Neuroinflammation and oxidative stress act in concert to promote neurodegeneration in the diabetic retina and optic nerve:galectin-3 participation

Diabetes is a lifelong disease characterized by glucose metabolic imbalance,in which low insulin levels or impaired insulin signaling lead to hyperglycemic state.Within 20 years of diabetes progression,95%of patients will have diabetic retinopathy,the leading cause of visual defects in working-age people worldwide.Although diabetes is considered a microvascular disease,recent studies have shown that neurodegeneration precedes vascular changes within the diabetic visual system,albeit its mechanisms are still under investigation.Neuroinflammation and oxidative stress are intrinsically related phenomena,since macrophage/microglia and astrocytes are the main sources of reactive oxygen species during central nervous system chronic degenerative diseases,and both pathological processes are increased in the visual system during diabetes.The present review will focus on recent findings of the contribution of oxidative stress derived from neuroinflammation in the early neurodegenerative aspects of the diabetic visual system and their relationship with galectin-3.

Effect of long-term weightlessness on retina and optic nerve in tail-suspension rats

AIM： To evaluate the effect of long weightlessness on retina and optic nerve in suspension （TS） rats. -term tail METHODS： A stimulated weightlessness model was established by suspending rats tail. After 12wk, the ultrastructure and the number of optic nerve axons were observed by transmission electron microscope. The number of survival retinal ganglion cells （RGCs） was calculated by fluorescent gold retrograde labeling. Retina cells apoptosis was detected by TUNEL staining. The function of optic nerve and retina was evaluated by the visual evoked potential （VEP） and oscillatory potentials （Ops）. RESULTS： The optic nerve axons were swollen and sparsely aligned, and the lamellar separation and myelin disintegration occurred after 12wk in TS rats. The density of optic nerve axons was 32.23±3.92 （ ys 37.43±4.13, P= 0.0145）, the RGCs density was 1645 ±46 cells/mm^2 （vs 1867±54 cells/mm^2 F=0.0000）, the incidence rate of retinal cells apoptosis was 5.38%±0.53% （ vs 4.75%±0.54%, P= 0.0238）, the amplitude of VEP-P100 was 15.43±2.14 μV （vs 17.67±2.17 μV, P=0.0424）, the latency of VEP-P100 was 69.05v5.34ms （vs 62.43±4.87ms P=0.0143） and the sum amplitude of Ops was 81.05±8.34 μV （Ys 91.67± 10.21 μV, P=0.0280） in TS group and the control group, respectively. CONCLUSION： Long-term weightlessness can induce the ultrastructural changes and functional depress of the optic nerve, as well as retinal cell damages in TS rats.

Taurine protects against retinal and optic nerve damage induced by endothelin-1 in rats via antioxidant effects

Endothelin-1（ET-1）, a potent vasoconstrictor, is involved in retinal vascular dysregulation and oxidative stress in glaucomatous eyes. Taurine（TAU）, a naturally occurring free amino acid, is known for its neuroprotective and antioxidant properties. Hence, we evaluated its neuroprotective properties against ET-1 induced retinal and optic nerve damage. ET-1 was administered intravitreally to Sprague-Dawley rats and TAU was injected as pre-, co-or post-treatment. Animals were euthanized seven days post TAU injection. Retinae and optic nerve were examined for morphology, and were also processed for caspase-3 immunostaining. Retinal redox status was estimated by measuring retinal superoxide dismutase, catalase, glutathione, and malondialdehyde levels using enzyme-linked immuosorbent assay. Histopathological examination showed significantly improved retinal and optic nerve morphology in TAU-treated groups. Morphometric examination showed that TAU pre-treatment provided marked protection against ET-1 induced damage to retina and optic nerve. In accordance with the morphological observations, immunostaining for caspase showed a significantly lesser number of apoptotic retinal cells in the TAU pre-treatment group. The retinal oxidative stress was reduced in all TAU-treated groups, and particularly in the pre-treatment group. The findings suggest that treatment with TAU, particularly pre-treatment, prevents apoptosis of retinal cells induced by ET-1 and hence prevents the changes in the morphology of retina and optic nerve. The protective effect of TAU against ET-1 induced retinal and optic nerve damage is associated with reduced retinal oxidative stress.

