RESUMO
Glaucoma is a neurodegenerative eye disease that causes permanent vision impairment. The main pathological characteristics of glaucoma are retinal ganglion cell (RGC) loss and optic nerve degeneration. Glaucoma can be caused by elevated intraocular pressure (IOP), although some cases are congenital or occur in patients with normal IOP. Current glaucoma treatments rely on medicine and surgery to lower IOP, which only delays disease progression. First-line glaucoma medicines are supported by pharmacotherapy advancements such as Rho kinase inhibitors and innovative drug delivery systems. Glaucoma surgery has shifted to safer minimally invasive (or microinvasive) glaucoma surgery, but further trials are needed to validate long-term efficacy. Further, growing evidence shows that adeno-associated virus gene transduction and stem cell-based RGC replacement therapy hold potential to treat optic nerve fiber degeneration and glaucoma. However, better understanding of the regulatory mechanisms of RGC development is needed to provide insight into RGC differentiation from stem cells and help choose target genes for viral therapy. In this review, we overview current progress in RGC development research, optic nerve fiber regeneration, and human stem cell-derived RGC differentiation and transplantation. We also provide an outlook on perspectives and challenges in the field.
Assuntos
Glaucoma , Doenças Neurodegenerativas , Doenças do Nervo Óptico , Humanos , Animais , Glaucoma/tratamento farmacológico , Glaucoma/patologia , Células Ganglionares da Retina/patologia , Doenças do Nervo Óptico/terapia , Doenças do Nervo Óptico/patologia , Progressão da Doença , Doenças Neurodegenerativas/patologia , Modelos Animais de DoençasRESUMO
OBJECTIVE: This study aims to investigate possible preventive effect of ATP on optic nerve damage caused by amiodarone in rats. MATERIAL AND METHOD: Thirty albino male Wistar rats weighing between 265 and 278 g were used in the study. Before the experiment, the rats were housed at 22 °C in a 12-h light/dark cycle under appropriate condition. The rats were equally divided into five groups of six animals each: healthy group, 50 mg/kg amiodarone (AMD-50), 100 mg/kg amiodarone (AMD-100), 25 mg/kg ATP + 50 mg/kg amiodarone (ATAD-50), and 25 mg/kg ATP + 100 mg/kg amiodarone (ATAD-100). At the end of 14th day, the animals were sacrificed using cardiac puncture under deep thiopental anaesthesia, and optic nerve tissues were harvested to measure superoxide dismutase (SOD), total glutathione (tGSH), malondialdehyde (MDA), and catalase (CAT) levels. RESULTS: The MDA levels were found to be significantly higher in the AMD-50 and AMD-100 groups compared to the healthy group (p Ë 0.001). There was also a significant difference between the AMD-50 and ATAD-50 groups, and between the AMD-100 and ATAD-100 groups regarding MDA levels (p Ë 0.001). tGSH, SOD, and CAT levels were significantly lower in the AMD-50 and AMD-100 groups compared to the healthy group (p Ë 0.001). ATP was found to partially inhibit amiodarone-induced optic neuropathy. CONCLUSION: The biochemical and histopathological results of this study demonstrated that amiodarone at high doses caused more severe optic neuropathy inducing oxidative damage, but ATP could relatively antagonise these negative effects on the optic nerve. Therefore, we believe that ATP may be beneficial in preventing amiodarone-induced optic neuropathy.
Assuntos
Amiodarona , Doenças do Nervo Óptico , Ratos , Animais , Amiodarona/toxicidade , Ratos Wistar , Trifosfato de Adenosina/farmacologia , Doenças do Nervo Óptico/induzido quimicamente , Doenças do Nervo Óptico/prevenção & controle , Doenças do Nervo Óptico/patologia , Nervo Óptico/patologia , Glutationa , Superóxido DismutaseRESUMO
The optic nerve (ON) can get compressed in different diseases. However, the pathological and functional changes occurring in the compressed ON over time under constant compression are still unclear. In the present study, we implanted an artificial tube around the optic nerve of a rabbit to primarily create a clinically relevant persistent compressive optic nerve axonopathy (PCOA). Due to the protuberance on the inner ring of the tube, steady and persistent compressions were maintained. In this model, we investigated the thickness of ganglion cell complex (GCC), retinal ganglion cell (RGC) density, axon density of optic nerve, flash visual evoked potential (FVEP), and anterograde axonal transport at various times in four different groups viz. the no comp, 1/2 comp, 3/4 comp, and crush groups. The GCC thickness, RGC density, and axon density of ON were hierarchically and significantly decreased in 1/2 comp, 3/4 comp, and crush groups. Compared to no comp eyes, the P2 amplitude ratio of FVEP was significantly decreased in 3/4 comp but not in 1/2 comp eyes. Only a portion of the optic nerve lost the ability of anterograde axonal transport in the 1/2 comp group. However, it was evident at 2-wpo and more prominent at 4-wpo in 3/4 comp eyes. This study reveals that the compression only induces the homolateral ON axons impairment and the proportion of the affected axons maintains the same for mild compression for at least three months. Furthermore, an underlying threshold effect highlights that mild compression does not require urgent surgery, while the severe compression warrants immediate surgical intervention.
