa G. Papini, Thomas O. Clarke, Alexander J. Wright, Eleanor Denham, Andrew Warnock, Terry McGonigle, Carole A. Bartlett, Melinda Fitzgerald and Chidozie C. Anyaegbu

Int. J. Mol. Sci. 2023, 24(4), 3463; https://doi.org/10.3390/ijms24043463 - 9 Feb 2023

Cited by 2 | Viewed by 1720

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Optic Neuropathies: Current and Future Strategies for Optic Nerve Protection and Repair)

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11 pages, 1962 KiB

Open AccessArticle

Specific Activation of Yamanaka Factors via HSF1 Signaling in the Early Stage of Zebrafish Optic Nerve Regeneration

by Kayo Sugitani, Takumi Mokuya, Shuichi Homma, Minami Maeda, Ayano Konno and Kazuhiro Ogai

Int. J. Mol. Sci. 2023, 24(4), 3253; https://doi.org/10.3390/ijms24043253 - 7 Feb 2023

Cited by 3 | Viewed by 3188

Abstract

In contrast to the case in mammals, the fish optic nerve can spontaneously regenerate and visual function can be fully restored 3–4 months after optic nerve injury (ONI). However, the regenerative mechanism behind this has remained unknown. This long process is reminiscent of [...] Read more.

In contrast to the case in mammals, the fish optic nerve can spontaneously regenerate and visual function can be fully restored 3–4 months after optic nerve injury (ONI). However, the regenerative mechanism behind this has remained unknown. This long process is reminiscent of the normal development of the visual system from immature neural cells to mature neurons. Here, we focused on the expression of three Yamanaka factors (Oct4, Sox2, and Klf4: OSK), which are well-known inducers of induced pluripotent stem (iPS) cells in the zebrafish retina after ONI. mRNA expression of OSK was rapidly induced in the retinal ganglion cells (RGCs) 1–3 h after ONI. Heat shock factor 1 (HSF1) mRNA was most rapidly induced in the RGCs at 0.5 h. The activation of OSK mRNA was completely suppressed by the intraocular injection of HSF1 morpholino prior to ONI. Furthermore, the chromatin immunoprecipitation assay showed the enrichment of OSK genomic DNA bound to HSF1. The present study clearly showed that the rapid activation of Yamanaka factors in the zebrafish retina was regulated by HSF1, and this sequential activation of HSF1 and OSK might provide a key to unlocking the regenerative mechanism of injured RGCs in fish. Full article

(This article belongs to the Special Issue Optic Neuropathies: Current and Future Strategies for Optic Nerve Protection and Repair)

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12 pages, 2901 KiB

Open AccessArticle

Protective Effect of Pioglitazone on Retinal Ganglion Cells in an Experimental Mouse Model of Ischemic Optic Neuropathy

by Ming-Hui Sun, Kuan-Jen Chen, Chi-Chin Sun and Rong-Kung Tsai

Int. J. Mol. Sci. 2023, 24(1), 411; https://doi.org/10.3390/ijms24010411 - 27 Dec 2022

Cited by 2 | Viewed by 2106

Abstract

The aim was to assess the protective effect of pioglitazone (PGZ) on retinal ganglion cells (RGCs) after anterior ischemic optic neuropathy (AION) in diabetic and non-diabetic mice. Adult C57BL/6 mice with induced diabetes were divided into three groups: group 1: oral PGZ (20 [...] Read more.

