glaucoma

摘要： Glaucoma is a multifactorial disease and occurs in many different species.In humans,glaucoma is accounted one of the leading causes for blindness worldwide.Due to glaucoma's complexity,it is still unclear what pathomechanisms may be involved in its development in humans as well as in other species,such as canines.Diagnosis of glaucoma can be delayed because patients often do not notice a visual field loss until approximately30%of retinal ganglion cells(RGCs)are lost(Kerrigan-Baumrind et al.,2000).Although the exact undergoing pathomechanisms of glaucoma disease are not fully understood yet,an increased intraocular pressure(IOP)is related to RGCdeath and is considered the main risk factor.

摘要： Glaucoma and visual pathway degeneration:Glaucoma is the leading cause of irreversible blindness worldwide,which leads to a progressive loss of vision.Glaucoma can be classified into two types:primary open-angle glaucoma and primary closed-angle glaucoma.Primary open-angle glaucoma can be caused by the blockage of the trabecular meshwork,and this results in elevation of the intraocular pressure(IOP),leading to retinal ganglion cell(RGC)death.However,many glaucoma patients have normal IOP;this is known as normal-tension glaucoma.Nevertheless,excitotoxic damage and oxidative stress can also lead to RGC damage in normal-tension glaucoma(Almasieh et al.,2012).Glaucomatous genes such as TIGR,OPTN,and CYP1B1 have been suggested to contribute to the pathogenesis of glaucoma.However,some glaucomatous patients may remain asymptomatic in the early,moderate,and late stages.Another type of glaucoma is primary closed-angle glaucoma.In this clinical condition,a relative pupillary block is contributed by the iris obstructing aqueous outflow.The patients may suffer from corneal swelling,headache,nausea,and blurred vision during the acute phase.

摘要： Vision is an ability that depends on the precise structure and functioning of the retina.Any kind of stress or injury can disrupt the retinal architecture and leads to vision impairment,vision loss,and blindness.Immune system and immune response function maintain homeostasis in the microenvironment.Several genetic,metabolic,and environmental factors may alter retinal homeostasis,and these events may initiate various inflammatory cascades.The prolonged inflammatory state may contribute to the initiation and development of retinal disorders such as glaucoma,age-related macular degeneration,diabetic retinopathy,and retinitis pigmentosa,which pose a threat to vision.In the current review,we attempted to provide sufficient evidence on the role of inflammation in these retinal disorders.Moreover,this review paves the way to focus on therapeutic targets of the disease,which are found to be promising.

摘要： Sphingosine-1-phosphate receptor(S1PR)signaling regulates diverse pathophysiological processes in the central nervous system.The role of S1PR signaling in neurodegenerative conditions is still largely unidentified.Siponimod is a specific modulator of S1P1 and S1P5 receptors,an immunosuppressant drug for managing secondary progressive multiple sclerosis.We investigated its neuroprotective properties in vivo on the retina and the brain in an optic nerve injury model induced by a chronic increase in intraocular pressure or acute N-methyl-D-aspartate excitotoxicity.Neuronal-specific deletion of sphingosine-1-phosphate receptor(S1PR1)was carried out by expressing AAV-PHP.eB-Cre recombinase under Syn1 promoter in S1PR1mice to define the role of S1PR1 in neurons.Inner retinal electrophysiological responses,along with histological and immunofluorescence analysis of the retina and optic nerve tissues,indicated significant neuroprotective effects of siponimod when administered orally via diet in chronic and acute optic nerve injury models.Further,siponimod treatment showed significant protection against trans-neuronal degenerative changes in the higher visual center of the brain induced by optic nerve injury.Siponimod treatment also reduced microglial activation and reactive gliosis along the visual pathway.Our results showed that siponimod markedly upregulated neuroprotective Akt and Erk1/2 activation in the retina and the brain.Neuronal-specific deletion of S1PR1 enhanced retinal and dorsolateral geniculate nucleus degenerative changes in a chronic optic nerve injury condition and attenuated protective effects of siponimod.In summary,our data demonstrated that S1PR1signaling plays a vital role in the retinal ganglion cell and dorsolateral geniculate nucleus neuronal survival in experimental glaucoma,and siponimod exerts direct neuroprotective effects through S1PR1 in neurons in the central nervous system independent of its peripheral immuno-modulatory effects.Our findings suggest that neuronal S1PR1 is a neuroprotective therapeutic target and its modulation by siponimod has positive implications in glaucoma conditions.

摘要： Neurosteroids are rapidly emerging as important new therapies in neuropsychiatry, with one such agent, brexanolone, already approved for treatment of postpartum depression, and others on the horizon. These steroids have unique properties, including neuroprotective effects that could benefit a wide range of brain illnesses including depression, anxiety, epilepsy, and neurodegeneration. Over the past 25 years, our group has developed ex vivo rodent models to examine factors contributing to several forms of neurodegeneration in the retina. In the course of this work, we have developed a model of acute closed angle glaucoma that involves incubation of ex vivo retinas under hyperbaric conditions and results in neuronal and axonal changes that mimic glaucoma. We have used this model to determine neuroprotective mechanisms that could have therapeutic implications. In particular, we have focused on the role of both endogenous and exogenous neurosteroids in modulating the effects of acute high pressure. Endogenous allopregnanolone, a major stress-activated neurosteroid in the brain and retina, helps to prevent severe pressure-induced retinal excitotoxicity but is unable to protect against degenerative changes in ganglion cells and their axons under hyperbaric conditions. However, exogenous allopregnanolone, at a pharmacological concentration, completely preserves retinal structure and does so by combined effects on gamma-aminobutyric acid type A receptors and stimulation of the cellular process of macroautophagy. Surprisingly, the enantiomer of allopregnanolone, which is inactive at gamma-aminobutyric acid type A receptors, is equally retinoprotective and acts primarily via autophagy. Both enantiomers are also equally effective in preserving retinal structure and function in an in vivo glaucoma model. These studies in the retina have important implications for the ongoing development of allopregnanolone and other neurosteroids as therapeutics for neuropsychiatric illnesses.