Assuntos
Doenças do Nervo Óptico , Traumatismos do Nervo Óptico , Animais , Coelhos , Potenciais Evocados Visuais , Nervo Óptico/patologia , Células Ganglionares da Retina/patologia , Doenças do Nervo Óptico/patologia , Traumatismos do Nervo Óptico/patologia , Axônios/patologia , Compressão Nervosa , Modelos Animais de DoençasRESUMO
Radiation is a commonly used treatment modality for head and neck as well as CNS tumours, both benign and malignant. As newer oncology treatments such as immunotherapies allow for longer survival, complications from radiation therapy are becoming more common. Radiation-induced optic neuropathy is a feared complication due to rapid onset and potential for severe and bilateral vision loss. Careful monitoring of high-risk patients and early recognition are crucial for initiating treatment to prevent severe vision loss due to a narrow therapeutic window. This review discusses presentation, aetiology, recent advances in diagnosis using innovative MRI techniques and best practice treatment options based on the most recent evidence-based medicine.
Assuntos
Doenças do Nervo Óptico , Humanos , Doenças do Nervo Óptico/diagnóstico , Doenças do Nervo Óptico/etiologia , Doenças do Nervo Óptico/patologia , Nervo Óptico/patologia , Transtornos da Visão/etiologia , CegueiraAssuntos
Doenças do Nervo Óptico , Glioma do Nervo Óptico , Adulto , Humanos , Glioma do Nervo Óptico/complicações , Glioma do Nervo Óptico/diagnóstico , Glioma do Nervo Óptico/patologia , Nervo Óptico/diagnóstico por imagem , Nervo Óptico/patologia , Doenças do Nervo Óptico/diagnóstico , Doenças do Nervo Óptico/etiologia , Doenças do Nervo Óptico/patologia , BiópsiaRESUMO
BACKGROUND: The authors present a case study which describes the development of bilateral optic neuropathy as a complication of allogeneic hematopoietic stem cell transplantation (HSCT) in a patient who underwent a transplant for B-cell acute lymphoblastic leukemia (B-ALL). The patient, who was in remission with regard to the underlying hematological disease, developed edema of both optic discs and maculas three months after transplantation. The morphological finding regressed after treatment with corticoids and comprehensive systemic anti-infective therapy. However, the loss of function was not entirely restored. CASE REPORT: One year after the healing, the atrophy of the optic discs persisted, with corresponding findings in vessel density (VD), retinal nerve fibre layer (RNFL) and visual field changes. Electrophysiological examination by pattern electroretinogram (PERG) showed an alteration in retinal ganglion cells in the left eye, but with significant damage to nerve fibres on both sides. Visual evoked potential (VEP) verified bilateral non-inflammatory neurogenic lesions. This finding was also confirmed by functional magnetic resonance imaging (fMRI). Examination by structural magnetic resonance imaging (MRI) showed inflammatory changes in the optic nerve sheaths over time and a consequent marked narrowing of them. CONCLUSION: The authors believe that edema of the optic discs and maculas was caused by a combination of several factors. Firstly, MRI showed inflammatory changes in the optic nerve sheaths, which led to a blockade of axoplasmic transport. Another factor that may have played a part in the outcome was endothelial damage to blood vessels with impaired microcirculation supplying the optic nerve fibres, which contributed to the occurrence of macular edema.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Macula Lutea , Doenças do Nervo Óptico , Humanos , Potenciais Evocados Visuais , Doenças do Nervo Óptico/etiologia , Doenças do Nervo Óptico/patologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Nervo Óptico , Tomografia de Coerência ÓpticaRESUMO