The aim was to assess the protective effect of pioglitazone (PGZ) on retinal ganglion cells (RGCs) after anterior ischemic optic neuropathy (AION) in diabetic and non-diabetic mice. Adult C57BL/6 mice with induced diabetes were divided into three groups: group 1: oral PGZ (20 mg/kg) in 0.1% dimethyl sulfoxide (DMSO) for 4 weeks; group 2: oral PGZ (10 mg/kg) in 0.1% DMSO for 4 weeks; and group 3: oral DMSO only for 4 weeks (control group). Two weeks after treatment, AION was induced through photochemical thrombosis. For non-diabetic mice, adult C57BL/6 mice were divided into four groups after AION was induced: group 1: oral DMSO for 4 weeks; group 2: oral PGZ (20 mg/kg) in 0.1% DMSO for 4 weeks; group 3: oral PGZ (20 mg/kg) in 0.1% DMSO + peritoneal injection of GW9662 (one kind of PPAR-γ inhibitor) (1 mg/kg) for 4 weeks; group 4: peritoneal injection of GW9662 (1 mg/kg) for 4 weeks; One week after the induction of AION in diabetic mice, apoptosis in RGCs was much lower in group 1 (8.0 ± 4.9 cells/field) than in group 2 (24.0 ± 11.5 cells/field) and 3 (25.0 ± 7.7 cells/field). Furthermore, microglial cell infiltration in the retina (group 1: 2.0 ± 2.6 cells/field; group 2: 15.6 ± 3.5 cells/field; and group 3: 14.8 ± 7.5 cells/field) and retinal thinning (group 1: 6.7 ± 5.7 μm; group 2: 12.8 ± 6.1 μm; and group 3: 15.8 ± 5.8 μm) were also lower in group 1 than in the other two groups. In non-diabetic mice, preserved Brn3A⁺ cells were significantly greater in group 2 (2382 ± 140 Brn3A+ cells/mm², n = 7) than in group 1 (1920 ± 228 Brn3A+ cells/mm²; p = 0.03, n = 4), group 3 (1938 ± 213 Brn3A+ cells/mm²; p = 0.002, n = 4), and group 4 (2138 ± 126 Brn3A+ cells/mm²; p = 0.03, n = 4), respectively; PGZ confers protection to RGCs from damage caused by ischemic optic neuropathy in diabetic and non-diabetic mice. Full article

(This article belongs to the Special Issue Optic Neuropathies: Current and Future Strategies for Optic Nerve Protection and Repair)

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20 pages, 2897 KiB

Open AccessArticle

Neuroprotection and Neuroregeneration Strategies Using the rNAION Model: Theory, Histology, Problems, Results and Analytical Approaches

by Steven L. Bernstein, Yan Guo, Zara Mehrabian and Neil R. Miller

Int. J. Mol. Sci. 2022, 23(24), 15604; https://doi.org/10.3390/ijms232415604 - 9 Dec 2022

Cited by 2 | Viewed by 1712

Abstract

Nonarteritic anterior ischemic optic neuropathy (NAION) is the most common cause of sudden optic nerve (ON)-related vision loss in humans. Study of this disease has been limited by the lack of available tissue and difficulties in evaluating both treatments and the window of [...] Read more.

Nonarteritic anterior ischemic optic neuropathy (NAION) is the most common cause of sudden optic nerve (ON)-related vision loss in humans. Study of this disease has been limited by the lack of available tissue and difficulties in evaluating both treatments and the window of effectiveness after symptom onset. The rodent nonarteritic anterior ischemic optic neuropathy model (rNAION) closely resembles clinical NAION in its pathophysiological changes and physiological responses. The rNAION model enables analysis of the specific responses to sudden ischemic axonopathy and effectiveness of potential treatments. However, there are anatomic and genetic differences between human and rodent ON, and the inducing factors for the disease and the model are different. These variables can result in marked differences in lesion development between the two species, as well as in the possible responses to various treatments. These caveats are discussed in the current article, as well as some of the species-associated differences that may be related to ischemic lesion severity and responses. Full article

(This article belongs to the Special Issue Optic Neuropathies: Current and Future Strategies for Optic Nerve Protection and Repair)

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13 pages, 1004 KiB

Open AccessArticle

Candidate Modifier Genes for the Penetrance of Leber’s Hereditary Optic Neuropathy

by Hui-Chen Cheng, Sheng-Chu Chi, Chiao-Ying Liang, Jenn-Yah Yu and An-Guor Wang

Int. J. Mol. Sci. 2022, 23(19), 11891; https://doi.org/10.3390/ijms231911891 - 6 Oct 2022

Cited by 5 | Viewed by 2285

Abstract

Leber’s hereditary optic neuropathy (LHON) is a maternally transmitted disease caused by mitochondria DNA (mtDNA) mutation. It is characterized by acute and subacute visual loss predominantly affecting young men. The mtDNA mutation is transmitted to all maternal lineages. However, only approximately 50% of [...] Read more.