Pathological changes in the retina and growth associated protein-43 expression following treatment of intracanalicular optic nerve injury via optic canal decompression,dexamethasone or their combination

BACKGROUND： The main clinical treatments for optic nerve injury are optic canal decompression and systemic administration of hormones, but both treatments have disadvantages. OBJECTIVE： To observe the pathological changes in the retina and growth associated protein-43 （GAP-43） expression, to compare the treatment of optic canal decompression, hormones, and their combination with the intracanalicular optic nerve injury.DESIGN, TIME AND SETTING： A randomized, controlled animal study was performed at the Department of Anatomy, Weifang Medical University, China, from September 2007 to November 2008.MATERIALS： Dexamethasone （Shandong Huaxin Pharmaceutical, China） and rabbit anti-GAP-43 polyclonal antibody （Boster, China） were used.METHODS： All 36 healthy adult rabbits were randomly assigned to control group （n = 4）, simple injury group （n = 20）, and treatment group （n = 12）. Intracanalicular optic nerve injury models were established using the metal cylinder free-fall impact method. The control group was left intact. The treatment group （four rabbits in each subgroup） was treated by optic nerve decompression, dexamethasone treatment （1 mg/kg daily via two intravenous infusions, 1/5 total dose reduction every 3 days, for 14 days）, and simultaneously giving surgery and hormone treatment.MAIN OUTCOME MEASURES： Pathological changes in the retina were determined using hematoxylin-eosin staining. GAP-43 expression was detected using immunohistochemistry in the retina.RESULTS： Retina injury induced obvious pathological changes in the retina. With prolonged time after optic nerve injury, the number of retinal ganglion cells was gradually decreased, and reached the minimum on day 14 （P〈0.01）. All three treatments increased the number of retinal ganglion cells （P〈0.01）, but surgery ＋ hormone treatment was most effective. No GAP-43 cells were present in the normal retinal, but they appeared 3 days after injury, peaked 7 days after injury, and then began to decline.CONCLUSION： Intracanalicular optic nerve injury induced obvious pathological changes in the retina, including increased GAP-43 expression. Optic canal decompression and hormones improved nerve repair after injury, and their combination produced better outcomes.

Phosphorylated S6K1 and 4E-BP1 play different roles in constitutively active Rheb-mediated retinal ganglion cell survival and axon regeneration after optic nerve injury

Ras homolog enriched in brain(Rheb) is a small GTPase that activates mammalian target of rapamycin complex 1(mTORC1).Previous studies have shown that constitutively active Rheb can enhance the regeneration of sensory axons after spinal cord injury by activating downstream effectors of mTOR.S6K1 and4E-BP1 are important downstream effectors of mTORC1.In this study,we investigated the role of Rheb/mTOR and its downstream effectors S6K1 and 4E-BP1in the protection of retinal ganglion cells.We transfected an optic nerve crush mouse model with adeno-associated viral 2-mediated constitutively active Rheb and observed the effects on retinal ganglion cell survival and axon regeneration.We found that overexpression of constitutively active Rheb promoted survival of retinal ganglion cells in the acute(14 days) and chronic(21 and 42 days) stages of injury.We also found that either co-expression of the dominant-negative S6K1mutant or the constitutively active 4E-BP1 mutant together with constitutively active Rheb markedly inhibited axon regeneration of retinal ganglion cells.This suggests that mTORC1-mediated S6K1 activation and 4E-BP1 inhibition were necessary components for constitutively active Rheb-induced axon regeneration.However,only S6K1 activation,but not 4E-BP1 knockdown,induced axon regeneration when applied alone.Furthermore,S6K1 activation promoted the survival of retinal ganglion cells at 14 days post-injury,whereas 4E-BP1 knockdown unexpectedly slightly decreased the survival of retinal ganglion cells at 14 days postinjury.Ove rexpression of constitutively active 4E-BP1 increased the survival of retinal ganglion cells at 14 days post-injury.Likewise,co-expressing constitutively active Rheb and constitutively active 4E-BP1 markedly increased the survival of retinal ganglion cells compared with overexpression of constitutively active Rheb alone at 14 days post-injury.These findings indicate that functional 4E-BP1 and S6K1 are neuroprotective and that 4E-BP1 may exert protective effects through a pathway at least partially independent of Rhe b/mTOR.Together,our results show that constitutively active Rheb promotes the survival of retinal ganglion cells and axon regeneration through modulating S6K1 and 4E-BP1 activity.Phosphorylated S6K1 and 4E-BP1 promote axon regeneration but play an antagonistic role in the survival of retinal ganglion cells.