Human pluripotent stem cell-derived neural progenitor cells (NPCs) have the potential to recover from nerve injury. We previously reported that human placenta-derived mesenchymal stem cells (PSCs) have neuroprotective effects. To evaluate the potential benefit of NPCs, we compared them to PSCs using R28 cells under hypoxic conditions and a rat model of optic nerve injury. NPCs and PSCs (2 × 106 cells) were injected into the subtenon space. After 1, 2, and 4 weeks, we examined changes in target proteins in the retina and optic nerve. NPCs significantly induced vascular endothelial growth factor (Vegf) compared to age-matched shams and PSC groups at 2 weeks; they also induced neurofilaments in the retina compared to the sham group at 4 weeks. In addition, the expression of brain-derived neurotrophic factor (Bdnf) was high in the retina in the NPC group at 2 weeks, while expression in the optic nerve was high in both the NPC and PSC groups. The low expression of ionized calcium-binding adapter molecule 1 (Iba1) in the retina had recovered at 2 weeks after NPC injection and at 4 weeks after PSC injection. The expression of the inflammatory protein NLR family, pyrin domain containing 3 (Nlrp3) was significantly reduced at 1 week, and that of tumor necrosis factor-α (Tnf-α) in the optic nerves of the NPC group was lower at 2 weeks. Regarding retinal ganglion cells, the expressions of Brn3a and Tuj1 in the retina were enhanced in the NPC group compared to sham controls at 4 weeks. NPC injections increased Gap43 expression from 2 weeks and reduced Iba1 expression in the optic nerves during the recovery period. In addition, R28 cells exposed to hypoxic conditions showed increased cell survival when cocultured with NPCs compared to PSCs. Both Wnt/ß-catenin signaling and increased Nf-ĸb could contribute to the rescue of damaged retinal ganglion cells via upregulation of neuroprotective factors, microglial engagement, and anti-inflammatory regulation by NPCs. This study suggests that NPCs could be useful for the cellular treatment of various optic neuropathies, together with cell therapy using mesenchymal stem cells.
Assuntos
Células-Tronco Neurais/transplante , Doenças do Nervo Óptico/terapia , Traumatismos do Nervo Óptico/terapia , Nervo Óptico/crescimento & desenvolvimento , Células-Tronco Pluripotentes/transplante , Animais , Axônios/metabolismo , Axônios/fisiologia , Sobrevivência Celular/genética , Terapia Baseada em Transplante de Células e Tecidos , Modelos Animais de Doenças , Feminino , Humanos , Regeneração Nervosa/genética , Nervo Óptico/patologia , Nervo Óptico/transplante , Doenças do Nervo Óptico/patologia , Gravidez , Ratos , Células Ganglionares da Retina/transplanteRESUMO
Glaucoma is a group of optic neuropathies that leads to irreversible vision loss. The optic nerve head (ONH) is the site of initial optic nerve damage in glaucoma. ONH-derived lamina cribrosa (LC) cells synthesize extracellular matrix (ECM) proteins; however, these cells are adversely affected in glaucoma and cause detrimental changes to the ONH. LC cells respond to mechanical strain by increasing the profibrotic cytokine transforming growth factor-beta 2 (TGFß2) and ECM proteins. Moreover, microRNAs (miRNAs or miR) regulate ECM gene expression in different fibrotic diseases, including glaucoma. A delicate homeostatic balance between profibrotic and anti-fibrotic miRNAs may contribute to the remodeling of ONH. This study aimed to determine whether modulation of miRNAs alters the expression of ECM in human LC cells. Primary human normal and glaucoma LC cells were grown to confluency and treated with or without TGFß2 for 24 h. Differences in expression of miRNAs were analyzed using miRNA qPCR arrays. miRNA PCR arrays showed that the miR-29 family was significantly decreased in glaucomatous LC cell strains compared to age-matched controls. TGFß2 treatment downregulated the expression of multiple miRNAs, including miR-29c-3p, compared to controls in LC cells. LC cells transfected with miR-29c-3p mimics or inhibitors modulated collagen expression.