Leber’s hereditary optic neuropathy (LHON) is a maternally transmitted disease caused by mitochondria DNA (mtDNA) mutation. It is characterized by acute and subacute visual loss predominantly affecting young men. The mtDNA mutation is transmitted to all maternal lineages. However, only approximately 50% of men and 10% of women harboring a pathogenic mtDNA mutation develop optic neuropathy, reflecting both the incomplete penetrance and its unexplained male prevalence, where over 80% of patients are male. Nuclear modifier genes have been presumed to affect the penetrance of LHON. With conventional genetic methods, prior studies have failed to solve the underlying pathogenesis. Whole exome sequencing (WES) is a new molecular technique for sequencing the protein-coding region of all genes in a whole genome. We performed WES from five families with 17 members. These samples were divided into the proband group (probands with acute onset of LHON, n = 7) and control group (carriers including mother and relative carriers with mtDNSA 11778 mutation, without clinical manifestation of LHON, n = 10). Through whole exome analysis, we found that many mitochondria related (MT-related) nuclear genes have high percentage of variants in either the proband group or control group. The MT genes with a difference over 0.3 of mutation percentage between the proband and control groups include AK4, NSUN4, RDH13, COQ3, and FAHD1. In addition, the pathway analysis revealed that these genes were associated with cofactor metabolism pathways. Family-based analysis showed that several candidate MT genes including METAP1D (c.41G > T), ACACB (c.1029del), ME3 (c.972G > C), NIPSNAP3B (c.280G > C, c.476C > G), and NSUN4 (c.4A > G) were involved in the penetrance of LHON. A GWAS (genome wide association study) was performed, which found that ADGRG5 (Chr16:575620A:G), POLE4 (Chr2:7495872T:G), ERMAP (Chr1:4283044A:G), PIGR (Chr1:2069357C:T;2069358G:A), CDC42BPB (Chr14:102949A:G), PROK1 (Chr1:1104562A:G), BCAN (Chr 1:1566582C:T), and NES (Chr1:1566698A:G,1566705T:C, 1566707T:C) may be involved. The incomplete penetrance and male prevalence are still the major unexplained issues in LHON. Through whole exome analysis, we found several MT genes with a high percentage of variants were involved in a family-based analysis. Pathway analysis suggested a difference in the mutation burden of MT genes underlining the biosynthesis and metabolism pathways. In addition, the GWAS analysis also revealed several candidate nuclear modifier genes. The new technology of WES contributes to provide a highly efficient candidate gene screening function in molecular genetics. Full article

(This article belongs to the Special Issue Optic Neuropathies: Current and Future Strategies for Optic Nerve Protection and Repair)

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12 pages, 52205 KiB

Open AccessArticle

Neuroprotective Effect of Azithromycin Following Induction of Optic Nerve Crush in Wild Type and Immunodeficient Mice

by Ofira Zloto, Alon Zahavi, Stephen Richard, Moran Friedman-Gohas, Shirel Weiss and Nitza Goldenberg-Cohen

Int. J. Mol. Sci. 2022, 23(19), 11872; https://doi.org/10.3390/ijms231911872 - 6 Oct 2022

Cited by 6 | Viewed by 1717

Abstract

This study evaluated the potential neuroprotective effect of azithromycin (AZ) intraperitoneal injections in male C57Bl/6 (wild type, WT) and female NOD scid gamma (NSG) mice subjected to optic nerve crush (ONC) as a model for optic neuropathy. Histologically, reduced apoptosis and improved retinal [...] Read more.