Beneficial effects of vincamine with thioctic acid and lutein on retinal and optic nerve functions in an opaque media

AIM: To detect whether the combination of vincamine, thioctic acid and lutein will improve the retina and optic nerve functions in cases of an opaque media with an optic nerve and/or a retinal defect or not.METHODS: Totally 2000 patients(2000 eyes) of corneal opacities with defects in the optic nerve or/and the retinal functions were studied. Every patient received three types of drugs: thioctic acid with cyanocobalamine, vincamine, and lutein. The drugs were given daily for 3-12 mo according to patient’s responses. Full field flash electroretinogram(ERG) and flash visual evoked potential(VEP) were done before treatment and at 1, 3, 6, and 12 mo sequentially. Patients were followed up for 12 mo.RESULTS: In the 2000 eyes, 1000 eyes had both moderate optic nerve and retinal function defects;and 840 eyes out of the 1000 improved with the medical treatment. Another 500 eyes out of the 2000 eyes had extinguished retinal function with normal optic nerve function and only 125 eyes of them improved. The 290 out of the 2000 eyes had severe defects in optic nerve with normal retinal function and 130 of them improved. Another 210 eyes have mild optic nerve and retinal function defects and 194 improved.CONCLUSION: The combination of vincamine, thioctic acid with cyanocobalamine, and lutein improved both retina and optic nerve functions mainly in mild and moderate defect than in severe cases.

Dose-dependent effects of NMDA on retinal and optic nerve morphology in rats

AIM: To investigate dose-dependent effects of N-methylD-aspartate(NMDA) on retinal and optic nerve morphology in rats.METHODS: Sprague Dawley rats, 180-250 g in weight were divided into four groups. Groups 1, 2, 3 and 4 were intravitreally administered with vehicle and NMDA at the doses 80, 160 and 320 nmol respectively. Seven days after injection, rats were euthanized, and their eyes were taken for optic nerve toluidine blue and retinal hematoxylin and eosin stainings. The TUNEL assay was done for detecting apoptotic cells.RESULTS: All groups treated with NMDA showed significantly reduced ganglion cell layer(GCL) thickness within inner retina, as compared to control group. Group NMDA 160 nmol showed a significantly greater GCL thickness than the group NMDA 320 nmol. Administration of NMDA also resulted in a dose-dependent decrease in the number of nuclei both per 100 μm GCL length and per 100 μm2 of GCL. Intravitreal NMDA injection caused dosedependent damage to the optic nerve. The degeneration of nerve fibres with increased clearing of cytoplasm was observed more prominently as the NMDA dose increased. In accordance with the results of retinal morphometry analysis and optic nerve grading, TUNEL staining demonstrated NMDA-induced excitotoxic retinal injury in a dose-dependent manner.CONCLUSION: Our results demonstrate dose-dependent effects of NMDA on retinal and optic nerve morphology in rats that may be attributed to differences in the severity of excitotoxicity and oxidative stress. Our results also suggest that care should be taken while making dose selections experimentally so that the choice might best uphold study objectives.