Assuntos
Regulação da Expressão Gênica , Glaucoma/genética , MicroRNAs/genética , Disco Óptico/metabolismo , Doenças do Nervo Óptico/genética , Fator de Crescimento Transformador beta2/farmacologia , Estudos de Casos e Controles , Perfilação da Expressão Gênica , Glaucoma/tratamento farmacológico , Glaucoma/patologia , Humanos , Disco Óptico/efeitos dos fármacos , Disco Óptico/patologia , Doenças do Nervo Óptico/tratamento farmacológico , Doenças do Nervo Óptico/patologiaRESUMO
RATIONALE: Enlargemento of the medial rectus is the most predominant factor of compressive optic neuropathy (CON) in Graves' disease. This case report indicates that CON could develop only from the hypertrophic superior levator and superior rectus (SL/SR) muscle in a patient with poorly controlled Graves' disease, and described the possible risk of FT3-thyrotoxicosis with a prominent goiter to develop the current rare case with a review of the literature. PATIENT CONCERNS: A 66-year-old woman undergoing endocrine management of hyperthyroidism with prominent goiter visited the Department of Ophthalmology due to right-eye upper-eyelid retraction. DIAGNOSES: At initial presentation, the right and left margin reflex distance-1 (MRD-1) was 3.2âmm and 2.1âmm, respectively, and no proptosis or visual dysfunction was observed. Despite insufficient hormonal regulation, she refused to undergo goiter removal. The upper eyelid retraction gradually worsened to 7.7âmm of MRD-1, followed by the onset of 20 prism diopters (PD) of the right hypertropia, resulting in right-eye CON after 6 months. Her free thyroxin level was 3.88âng/dl and free triiodothyronine was 24.90âpg/ml. Computed tomography and magnetic resonance imaging showed only SL/SR enlargement in the right orbit. INTERVENTIONS: Intravenous steroid and radiation therapy resulted in visual improvement; however, a prominent upper eyelid retraction and 35PD of hypertropia remained in her right eye. Orbital decompression, upper retraction repair, and superior rectus recession were performed to prevent the recurrence of CON and correct any disfigurement. OUTCOMES: The combination of conventional intravenous steroid pulse therapy, radiotherapy, and orbital decompression was effective, and no recurrence was observed for more than 1.5-years postoperatively. LESSONS: Enlargement of the SL/SR muscle complex may independently induce the CON. We believe that strict attention should be paid to patients with triiodothyronine thyrotoxicosis with progressive eyelid retraction and hypertropia.
Assuntos
Doenças Palpebrais/etiologia , Oftalmopatia de Graves/complicações , Doenças do Nervo Óptico/etiologia , Estrabismo/complicações , Idoso , Doenças Palpebrais/cirurgia , Feminino , Bócio/etiologia , Humanos , Músculos Oculomotores/patologia , Músculos Oculomotores/cirurgia , Doenças do Nervo Óptico/diagnóstico por imagem , Doenças do Nervo Óptico/patologia , Doenças do Nervo Óptico/terapia , Estrabismo/cirurgiaRESUMO
We evaluated changes in parafoveal and peripapillary vessel density in chiasmal compression after decompression surgery using optical coherence tomography angiography (OCT-A). Sixty-two eyes with chiasmal compression for which preoperative and postoperative (4-6 months) OCT, OCT-A, visual field (VF), and comprehensive ophthalmic data were available, and 44 healthy eyes were evaluated. Vessel densities of the superficial retinal capillary plexus (SRCP), deep retinal capillary plexus (DRCP), and radial peripapillary capillary (RPC) segment were assessed using OCT-A. The postoperative measurements were compared with preoperative data. Preoperative peripapillary retinal nerve fiber layer, macular ganglion cell-inner plexiform layer thickness, and vessel densities of SRCP and RPC segments in patients' eyes were significantly reduced compared to those of healthy controls (P < 0.0001, P < 0.0001, P = 0.0052, and P = 0.0085, respectively). Vessel densities were significantly decreased in the SRCP (P < 0.0001), DRCP (P = 0.0017), and RPC segments (P < 0.0001) after surgery compared to the preoperative values. Significant associations between the postoperative SRCP and DRCP vessel density changes and preoperative SRCP (r = - 0.3195, P = 0.0114) and DRCP (r = - 0.5165, P < 0.0001) vessel densities were found, respectively. There were also significant associations between postoperative SRCP vessel density changes and VF changes (r = - 0.2586, P = 0.0424). These findings indicate that decreased perfusion around the optic nerve head and on the macula associated with chiasmal compression could further progress after decompression surgery. Further functional and longer-term clinical studies are needed to elucidate the clinical implications of these findings.