This study evaluated the potential neuroprotective effect of azithromycin (AZ) intraperitoneal injections in male C57Bl/6 (wild type, WT) and female NOD scid gamma (NSG) mice subjected to optic nerve crush (ONC) as a model for optic neuropathy. Histologically, reduced apoptosis and improved retinal ganglion cell (RGC) preservation were noted in the AZ-treated mice as shown by TUNEL staining—in the WT mice more than in the NSG mice. The increased microglial activation following ONC was reduced with the AZ treatment. In the molecular analysis of WT and NSG mice, similar trends were detected regarding apoptosis, as well as stress-related and inflammatory markers examining BCL2-associated X (Bax), heme oxygenase 1 (Ho-1), interleukin 1 beta (Il1β), superoxide dismutase 1 (Sod1), and nuclear factor-kappa B (Nfkb) levels. In the optic nerve, AZ increased the levels of expression of Sod1 and Nfkb only in the WT mice and decreased them in the NSG mice. In the retinas of the WT and NSG mice, the Bax and Ho-1 levels of expression decreased following the AZ treatment, while the Sod1 and Nfkb expression decreased only in the WT mice, and remained stable near the baseline in the NSG mice. Il1β remained at the baseline in WT mice while it decreased towards the baseline in AZ-treated NSG mice. The neuroprotective effects demonstrated by the reduced RGC apoptosis in AZ-treated WT mice retinae, and in the optic nerves as stress-related and inflammatory gene expression increase. This did not occur in the immunodeficient NSG mice. AZ modulated the inflammatory reaction and microglial activation. The lack of an effect in NSG mice supports the assumption that AZ acts by immunomodulation, which is known to play a role in ONC damage. These findings have implications for the development and repurposing of drugs to preserve RGCs after acute optic neuropathies. Full article

(This article belongs to the Special Issue Optic Neuropathies: Current and Future Strategies for Optic Nerve Protection and Repair)

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16 pages, 3927 KiB

Open AccessArticle

Transcriptomic Analysis Reveals That Granulocyte Colony-Stimulating Factor Trigger a Novel Signaling Pathway (TAF9-P53-TRIAP1-CASP3) to Protect Retinal Ganglion Cells after Ischemic Optic Neuropathy

by Rong-Kung Tsai, Keh-Liang Lin, Chin-Te Huang and Yao-Tseng Wen

Int. J. Mol. Sci. 2022, 23(15), 8359; https://doi.org/10.3390/ijms23158359 - 28 Jul 2022

Cited by 4 | Viewed by 2092

Abstract

Optic nerve head (ONH) infarct can result in progressive retinal ganglion cell (RGC) death. The granulocyte colony-stimulating factor (GCSF) protects the RGC after ON infarct. However, protective mechanisms of the GCSF after ONH infarct are complex and remain unclear. To investigate the complex [...] Read more.

Optic nerve head (ONH) infarct can result in progressive retinal ganglion cell (RGC) death. The granulocyte colony-stimulating factor (GCSF) protects the RGC after ON infarct. However, protective mechanisms of the GCSF after ONH infarct are complex and remain unclear. To investigate the complex mechanisms involved, the transcriptome profiles of the GCSF-treated retinas were examined using microarray technology. The retinal mRNA samples on days 3 and 7 post rat anterior ischemic optic neuropathy (rAION) were analyzed by microarray and bioinformatics analyses. GCSF treatment influenced 3101 genes and 3332 genes on days 3 and 7 post rAION, respectively. ONH infarct led to changes in 702 and 179 genes on days 3 and 7 post rAION, respectively. After cluster analysis, the levels of TATA box-binding protein (TBP)-associated factor were significantly reduced after ONH infarct, but these significantly increased after GCSF treatment. The network analysis revealed that TBP associated factor 9 (TAF9) can bind to P53 to induce TP53-regulated inhibitor of apoptosis 1 (TRIAP1) expression. To evaluate the function of TAF9 in RGC apoptosis, GCSF plus TAF9 siRNA-treated rats were evaluated using retrograde labeling with FluoroGold assay, TUNEL assay, and Western blotting in an rAION model. The RGC densities in the GCSF plus TAF9 siRNA-treated rAION group were 1.95-fold (central retina) and 1.75-fold (midperipheral retina) lower than that in the GCSF-treated rAION group (p < 0.05). The number of apoptotic RGC in the GCSF plus TAF9 siRNA-treated group was threefold higher than that in the GCSF-treated group (p < 0.05). Treatment with TAF9 siRNA significantly reduced GCSF-induced TP53 and TRIAP1 expression by 2.4-fold and 4.7-fold, respectively, in the rAION model. Overexpression of TAF9 significantly reduced apoptotic RGC and CASP3 levels, and induced TP53 and TRIAP1 expression in the rAION model. Therefore, we have demonstrated that GCSF modulated a new pathway, TAF9-P53-TRIAP1-CASP3, to control RGC death and survival after ON infarct. Full article

(This article belongs to the Special Issue Optic Neuropathies: Current and Future Strategies for Optic Nerve Protection and Repair)