Protective Effect of Paeoniflorin against Optic Nerve Crush

In order to evaluate the efficacy of traditional paeonia extract paeoniflorin against optic nerve crush, 16 Brown Norway rats were divided into two groups at random, with 8 rats in each group. In paeoniaflorin-treated group, 2 mg paeoniaflorin （total volum： 1 mL） was injected into rat＇s peritoneum one time a day for a period of 8 days. Rats in untreated group were given a single dose of vehicle. The optic nerve was crushed by a special forceps for 30 s in the left eye and a sham procedure was performed in the right eye on the 2nd day after the first injection. The retrograde fluorogold labeling of ganglion cells was conducted 5 days after optic nerve crush. The whole retina was flat-mounted thereafter. The ganglion cells that survived the crush were counted under fluorescent microscope by using an automatic counting software. As compared with the contralateral eye, the survival rate of ganglion cells in the left eye increased from 40.22% to 64.53% with a significant difference found between them （t=2.55, P=0.023）. The results suggested that the paeonia extract paeoniflorin possessed a protective effect against optic nerve crush.

Optic nerve injury-induced regeneration in the adult zebrafish is accompanied by spatiotemporal changes in mitochondrial dynamics

Axonal regeneration in the central nervous system is an energy-intensive process.In contrast to mammals,adult zebrafish can functionally recover from neuronal injury.This raises the question of how zebrafish can cope with this high energy demand.We previously showed that in adult zebrafish,subjected to an optic nerve crush,an antagonistic axon-dendrite interplay exists wherein the retraction of retinal ganglion cell dendrites is a prerequisite for effective axonal repair.We postulate a‘dendrites for regeneration’paradigm that might be linked to intraneuronal mitochondrial reshuffling,as ganglion cells likely have insufficient resources to maintain dendrites and restore axons simultaneously.Here,we characterized both mitochondrial distribution and mitochondrial dynamics within the different ganglion cell compartments(dendrites,somas,and axons)during the regenerative process.Optic nerve crush resulted in a reduction of mitochondria in the dendrites during dendritic retraction,whereafter enlarged mitochondria appeared in the optic nerve/tract during axonal regrowth.Upon dendritic regrowth in the retina,mitochondrial density inside the retinal dendrites returned to baseline levels.Moreover,a transient increase in mitochondrial fission and biogenesis was observed in retinal ganglion cell somas after optic nerve damage.Taken together,these findings suggest that during optic nerve injury-induced regeneration,mitochondria shift from the dendrites to the axons and back again and that temporary changes in mitochondrial dynamics support axonal and dendritic regrowth after optic nerve crush.

Retinal thickness and vascular parameters using optical coherence tomography in Alzheimer's disease:a meta-analysis

Examining the retinal tissue has the potential to provide a unique method and technique to quantify Alzheimer’s disease-related changes in participants at various stages of the disease.In this metaanalysis,we aimed to investigate the association of various optical coherence tomography parameters with Alzheimer’s disease and whether retinal measurements can be used to diffe rentiate between Alzheimer’s disease and control subjects.Scientific databases including Google Schola r,Web of Science,and PubMed were systematically searched for published articles that evaluated retinal nerve fiber layer thickness and retinal microvascular network in Alzheimer’s disease and control subjects.Seventy-three studies(5850 participants,including 2249 Alzheimer’s disease patients and 3601controls) were included in this meta-analysis.Relative to controls,Alzheimer’s disease patients had a significantly lower global retinal nerve fiber layer thickness(standardized mean difference [SMD]=-0.79,95% confidence intervals [CI]:-1.03 to-0.54,P <0.00001) as well as each quadrant being thinner in Alzheimer’s disease versus controls.Regarding macular paramete rs,values measured by optical coherence tomography were significantly lower in Alzheimer’s disease than controls for macular thickness(pooled SMD:-0.44,95% CI:-0.67 to-0.20,P=0.0003),foveal thickness(pooled SMD=-0.39,95% CI:-0.58 to-0.19,P <0.0001),ganglion cell inner plexiform layer(SMD=-1.26,95% CI:-2.24 to-0.27,P=0.01) and macular volume(pooled SMD=-0.41,95% CI-0.76 to-0.07,P=0.02).Analysis using optical coherence tomography angiography parameters revealed mixed results between Alzheimer’s disease and controls.Superficial vessel density(pooled SMD=-0.42,95% CI:-0.68 to-0.17,P=0.0001) and deep vessel density(pooled SMD=-0.46,95% CI:-0.75 to-0.18,P=0.001) were found to be thinner in Alzheimer’s disease patients whereas the foveal avascular zone(SMD=0.84,95% CI:0.17-1.51,P=0.01) was larger in controls.Vascular density and thickness of various retinal laye rs were decreased in Alzheimer’s disease patients compared to controls.Our results provide evidence for optical coherence tomography technology having the potential to detect retinal and microvascular changes in patients diagnosed with Alzheimer’s disease and aid in monito ring and early diagnosis methods.