Assuntos
Descompressão , Quiasma Óptico/patologia , Doenças do Nervo Óptico/cirurgia , Neoplasias Hipofisárias/complicações , Vasos Retinianos/patologia , Adulto , Idoso , Capilares/patologia , Feminino , Angiofluoresceinografia , Humanos , Masculino , Pessoa de Meia-Idade , Doenças do Nervo Óptico/etiologia , Doenças do Nervo Óptico/patologia , Perfusão , Neoplasias Hipofisárias/patologia , Retina/patologia , Estudos Retrospectivos , Tomografia de Coerência Óptica , Acuidade Visual , Campos Visuais , Adulto JovemRESUMO
INTRODUCTION: The common etiology of central nervous system (CNS) complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT) includes CNS infection, metabolic abnormalities, drug toxicity, cerebrovascular events, Epstein-Barr virus-associated posttransplant lymphoproliferative diseases, and hematologic CNS relapse of leukemia. Although graft-versus-host disease (GVHD) is a major complication of allo-HSCT, its CNS involvement is exceedingly rare. CASE PRESENTATION: In this report, we describe a patient who exhibited acute myeloid leukemia with t(8;21) (q22;q22) and who suddenly lost visual acuity ~1 year after receipt of allo-HSCT. Given the observation of negative cerebrospinal fluid findings, cyclosporine-related encephalopathy, intracranial hemorrhage, CNS infection, leukemia recurrence, and tumors were excluded. He was diagnosed with both CNS and pulmonary GVHD. After steroid treatment, the lesions gradually reduced in images acquired via cranial and pulmonary computed tomography. CONCLUSIONS: CNS-GVHD is a rare, serious complication of allo-HSCT that is difficult to diagnose. Biopsy and autopsy may identify the CNS as the target of GVHD in some patients. Treatment is mainly based on the use of immunosuppressive drugs, including high doses of steroids. Early diagnosis and treatment can improve disease outcome.
Assuntos
Doenças do Sistema Nervoso Central/patologia , Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia Mieloide Aguda/terapia , Pneumopatias/patologia , Doenças do Nervo Óptico/patologia , Acuidade Visual , Doenças do Sistema Nervoso Central/etiologia , Criança , Doença Enxerto-Hospedeiro/etiologia , Humanos , Leucemia Mieloide Aguda/patologia , Pneumopatias/etiologia , Masculino , Doenças do Nervo Óptico/etiologia , PrognósticoRESUMO
Purpose: The lamina cribrosa (LC) is a key site of damage in glaucomatous optic neuropathy. We previously found that glaucoma LC cells have an increased profibrotic gene expression, with mitochondrial dysfunction in the form of decreased mitochondrial membrane potential. Altered cell bioenergetics have recently been reported in organ fibrosis and in cancer. In this study, we carried out a systematic mitochondrial bioenergetic assessment and measured markers of alternative sources of cellular energy in normal and glaucoma LC cells. Methods: LC cells from three glaucoma donors and three age-matched normal controls were assessed using VICTOR X4 Perkin Elmer (Waltham, MA) plate reader with different phosphorescent and luminescent probes. adenosine triphosphate levels, oxygen consumption rate, and extracellular acidification were measured and normalized to total protein content. RNA and protein expression levels of MCT1, MCT4, MTFHD2, and GLS2 were quantified using real-time RT-PCR and Western blotting. Results: Glaucoma LC cells contain significantly less adenosine triphosphate (P < .05) when supplied with either glucose or galactose. They also showed significantly diminished oxygen consumption in both basal and maximal respiration with more lactic acid contribution in ECA. Both mRNA and protein expression levels of MCT1, MCT4, MTHFD2, and GLS2 were significantly increased in glaucoma LC cells. Conclusions: We demonstrate evidence of metabolic reprogramming (The Warburg effect) in glaucoma LC cells. Expression of markers of glycolysis, glutamine, and one carbon metabolism are elevated in glaucoma cells at both the mRNA and protein levels. A better understanding of bioenergetics in glaucoma may help in the development of new therapeutics.