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17 pages, 3296 KiB

Open AccessArticle

Sera of Neuromyelitis Optica Patients Increase BID-Mediated Apoptosis in Astrocytes

by Omri Zveik, Ariel Rechtman, Nitzan Haham, Irit Adini, Tamar Canello, Iris Lavon, Livnat Brill and Adi Vaknin-Dembinsky

Int. J. Mol. Sci. 2022, 23(13), 7117; https://doi.org/10.3390/ijms23137117 - 27 Jun 2022

Cited by 5 | Viewed by 2922

Abstract

Neuromyelitis optica (NMO) is a rare disease usually presenting with bilateral or unilateral optic neuritis with simultaneous or sequential transverse myelitis. Autoantibodies directed against aquaporin-4 (AQP4-IgG) are found in most patients. They are believed to cross the blood–brain barrier, target astrocytes, activate complement, [...] Read more.

Neuromyelitis optica (NMO) is a rare disease usually presenting with bilateral or unilateral optic neuritis with simultaneous or sequential transverse myelitis. Autoantibodies directed against aquaporin-4 (AQP4-IgG) are found in most patients. They are believed to cross the blood–brain barrier, target astrocytes, activate complement, and eventually lead to astrocyte destruction, demyelination, and axonal damage. However, it is still not clear what the primary pathological event is. We hypothesize that the interaction of AQP4-IgG and astrocytes leads to DNA damage and apoptosis. We studied the effect of sera from seropositive NMO patients and healthy controls (HCs) on astrocytes’ immune gene expression and viability. We found that sera from seropositive NMO patients led to higher expression of apoptosis-related genes, including BH3-interacting domain death agonist (BID), which is the most significant differentiating gene (p < 0.0001), and triggered more apoptosis in astrocytes compared to sera from HCs. Furthermore, NMO sera increased DNA damage and led to a higher expression of immunological genes that interact with BID (TLR4 and NOD-1). Our findings suggest that sera of seropositive NMO patients might cause astrocytic DNA damage and apoptosis. It may be one of the mechanisms implicated in the primary pathological event in NMO and provide new avenues for therapeutic intervention. Full article

(This article belongs to the Special Issue Optic Neuropathies: Current and Future Strategies for Optic Nerve Protection and Repair)

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Review

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16 pages, 1424 KiB

Open AccessReview

Solutions to a Radical Problem: Overview of Current and Future Treatment Strategies in Leber’s Hereditary Opic Neuropathy

by Samuel J. Spiegel and Alfredo A. Sadun

Int. J. Mol. Sci. 2022, 23(21), 13205; https://doi.org/10.3390/ijms232113205 - 30 Oct 2022

Cited by 5 | Viewed by 2343

Abstract

Leber’s Hereditary Optic Neuropathy (LHON) is the most common primary mitochondrial DNA disorder. It is characterized by bilateral severe central subacute vision loss due to specific loss of Retinal Ganglion Cells and their axons. Historically, treatment options have been quite limited, but ongoing [...] Read more.

Leber’s Hereditary Optic Neuropathy (LHON) is the most common primary mitochondrial DNA disorder. It is characterized by bilateral severe central subacute vision loss due to specific loss of Retinal Ganglion Cells and their axons. Historically, treatment options have been quite limited, but ongoing clinical trials show promise, with significant advances being made in the testing of free radical scavengers and gene therapy. In this review, we summarize management strategies and rational of treatment based on current insights from molecular research. This includes preventative recommendations for unaffected genetic carriers, current medical and supportive treatments for those affected, and emerging evidence for future potential therapeutics. Full article

(This article belongs to the Special Issue Optic Neuropathies: Current and Future Strategies for Optic Nerve Protection and Repair)

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14 pages, 868 KiB

Open AccessReview

The Role of miR-29 Family in TGF-β Driven Fibrosis in Glaucomatous Optic Neuropathy

by Aoife Smyth, Breedge Callaghan, Colin E. Willoughby and Colm O’Brien

Int. J. Mol. Sci. 2022, 23(18), 10216; https://doi.org/10.3390/ijms231810216 - 6 Sep 2022

Cited by 15 | Viewed by 2744

Abstract

Primary open angle glaucoma (POAG), a chronic optic neuropathy, remains the leading cause of irreversible blindness worldwide. It is driven in part by the pro-fibrotic cytokine transforming growth factor beta (TGF-β) and leads to extracellular matrix remodelling at the lamina cribrosa of the [...] Read more.