Expression of SoxC Transcription Factors during Zebrafish Retinal and Optic Nerve Regeneration

The SoxC transcription factors （Sox4, Sox11, and Sox12） play important roles in the development of the vertebrate eye and retina. However, their expression and function during retinal and optic nerve regeneration remain elusive. In this study, we investigated the expression and possible functions of the SoxC genes after retinal and optic nerve injury in adult zebrafish. We found that among the five SoxC members, Soxllb was strongly induced in BrdU-positive cells in the inner nuclear layer （INL） after retinal injury, and morpholino-mediated Soxllb-knockdown significantly reduced the number of proliferating cells in the INL at 4 days post-injury. After optic nerve lesion, both Soxl la and Soxl lb were strongly expressed in retinal ganglion cells （RGCs）, and knockdown of both Soxl la and Soxllb inhibited RGC axon regrowth in retinal explants. Our study thus uncovered a novel expression pattern of SoxC family genes after retinal and optic nerve injury, and suggests that they have important functions during retinal and optic nerve regeneration.

Damage patterns of retinal nerve fiber layer in acute and chronic intraocular pressure elevation in primary angle closure glaucoma

AIMTo observe the differences of damage patterns of retinal nerve fiber layer (RNFL) between acute and chronic intraocular pressure (IOP) elevation in primary angle closure glaucoma (PACG) using optical coherence tomography (OCT).

Cell transplantation to replace retinal ganglion cells faces challenges-the Switchboard Dilemma

The mammalian retina displays incomplete intrinsic regenerative capacities;therefore,retina degeneration is a major cause of irreversible blindness such as glaucoma,agerelated macular degeneration and diabetic retinopathy.These diseases lead to the loss of retinal cells and serious vision loss in the late stage.Stem cell transplantation is a great promising novel treatment for these incurable retinal degenerative diseases and represents an exciting area of regenerative neurotherapy.Several suitable stem cell sources for transplantation including human embryonic stem cells,induced pluripotent stem cells and adult stem cells have been identified as promising target populations.However,the retina is an elegant neuronal complex composed of various types of cells with different functions.The replacement of these different types of cells by transplantation should be addressed separately.So far,retinal pigment epithelium transplantation has achieved the most advanced stage of clinical trials,while transplantation of retinal neurons such as retinal ganglion cells and photoreceptors has been mostly studied in pre-clinical animal models.In this review,we opine on the key problems that need to be addressed before stem cells transplantation,especially for replacing injured retinal ganglion cells,may be used practically for treatment.A key problem we have called the Switchboard Dilemma is a major block to have functional retinal ganglion cell replacement.We use the public switchboard telephone network as an example to illustrate different difficulties for replacing damaged components in the retina that allow for visual signaling.Retinal ganglion cell transplantation is confronted by significant hurdles,because retinal ganglion cells receive signals from different interneurons,integrate and send signals to the correct targets of the visual system,which functions similar to the switchboard in a telephone network-therefore the Switchboard Dilemma.