Assuntos
Glaucoma de Ângulo Aberto/metabolismo , Glicólise/fisiologia , Doenças Mitocondriais/metabolismo , Disco Óptico/metabolismo , Doenças do Nervo Óptico/metabolismo , Fosforilação Oxidativa , Trifosfato de Adenosina/metabolismo , Aminoidrolases/genética , Aminoidrolases/metabolismo , Biomarcadores , Western Blotting , Células Cultivadas , Perfilação da Expressão Gênica , Glaucoma de Ângulo Aberto/patologia , Proteína Glial Fibrilar Ácida/metabolismo , Glutaminase/genética , Glutaminase/metabolismo , Humanos , Metilenotetra-Hidrofolato Desidrogenase (NADP)/genética , Metilenotetra-Hidrofolato Desidrogenase (NADP)/metabolismo , Doenças Mitocondriais/patologia , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Enzimas Multifuncionais/genética , Enzimas Multifuncionais/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Disco Óptico/patologia , Doenças do Nervo Óptico/patologia , Consumo de Oxigênio/fisiologia , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Simportadores/genética , Simportadores/metabolismo , Doadores de TecidosRESUMO
Background: While orbital decompression can alleviate optic nerve compression and prevent further vision loss in dysthyroid optic neuropathy (DON), it cannot relieve inflammatory symptoms. Very high doses of intravenous glucocorticoids (GCs) are the first-line therapy for DON; however, the effective rate is only 40% and might be much lower in patients who fail high-dose GC pulse therapy and progressed to DON. The results of two case series studies indicated that rituximab treatment had a much better curative effect compared to very high doses of intravenous GCs, but some patients required urgent orbital decompression after rituximab injection because rituximab might lead to the release of cytokines, aggravated intraorbital edema, and further vision loss. Methods: We retrospectively studied the therapeutic process of two Grave's ophthalmopathy (GO) patients complicated with DON who failed high-dose GC pulse therapy and underwent orbital decompression. Both patients received single-dose (500 mg) rituximab treatment. Results: During more than 2 years of follow-up, rituximab treatment exhibited significant improvement in inflammatory symptoms, as manifested by a substantial decrease in Clinical Activity Score (CAS); meanwhile, the vision of both patients improved significantly and their diplopia was relieved. Conclusions: The results of this study were consistent with those of two previous case series studies indicating the significant and lasting effect of rituximab treatment on DON, especially for patients with GC resistance or recurrence after GC therapy. Orbital decompression before rituximab treatment might reduce the incidence of rapid vision loss and urgent orbital decompression surgery caused by aggravated orbital edema after rituximab injection; however, the necessity for preventive decompression surgery requires further study.
Assuntos
Descompressão Cirúrgica/efeitos adversos , Oftalmopatia de Graves/cirurgia , Inflamação/prevenção & controle , Procedimentos Cirúrgicos Oftalmológicos/efeitos adversos , Doenças do Nervo Óptico/tratamento farmacológico , Rituximab/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Oftalmopatia de Graves/patologia , Humanos , Inflamação/etiologia , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , Doenças do Nervo Óptico/etiologia , Doenças do Nervo Óptico/patologia , Prognóstico , Estudos RetrospectivosRESUMO
Radiation-induced optic neuropathy (RION) is a devastating complication following external beam radiation therapy (EBRT) that leads to acute vision loss. To date, no efficient, available treatment for this complication, due partly to the lack of understanding regarding the developmental processes behind RION. Here, we report radiation caused changes in mitochondrial dynamics by regulating the mitochondrial fission proteins dynamin-related protein 1 (Drp1) and fission-1 (Fis1). Concurrent with an excessive production of reactive oxygen species (ROS), both neuronal injury and visual dysfunction resulted. Further, our findings delineate an important mechanism by which cyclin-dependent kinase 5 (Cdk5)-mediated phosphorylation of Drp1 (Ser616) regulates defects in mitochondrial dynamics associated with neuronal injury in the development of RION. Both the pharmacological inhibition of Cdk5 by roscovitine and the inhibition of Drp1 by mdivi-1 inhibited mitochondrial fission and the production of ROS associated with radiation-induced neuronal loss. Taken together, these findings may have clinical significance in preventing the development of RION.
Assuntos
Quinase 5 Dependente de Ciclina/metabolismo , Dinaminas/metabolismo , Mitocôndrias/efeitos da radiação , Doenças do Nervo Óptico/etiologia , Animais , Apoptose/efeitos da radiação , Quinase 5 Dependente de Ciclina/antagonistas & inibidores , Dinaminas/antagonistas & inibidores , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Mitocôndrias/metabolismo , Dinâmica Mitocondrial/efeitos da radiação , Neurônios/metabolismo , Neurônios/patologia , Neurônios/efeitos da radiação , Doenças do Nervo Óptico/sangue , Doenças do Nervo Óptico/metabolismo , Doenças do Nervo Óptico/patologia , Fosforilação , Quinazolinonas/farmacologia , Lesões Experimentais por Radiação/metabolismo , Radioterapia/efeitos adversos , Ratos , Roscovitina/farmacologiaRESUMO
Glaucoma is a blinding optic neuropathy, the main risk factor for which is increased intraocular pressure (IOP). The trabecular meshwork, located within the iridocorneal angle, is the main pathway for drainage of aqueous humor (AH) out of the eye, and its dysfunction is responsible for the IOP elevation. The trabecular meshwork is a complex, fenestrated, three-dimensional structure composed of trabecular meshwork cells (TMC) interdigitated into a multilayered organization within the extracellular matrix (ECM). The purpose of this literature review is to provide an overview of current understanding of the trabecular meshwork and its pathophysiology in glaucoma. Thus, we will present the main anatomical and cellular bases for the regulation of aqueous humor outflow resistance, the pathophysiological mechanisms involved in trabecular dysfunction in the various types of glaucoma, as well as current and future therapeutic strategies targeting the trabecular meshwork.