Primary open angle glaucoma (POAG), a chronic optic neuropathy, remains the leading cause of irreversible blindness worldwide. It is driven in part by the pro-fibrotic cytokine transforming growth factor beta (TGF-β) and leads to extracellular matrix remodelling at the lamina cribrosa of the optic nerve head. Despite an array of medical and surgical treatments targeting the only known modifiable risk factor, raised intraocular pressure, many patients still progress and develop significant visual field loss and eventual blindness. The search for alternative treatment strategies targeting the underlying fibrotic transformation in the optic nerve head and trabecular meshwork in glaucoma is ongoing. MicroRNAs are small non-coding RNAs known to regulate post-transcriptional gene expression. Extensive research has been undertaken to uncover the complex role of miRNAs in gene expression and miRNA dysregulation in fibrotic disease. MiR-29 is a family of miRNAs which are strongly anti-fibrotic in their effects on the TGF-β signalling pathway and the regulation of extracellular matrix production and deposition. In this review, we discuss the anti-fibrotic effects of miR-29 and the role of miR-29 in ocular pathology and in the development of glaucomatous optic neuropathy. A better understanding of the role of miR-29 in POAG may aid in developing diagnostic and therapeutic strategies in glaucoma. Full article

(This article belongs to the Special Issue Optic Neuropathies: Current and Future Strategies for Optic Nerve Protection and Repair)

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16 pages, 5517 KiB

Open AccessReview

Retinal Ganglion Cell Survival and Axon Regeneration after Optic Nerve Injury: Role of Inflammation and Other Factors

by Kimberly A. Wong and Larry I. Benowitz

Int. J. Mol. Sci. 2022, 23(17), 10179; https://doi.org/10.3390/ijms231710179 - 5 Sep 2022

Cited by 25 | Viewed by 4697

Abstract

The optic nerve, like most pathways in the mature central nervous system, cannot regenerate if injured, and within days, retinal ganglion cells (RGCs), the neurons that extend axons through the optic nerve, begin to die. Thus, there are few clinical options to improve [...] Read more.

The optic nerve, like most pathways in the mature central nervous system, cannot regenerate if injured, and within days, retinal ganglion cells (RGCs), the neurons that extend axons through the optic nerve, begin to die. Thus, there are few clinical options to improve vision after traumatic or ischemic optic nerve injury or in neurodegenerative diseases such as glaucoma, dominant optic neuropathy, or optic pathway gliomas. Research over the past two decades has identified several strategies to enable RGCs to regenerate axons the entire length of the optic nerve, in some cases leading to modest reinnervation of di- and mesencephalic visual relay centers. This review primarily focuses on the role of the innate immune system in improving RGC survival and axon regeneration, and its synergy with manipulations of signal transduction pathways, transcription factors, and cell-extrinsic suppressors of axon growth. Research in this field provides hope that clinically effective strategies to improve vision in patients with currently untreatable losses could become a reality in 5–10 years. Full article

(This article belongs to the Special Issue Optic Neuropathies: Current and Future Strategies for Optic Nerve Protection and Repair)

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40 pages, 6695 KiB

Open AccessReview

Treatment and Relapse Prevention of Typical and Atypical Optic Neuritis

by George Saitakis and Bart K. Chwalisz

Int. J. Mol. Sci. 2022, 23(17), 9769; https://doi.org/10.3390/ijms23179769 - 29 Aug 2022

Cited by 9 | Viewed by 5435

Abstract

Optic neuritis (ON) is an inflammatory condition involving the optic nerve. Several important typical and atypical ON variants are now recognized. Typical ON has a more favorable prognosis; it can be idiopathic or represent an early manifestation of demyelinating diseases, mostly multiple sclerosis [...] Read more.