In vivo detection of severity of optic nerve crush using manganese-enhanced magnetic resonance imaging in rats

Background Traumatic optic neuropathy （TON） is one of the reasons for permanent vision loss.Currently,the clinical practices may not be sufficient for direct assessments and comprehensively determining the location and extent of the patients with optic nerve injury in traumatic optic neuropathy.Magnetic resonance imaging （MRI） provides a non-invasive option.However,rare reports have found whether the differentdegree of injury of the optic nerve can be detected by manganese-enhanced MRI （MEMRI）.This study aimed to explore the efficacy of MEMRI in the visual pathway for different severity of opitic nerve injury in rats.Methods The different injuries of mild,moderate,and heavy damages were created by modified reverse tweezer and were evaluated by counting retinal ganglion cells （RGCs） and VEP ananlysis.Sprague-Dawley （SD） rats were intravitreally injected with 2 I of 25 mmol/L MnCl2,which has been confirmed as a safe injection concentration.The contrast-to-noise ratio （CNR） of MEMRI for optic nerve enhancement at different injury levels was measured.Results The location of the significantly decreased signal point on optic nerve （ON） was corresponding to the location we made.However,similar findings are not obvious,or even have not been observed in 28 days in each group and also in 14 days at F100 group,indicating that MEMRI could be directly intuitive positioned in the early stage on the optic nerve injury.Conclusions The possibility of using MEMRI in optic nerve injury in a safe injection concentration of 25 mmol/L is confirmed.Therefore,it is possible to detect the severity of the optic nerve by MEMRI examination.

Optic disc area in different types of glaucoma

AIMTo evaluate the possible relationship of optic disc area with retina nerve fiber layer in different glaucoma subtypes.METHODSOne eye each was chosen from 45 patients with ocular hypertension, 45 patients with primary open angle glaucoma, 45 patients with pseudoexfoliation glaucoma and 45 healthy controls followed in our hospital. The records of the patients were reviewed retrospectively. Optic disc area and circumpapillary retina nerve fiber layer measurements were obtained using optical coherence tomography. Central corneal thickness was measured by ultrasound pachymetry.RESULTSThe median disc area in the patients with primary open angle glaucoma was significantly higher than the patients with ocular hypertension (2.19 vs 1.90 mm2, P=0.030). The median retina nerve fiber layer was thinner in the patients with primary open angle glaucoma and pseudoexfoliation glaucoma than the patients with ocular hypertension for superior, inferior and temporal quadrants. After adjustment for age, no difference in central corneal thickness was found between the groups. Greater disc area was associated with thicker retinal nerve fiber layer for superior, inferior and nasal quadrants in the patients with primary open angle glaucoma. There was no correlation between disc area and central corneal thickness measurements of the groups.CONCLUSIONDisc size affects the retinal nerve fiber layer thickness in eyes with primary open angle glaucoma and is a possible risk factor for glaucomatous optic nerve damage.

Molecular mechanisms of the suppression of axon regeneration by KLF transcription factors

Molecular mechanisms of the Kruppel-like family of transcription factors （KLFs） have been studied more in proliferating cells than in post-mitotic cells such as neurons. We recently found that KLFs regulate intrinsic axon growth ability in central nervous system （CNS） neurons in- cluding retinal ganglion cells, and hippocampal and cortical neurons. With at least 15 of 17 KLF family members expressed in neurons and at least 5 structurally unique subfamilies, it is import- ant to determine how this complex family functions in neurons to regulate the intricate genetic programs of axon growth and regeneration. By characterizing the molecular mechanisms of the KLF family in the nervous system, including binding partners and gene targets, and comparing them to defined mechanisms defined outside the nervous system, we may better understand how KLFs regulate neurite growth and axon regeneration.

Mechanisms implicated in the contralateral effect in the central nervous system after unilateral injury:focus on the visual system

The retina,as part of the central nervous system is an ideal model to study the response of neurons to injury and disease and to test new treatments.During the last decade is becoming clear that unilateral lesions in bilateral areas of the central nervous system trigger an inflammatory response in the contralateral uninjured site.This effect has been better studied in the visual system where,as a rule,one retina is used as experimental and the other as control.Contralateral retinas in unilateral models of retinal injury show neuronal degeneration and glial activation.The mechanisms by which this adverse response in the central nervous system occurs are discussed in this review,focusing primarily on the visual system.