Assuntos
Glaucoma/etiologia , Malha Trabecular/química , Malha Trabecular/fisiologia , Glaucoma/patologia , Glaucoma/fisiopatologia , Humanos , Pressão Intraocular/fisiologia , Doenças do Nervo Óptico/patologia , Doenças do Nervo Óptico/fisiopatologia , Malha Trabecular/citologia , Malha Trabecular/patologiaRESUMO
Glaucoma is a blinding optic neuropathy, the main risk factor for which is increased intraocular pressure (IOP). The trabecular meshwork, located within the iridocorneal angle, is the main pathway for drainage of aqueous humor (AH) out of the eye, and its dysfunction is responsible for the IOP elevation. The trabecular meshwork is a complex, fenestrated, three-dimensional structure composed of trabecular meshwork cells (TMC) interdigitated into a multilayered organization within the extracellular matrix (ECM). The purpose of this literature review is to provide an overview of current understanding of the trabecular meshwork and its pathophysiology in glaucoma. Thus, we will present the main anatomical and cellular bases for the regulation of aqueous humor outflow resistance, the pathophysiological mechanisms involved in trabecular dysfunction in the various types of glaucoma, as well as current and future therapeutic strategies targeting the trabecular meshwork.
Assuntos
Glaucoma/etiologia , Malha Trabecular/química , Malha Trabecular/fisiologia , Humor Aquoso/química , Humor Aquoso/fisiologia , Glaucoma/classificação , Glaucoma/fisiopatologia , Glaucoma/cirurgia , Humanos , Pressão Intraocular/fisiologia , Doenças do Nervo Óptico/patologia , Doenças do Nervo Óptico/fisiopatologia , Doenças do Nervo Óptico/cirurgia , Malha Trabecular/patologia , Malha Trabecular/cirurgia , Trabeculectomia/métodosRESUMO
PURPOSE: To examine the effects of SRT2104, an SIRT1 activator, in optic nerve degeneration induced by TNF and to investigate whether it affects the autophagic status after induction of axonal degeneration. STUDY DESIGN: Experimental. METHODS: Adult male Wistar rats received intravitreal injection of TNF alone, concomitant injection of SRT2104 and TNF, or injection of SRT2104 alone. The autophagic status in the optic nerve was evaluated to examine p62 and LC3-II expression by immunoblot analysis. The effect of SRT2104 on TNF-induced axon loss was determined by counting the number of axons. RESULTS: Intravitreal injection of SRT2104 showed a modest protective tendency in the 2-pmol-treated groups against TNF-induced axon loss, although the tendency was not significant on quantitative analysis. However, significant protective effects were found in the 20- or 200-pmol-treated groups. Injection of SRT2104 alone significantly decreased the p62 levels and increased the LC3-II levels as compared with the basal levels. Similarly, concomitant injection of SRT2104 and TNF significantly decreased the p62 levels and increased the LC3-II levels as compared with the TNF-treated group. Upregulation of SIRT1 expression was observed in the optic nerve after SRT2104 treatment. CONCLUSION: The SIRT1 activator SRT2104 exerts axonal protection in TNF-induced optic nerve degeneration. This effect may be associated with upregulated autophagic status in the optic nerve.