Optic neuritis (ON) is an inflammatory condition involving the optic nerve. Several important typical and atypical ON variants are now recognized. Typical ON has a more favorable prognosis; it can be idiopathic or represent an early manifestation of demyelinating diseases, mostly multiple sclerosis (MS). The atypical spectrum includes entities such as antibody-driven ON associated with neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD), chronic/relapsing inflammatory optic neuropathy (CRION), and sarcoidosis-associated ON. Appropriate and timely diagnosis is essential to rapidly decide on the appropriate treatment, maximize visual recovery, and minimize recurrences. This review paper aims at presenting the currently available state-of-the-art treatment strategies for typical and atypical ON, both in the acute phase and in the long-term. Moreover, emerging therapeutic approaches and novel steps in the direction of achieving remyelination are discussed. Full article

(This article belongs to the Special Issue Optic Neuropathies: Current and Future Strategies for Optic Nerve Protection and Repair)

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15 pages, 1591 KiB

Open AccessReview

Epigenetic Regulation of Optic Nerve Development, Protection, and Repair

by Ajay Ashok, Sarita Pooranawattanakul, Wai Lydia Tai, Kin-Sang Cho, Tor P. Utheim, Dean M. Cestari and Dong Feng Chen

Int. J. Mol. Sci. 2022, 23(16), 8927; https://doi.org/10.3390/ijms23168927 - 10 Aug 2022

Cited by 6 | Viewed by 3253

Abstract

Epigenetic factors are known to influence tissue development, functionality, and their response to pathophysiology. This review will focus on different types of epigenetic regulators and their associated molecular apparatus that affect the optic nerve. A comprehensive understanding of epigenetic regulation in optic nerve [...] Read more.

Epigenetic factors are known to influence tissue development, functionality, and their response to pathophysiology. This review will focus on different types of epigenetic regulators and their associated molecular apparatus that affect the optic nerve. A comprehensive understanding of epigenetic regulation in optic nerve development and homeostasis will help us unravel novel molecular pathways and pave the way to design blueprints for effective therapeutics to address optic nerve protection, repair, and regeneration. Full article

(This article belongs to the Special Issue Optic Neuropathies: Current and Future Strategies for Optic Nerve Protection and Repair)

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19 pages, 1280 KiB

Open AccessReview

Remodeling of the Lamina Cribrosa: Mechanisms and Potential Therapeutic Approaches for Glaucoma

by Ryan G. Strickland, Mary Anne Garner, Alecia K. Gross and Christopher A. Girkin

Int. J. Mol. Sci. 2022, 23(15), 8068; https://doi.org/10.3390/ijms23158068 - 22 Jul 2022

Cited by 19 | Viewed by 6375

Abstract

Glaucomatous optic neuropathy is the leading cause of irreversible blindness in the world. The chronic disease is characterized by optic nerve degeneration and vision field loss. The reduction of intraocular pressure remains the only proven glaucoma treatment, but it does not prevent further [...] Read more.

Glaucomatous optic neuropathy is the leading cause of irreversible blindness in the world. The chronic disease is characterized by optic nerve degeneration and vision field loss. The reduction of intraocular pressure remains the only proven glaucoma treatment, but it does not prevent further neurodegeneration. There are three major classes of cells in the human optic nerve head (ONH): lamina cribrosa (LC) cells, glial cells, and scleral fibroblasts. These cells provide support for the LC which is essential to maintain healthy retinal ganglion cell (RGC) axons. All these cells demonstrate responses to glaucomatous conditions through extracellular matrix remodeling. Therefore, investigations into alternative therapies that alter the characteristic remodeling response of the ONH to enhance the survival of RGC axons are prevalent. Understanding major remodeling pathways in the ONH may be key to developing targeted therapies that reduce deleterious remodeling. Full article

(This article belongs to the Special Issue Optic Neuropathies: Current and Future Strategies for Optic Nerve Protection and Repair)

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18 pages, 950 KiB

Open AccessReview

Neuromyelitis Optica Spectrum Disorder: From Basic Research to Clinical Perspectives

by Tzu-Lun Huang, Jia-Kang Wang, Pei-Yao Chang, Yung-Ray Hsu, Cheng-Hung Lin, Kung-Hung Lin and Rong-Kung Tsai

Int. J. Mol. Sci. 2022, 23(14), 7908; https://doi.org/10.3390/ijms23147908 - 18 Jul 2022

Cited by 7 | Viewed by 7838

Abstract

Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disease of the central nervous system characterized by relapses and autoimmunity caused by antibodies against the astrocyte water channel protein aquaporin-4. Over the past decade, there have been significant advances in the biologic knowledge of [...] Read more.

Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disease of the central nervous system characterized by relapses and autoimmunity caused by antibodies against the astrocyte water channel protein aquaporin-4. Over the past decade, there have been significant advances in the biologic knowledge of NMOSD, which resulted in the IDENTIFICATION of variable disease phenotypes, biomarkers, and complex inflammatory cascades involved in disease pathogenesis. Ongoing clinical trials are looking at new treatments targeting NMOSD relapses. This review aims to provide an update on recent studies regarding issues related to NMOSD, including the pathophysiology of the disease, the potential use of serum and cerebrospinal fluid cytokines as disease biomarkers, the clinical utilization of ocular coherence tomography, and the comparison of different animal models of NMOSD. Full article

(This article belongs to the Special Issue Optic Neuropathies: Current and Future Strategies for Optic Nerve Protection and Repair)

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19 pages, 1213 KiB

Open AccessReview

Erythropoietin in Optic Neuropathies: Current Future Strategies for Optic Nerve Protection and Repair

by Yi-Fen Lai, Ting-Yi Lin, Pin-Kuan Ho, Yi-Hao Chen, Yu-Chuan Huang and Da-Wen Lu

Int. J. Mol. Sci. 2022, 23(13), 7143; https://doi.org/10.3390/ijms23137143 - 27 Jun 2022

Cited by 12 | Viewed by 3282

Abstract

Erythropoietin (EPO) is known as a hormone for erythropoiesis in response to anemia and hypoxia. However, the effect of EPO is not only limited to hematopoietic tissue. Several studies have highlighted the neuroprotective function of EPO in extra-hematopoietic tissues, especially the retina. EPO [...] Read more.

Erythropoietin (EPO) is known as a hormone for erythropoiesis in response to anemia and hypoxia. However, the effect of EPO is not only limited to hematopoietic tissue. Several studies have highlighted the neuroprotective function of EPO in extra-hematopoietic tissues, especially the retina. EPO could interact with its heterodimer receptor (EPOR/βcR) to exert its anti-apoptosis, anti-inflammation and anti-oxidation effects in preventing retinal ganglion cells death through different intracellular signaling pathways. In this review, we summarized the available pre-clinical studies of EPO in treating glaucomatous optic neuropathy, optic neuritis, non-arteritic anterior ischemic optic neuropathy and traumatic optic neuropathy. In addition, we explore the future strategies of EPO for optic nerve protection and repair, including advances in EPO derivates, and EPO deliveries. These strategies will lead to a new chapter in the treatment of optic neuropathy. Full article

(This article belongs to the Special Issue Optic Neuropathies: Current and Future Strategies for Optic Nerve Protection and Repair)

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11 pages, 3216 KiB

Open AccessPerspective

Using Noninvasive Electrophysiology to Determine Time Windows of Neuroprotection in Optic Neuropathies

by Vittorio Porciatti and Tsung-Han Chou

Int. J. Mol. Sci. 2022, 23(10), 5751; https://doi.org/10.3390/ijms23105751 - 20 May 2022

Cited by 6 | Viewed by 1650

Abstract

The goal of neuroprotection in optic neuropathies is to prevent loss of retinal ganglion cells (RGCs) and spare their function. The ideal time window for initiating neuroprotective treatments should be the preclinical period at which RGCs start losing their functional integrity before dying. [...] Read more.

The goal of neuroprotection in optic neuropathies is to prevent loss of retinal ganglion cells (RGCs) and spare their function. The ideal time window for initiating neuroprotective treatments should be the preclinical period at which RGCs start losing their functional integrity before dying. Noninvasive electrophysiological tests such as the Pattern Electroretinogram (PERG) can assess the ability of RGCs to generate electrical signals under a protracted degenerative process in both clinical conditions and experimental models, which may have both diagnostic and prognostic values and provide the rationale for early treatment. The PERG can be used to longitudinally monitor the acute and chronic effects of neuroprotective treatments. User-friendly versions of the PERG technology are now commercially available for both clinical and experimental use. Full article

(This article belongs to the Special Issue Optic Neuropathies: Current and Future Strategies for Optic Nerve Protection and Repair)

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