Ocular manifestations of central insulin resistance

Central insulin resistance, the diminished cellular sensitivity to insulin in the brain, has been implicated in diabetes mellitus, Alzheimer’s disease and other neurological disorders. However, whether and how central insulin resistance plays a role in the eye remains unclear. Here, we performed intracerebroventricular injection of S961, a potent and specific blocker of insulin receptor in adult Wistar rats to test if central insulin resistance leads to pathological changes in ocular structures. 80 mg of S961 was stereotaxically injected into the lateral ventricle of the experimental group twice at 7 days apart, whereas buffer solution was injected to the sham control group. Blood samples, intraocular pressure, trabecular meshwork morphology, ciliary body markers, retinal and optic nerve integrity, and whole genome expression patterns were then evaluated. While neither blood glucose nor serum insulin level was significantly altered in the experimental or control group, we found that injection of S961 but not buffer solution significantly increased intraocular pressure at 14 and 24 days after first injection, along with reduced porosity and aquaporin 4 expression in the trabecular meshwork, and increased tumor necrosis factor α and aquaporin 4 expression in the ciliary body. In the retina, cell density and insulin receptor expression decreased in the retinal ganglion cell layer upon S961 injection. Fundus photography revealed peripapillary atrophy with vascular dysregulation in the experimental group. These retinal changes were accompanied by upregulation of pro-inflammatory and pro-apoptotic genes, downregulation of anti-inflammatory, anti-apoptotic, and neurotrophic genes, as well as dysregulation of genes involved in insulin signaling. Optic nerve histology indicated microglial activation and changes in the expression of glial fibrillary acidic protein, tumor necrosis factor α, and aquaporin 4. Molecular pathway architecture of the retina revealed the three most significant pathways involved being inflammation/cell stress, insulin signaling, and extracellular matrix regulation relevant to neurodegeneration. There was also a multimodal crosstalk between insulin signaling derangement and inflammation-related genes. Taken together, our results indicate that blocking insulin receptor signaling in the central nervous system can lead to trabecular meshwork and ciliary body dysfunction, intraocular pressure elevation, as well as inflammation, glial activation, and apoptosis in the retina and optic nerve. Given that central insulin resistance my lead to neurodegenerative phenotype in the visual system, targeting insulin signaling may hold promise for vision disorders involving the retina and optic nerve.

视神经损伤诱导小胶质细胞表型变化与视网膜神经节细胞死亡的关系

目的探究视神经损伤后视网膜小胶质细胞表型改变与视网膜神经节细胞(retinal ganglion cells,RGCs)死亡的关系。方法将6~8周龄雄性C57BL/6J小鼠按照随机数字表法分为造模后1、3、7、14 d损伤组和Sham组,每组4只。对损伤组进行视神经钳夹(optic nerve crush,ONC),对Sham组行相同的手术操作但不夹持视神经;结合闪光视觉诱发电位(flash visual evoked potential,fVEP)和免疫荧光染色评估视神经损伤对小鼠视觉功能和RGCs数量的影响;RT-qPCR和免疫荧光染色检测视神经损伤对视网膜小胶质细胞表型变化的影响。结果fVEP结果显示,与Sham组相比,损伤组的视觉传导功能随时间进展逐渐下降(P<0.01)。免疫荧光染色结果显示RGCs数量减少主要发生在损伤后7 d内(P<0.01);同时视网膜小胶质细胞的数量在损伤后7 d达到峰值(P<0.01)。RT-qPCR显示与Sham组相比,ONC后7 d视网膜疾病相关型小胶质细胞(disease-associated microglia,DAM)及干扰素反应型小胶质细胞(interferon-responsive microglia,IRM)特征基因表达均显著增加(P<0.01)。免疫荧光染色提示DAM的数量在ONC后3 d达到峰值(P<0.01),但随着时间的进展比例逐渐降低(P<0.05);而IRM的数量及比例在ONC后7 d达到峰值(P<0.01)。相关性分析提示IRM的数量与神经节细胞死亡强烈相关(P<0.01)。结论视神经损伤后视网膜小胶质细胞由早期的DAM型向IRM型转化可能是RGCs死亡的重要原因。

Astrocyte polarization in glaucoma: a new opportunity

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.