Assuntos
Axônios/efeitos dos fármacos , Ativadores de Enzimas/farmacologia , Compostos Heterocíclicos com 2 Anéis/farmacologia , Degeneração Neural/prevenção & controle , Doenças do Nervo Óptico/prevenção & controle , Sirtuína 1/metabolismo , Fator de Necrose Tumoral alfa/toxicidade , Animais , Autofagia/efeitos dos fármacos , Axônios/metabolismo , Axônios/patologia , Immunoblotting , Injeções Intravítreas , Masculino , Degeneração Neural/induzido quimicamente , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Fármacos Neuroprotetores , Doenças do Nervo Óptico/induzido quimicamente , Doenças do Nervo Óptico/metabolismo , Doenças do Nervo Óptico/patologia , Ratos , Ratos Wistar , Regulação para CimaRESUMO
To assess differences between secondary high myopia (SHM) due to congenital glaucoma and primary high myopia (PHM) and non-highly myopic eyes (NHM) in the relationships between axial length and Bruch's membrane (BM) thickness and retinal pigment epithelium (RPE) density. The histomorphometric study included human globes enucleated for reasons such as malignant uveal melanoma, end-stage painful secondary angle-closure glaucoma and congenital glaucoma. BM thickness and RPE cell density were measured upon light microscopy. The investigation included 122 eyes (mean axial length: 26.7 ± 3.7 mm; range: 20.0-37.0 mm): 7 eyes with SHM (axial length: 33.7 ± 2.1 mm; range: 31.0-37.0 mm), 56 eyes with PHM (mean axial length: 29.1 ± 2.4 mm; range: 26.0-36.0 mm) and 59 eyes in the NHM-group (axial length: 23.5 ± 1.3 mm; range: 20.0-25.5 mm). In the SHM group, longer axial length was associated with lower RPE cell density at the posterior pole (standardized regression coefficient beta: 0.92; non- standardized regression coefficient B: -2.76; 95% confidence interval (CI): -4.41, -1.10;P = 0.01), at the midpoint posterior pole/equator (beta: -0.87; B: -3.60; 95% CI: -6.48, -0.73;P = 0.03), and at the equator (beta: -0.88; B: -0.95; 95% CI: -1.68, -0.23; P = 0.02), but not at the ora serrata (P = 0.88). In the PHM-group and NHM group, RPE cell density at the posterior pole (P = 0.08) and ora serrata (P = 0.88) was statistically independent of axial length, while at the midpoint posterior pole/equator (P = 0.01) and equator (P < 0.001), RPE cell density decreased with longer axis. BM thickness in the SHM group decreased with longer axial length at the posterior pole (beta: -0.93;B: -0.29; 95% CI: -0.39, -0.14; P = 0.003), midpoint posterior pole/equator (beta: -0.79; B: -0.22; 95% CI: -0.42, -0.02; P = 0.035) and equator (beta: -0.84; B: -0.21; 95% CI: -0.37, -0.06; P = 0.017), while in the PHM-group and NHM-group, BM thickness at any ocular region was not statistically significantly correlated with axial length (all P > 0.05). In the SHM-group, but not in the PHM-group or NHM-group (P = 0.98), lower BM thickness was associated with lower RPE cell density (beta: 0.93; B: 0.09; 95% CI: 0.04, 0.14; P = 0.007), while in the eyes without congenital glaucoma the relationship was not statistically significant. In SHM in contrast to PHM, BM thickness and RPE cell density decrease in a parallel manner with longer axial length. The findings fit with the notion of BM being a primary driver in the process of axial elongation in PHM as compared to SHM.
Assuntos
Lâmina Basilar da Corioide/patologia , Miopia Degenerativa/patologia , Epitélio Pigmentado da Retina/patologia , Comprimento Axial do Olho/patologia , Emetropia/fisiologia , Enucleação Ocular , Feminino , Glaucoma/patologia , Glaucoma de Ângulo Fechado/patologia , Humanos , Masculino , Miopia/patologia , Disco Óptico/patologia , Doenças do Nervo Óptico/patologia , Retina/patologia , Esclera/patologiaRESUMO
A 19-year-old man presented with a 3-year history of episodic headaches, right hemiparesis, and progressive vision loss in both eyes. Initially, extensive laboratory testing was unrevealing. MRI later demonstrated progressive enlargement and enhancement of the left optic nerve poorly correlated with the timing of his clinical manifestations. There was no clinical or radiological response to treatment with corticosteroids, mycophenolate mofetil, or rituximab administered empirically for possible inflammatory processes. Later in the disease course, he developed diabetes insipidus (DI), worsening vision to light perception bilaterally, severe cognitive decline, and spastic quadriparesis. Cerebrospinal fluid (CSF) beta human chorionic gonadotropin (ß-hCG) was elevated. Eventually, a left optic nerve biopsy was performed, which was consistent with an intracranial pure germinoma with infiltration of the optic nerve and disseminated leptomeningeal disease. Although rare, intracranial germ cell tumors can primarily involve the anterior visual pathways and should be considered in the setting of DI and elevated CSF ß-hCG.