摘要： Neurodegeneration of the central nervous system(CNS)underscores many of humanity’s most debilitating diseases,including Alzheimer’s disease,Parkinson’s disease,and multiple sclerosis.Recently,the nitric oxide-guanylate cyclase-cyclic guanosine monophosphate(NO-GC-cGMP)signaling pathway has gained traction as a neuroprotective pathway in the CNS.As an extension of the CNS,the retina is also susceptible to neurodegeneration with age.The most prevalent optic neuropathy is glaucoma,the world’s leading cause of irreversible blindness,predicted to affect more than 112 million people worldwide by 2040(Calkins,2021).In glaucoma,vision loss occurs due to the progressive degeneration of retinal ganglion cells(RGCs),the output neurons of the retina,along with their axons which form the optic nerve(Wareham et al.,2022).Degeneration of RGCs leads to a characteristic pattern of scotopic visual field deficiencies that spread from one retinotopic sector to the next(Elze et al.,2015).Visual deficits are linked to increasing age and the sensitivity of RGCs to intraocular pressure(Calkins,2021).

摘要： Retinal ganglion cells(RGCs)are the sole output neurons of the retina that project long axons and transmit visual information to the brain.The degeneration of RGCs leads to irreversible vision loss in a variety of pathological states,including excitotoxicity,traum atic nerve injury,and glaucoma.

摘要： Astrocyte polarization is a new concept which is similar to microglia polarization and in which astrocytes are classified as A1(neurotoxic)and A2(neuroprotective).Several studies on astrocyte polarization have focused mainly on neurodegenerative diseases,trauma,and infections.However,the role of astrocyte polarization in glaucoma,a neurodegenerative disease,has not been fully explored.In this review,we first describe the characteristics of astrocyte astrogliosis in glaucoma,including morphological,molecular,proliferative and functional changes.We then summarize understanding of astrocyte polarization in other diseases,and show that A1 astrocytes are involved in the death of retinal ganglion cells in glaucoma,and that their neurotoxins kill only damaged retinal ganglion cells.Based on this,we propose new interesting conjecture on astrocyte polarization in glaucoma:(1)That the neurotoxin from A1 astrocytes is a product of the complement system(membrane-attacking complex),since this system is known to mediate synaptic elimination and the C3 expression is clearly increased in A1 astrocytes;(2)that reactive scar-forming astrocytes in the optic nerve head may be classified as A2 astrocytes since their ablation leads to a worse prognosis in glaucoma.Finally,current therapeutic research progress on astrocyte polarization in other diseases is also addressed.Regulation of astrocyte polarization can be achieved by extracellular microglia-related and intracellular pathways.Reduced A1 or increased A2 astrocytes can rescue the nerve.For example,glucagon-like peptide-1 receptor agonist rescues retinal ganglion cells by reducing A1 astrocytes via the extracellular microglia-related pathway in an ocular hypertension model,suggesting that regulation of astrocyte polarization as a therapeutic target in glaucoma is feasible.

摘要： Glaucoma is a neurodegenerative disease in which optic nerve damage and visual field defects occur.It is a leading cause of irreversible blindness.Its pathogenesis is largely unknown although several risk factors have been identified,with an increase in intraocular pressure being the main one.Lowering of intraocular pressure is the only treatment available.Open-angle glaucoma is the most common form of the condition,accounting for~90%of all cases of glaucoma,with primary open-angle glaucoma and exfoliation glaucoma being the most frequent types.There are strong indications that microRNAs play important roles in the pathogenesis of primary open-angle glaucoma.Most of the recent studies reviewed had performed microRNA profiling in aqueous humor from glaucoma patients compared to controls who were chiefly cataract patients.A very large number of microRNAs were dysregulated but with limited overlap between individual studies.MiRNAs in aqueous humor that could be possible targets for therapeutic intervention are miR-143-3p,miR-125b-5p,and miR-1260b.No ove rlap of findings occurred within the dysregulated miRNAs for blood plasma,blood serum,peripheral blood mononuclear cells,and tears of primary open-angle glaucoma patients.Seve ral impo rtant limitations were identified in these studies.Further studies are warranted of mic roRNA expression in aqueous humor and blood samples of primary open-angle glaucoma patients in the early stages of the disease so that validated biomarkers can be identified and treatment initiated.In addition,whether modifying the levels of specific microRNAs in aqueous humor or tears has a beneficial effect on intraocular pressure and ophthalmic examination of the eyes should be investigated using suitable animal models of glaucoma.

摘要： Clinically,glaucoma patients often suffer from circadian rhythm(CR)disorder.It is well-known that the imbalance of CR can be one of the triggering mechanisms of glaucoma.However,as a disease involving neurodegeneration and mood dysregulation,glaucoma is more of a pathological process than a disease.Glaucoma pathogenesis exists throughout the whole process of life rhythm disorder,and its complex impact on CR deserves more attention.Glaucoma can cause CR disorder through a variety of mechanisms,while long-term CR disorder can lead to sleep disorder,depression,anxiety,metabolic syndrome and other related diseases,which in turn aggravate the process of glaucoma,forming a vicious cycle.Overall,glaucoma can affect the stability of CR not only by altering the optical signal reception,non-image-forming visual system,related hormone secretion and nerve damage,but also through mental disorders such as depression and anxiety.In this paper,we review the mechanism of glaucoma affecting CR in order to provide research ideas and therapeutic insights for glaucomatous CR disorder.