Intense exposure to light, robust metabolic activity, and high oxygen tension render the human eye particularly vulnerable to oxidative damage and the list of ophthalmological disorders implicating ...reactive oxygen and nitrogen species is rapidly expanding. Here, we review the roles of oxidative stress in the etiopathogeneses and pathophysiology of diseases of the human cornea including pterygium, keratoconus, trauma and chemical injury, and a host of inflammatory, metabolic, degenerative, and iatrogenic conditions. Data from animal and tissue culture experimentation germane to these conditions are also adduced.
To assess the outcomes and failure risk factors for Kahook Dual Blade (KDB) excisional goniotomy with cataract surgery (phaco-KDB) in eyes with various glaucoma subtypes and severities.
This ...multisurgeon consecutive case series included glaucomatous eyes with cataract that underwent phaco-KDB and had a minimum follow-up of 12 months postoperatively. Efficacy was assessed by absolute and qualified surgical success (defined by different criteria) and changes in intraocular pressure (IOP) and antiglaucoma medication (AGM) at the last postoperative follow-up. Safety included best-corrected visual acuity, cup-to-disc ratio, visual field mean deviation, retinal nerve fibre layer thickness, and adverse events.
A total of 108 eyes of 89 patients with a median follow-up of 18 months (range, 12–47 months) were included. IOP decreased by 26% from 19.1 ± 5.0 mm Hg to 14.1 ± 3.5 mm Hg (p < 0.001), AGM use decreased by 29% from 2.4 ± 1.3 medications to 1.7 ± 1.3 (p < 0.001), and 25% of eyes became free of AGMs (vs 3% at baseline). Qualified success rates achieved for IOP cutoffs of 18, 15, and 12 mm Hg were 87%, 68%, and 46%, respectively. Higher baseline IOP and postoperative incidence of IOP spikes were associated with a higher risk of surgical failure. Best-corrected visual acuity improved postoperatively (p < 0.001), and visual field mean deviation, cup-to-disc ratio, and retinal nerve fibre layer thickness remained stable. Overall, safety was favourable, and adverse events were transient and not sight threatening.
This multicentre Canadian study provides real-world data that support the safety and efficacy of phaco-KDB in reducing IOP and AGM use with no evidence of disease progression during the follow-up period.
In cultured astroglia, cysteamine induces the accumulation of peroxidase-positive cytoplasmic inclusions in the context of a generalized cellular stress response. In the present study, systemic ...cysteamine administration over a 3 week period induced HSP27, 72, 90, and GRP94 (stress proteins) in astrocytes and significantly increased numbers of peroxidase-positive astrocytic inclusions in the various brain regions relative to controls. Similar patterns of HSP expression were also observed at 24 hours following cysteamine treatment indicating that cellular stress may be a very proximal event in the biogenesis of the astrocytic inclusions. The topography of glial peroxidase activity may provide a "map" of central nervous system regions particularly prone to oxidative stress during normal aging and under pathologic conditions.
The aminothiol compound, cysteamine (CSH), induces astrocyte hypertrophy (gliosis) and the appearance of autofluorescent, peroxidase-positive cytoplasmic granules in these cells akin to changes that ...occur spontaneously in astroglia of the aging periventricular brain. Paradoxically, CSH damages astroglial mitochondria (granule precursors) while protecting these cells from subsequent H
2O
2 and mechanoenzymatic stress. In this study, in vitro CSH administration significantly increased manganese superoxide dismutase (MnSOD) activity in cultured astroglia. Immunoblot and Northern analyses indicated that MnSOD protein and mRNA levels were increased in cultured astrocytes after 3–6 days of CSH treatment. Systemic administration of CSH also significantly augmented MnSOD activity in the intact diencephalon. CSH caused a pronounced (6-fold), but transient, increase in the level of reduced glutathione (GSH) in cultured astrocytes. In contrast, catalase and glutathione reductase (GR) activities were suppressed, whereas copper-zinc superoxide dismutase (CuZnSOD) activity remained unchanged both in cultured astroglia and in the intact diencephalon following CSH treatment. Glutathione peroxidase (GP) activity was increased after 3 and 48 h of CSH treatment and then declined below control levels in cultured astrocytes. CSH inhibited the formation of thiobarbituric acid-reactive products (TBAR) in whole astrocyte monolayers, although it promoted TBAR formation in suspensions of isolated astroglial mitochondria. CSH-related oxidative stress may accelerate aging-related changes in astroglial mitochondria while conferring cytoprotection to these cells by stimulating the upregulation of various heat shock proteins and MnSOD. These cytoprotective responses may facilitate astrocyte survival and the development of reactive gliosis in the face of concomitant neuronal degeneration. CSH-treated astrocytes may serve as a model for the (dys)regulation of neuroglial MnSOD and other antioxidant enzymes in the aging and degenerating nervous system.
In the aging mammalian hypothalamus, a unique sub-population of glial cells accumulates peroxidase-positive cytoplasmic inclusions distinct from lipofuscin. In adult rodents, this ...senescence-dependent filial granulation is accelerated by administration of estradiol valerate. In the present study, brain sections derived from male rats given 3 monthly intramuscular injections of estradiol valerate (0.2 mg or 2.0 mg) were immunostained for heat shock proteins and glial fibrillary acidic protein to determine whether a glial stress response is implicated in estrogen-induced granulation. Our findings indicate that estrogen elicits a heat shock response and subsequent granulation in astrocytes residing in estradiol receptor-rich brain regions including the arcuate nucleus and the wall surrounding the third ventricle but not in estradiol receptor-deficient regions such as the striatum and corpus callosum. The heat shock proteins induced by estrogen, namely, the 27, 72, and 90 kDa stress proteins, are upregulated in astrocytes in response to oxidative challenge supporting our hypothesis that estrogen mediates senescent changes in the rodent hypothalamus through oxidative mechanisms.
In the aging brain, a unique subpopulation of limbic and periventricular astrocytes accumulates red autofluorescent, peroxidase-positive cytoplasmic inclusions distinct from lipofuscin. Cysteamine ...(CSH) exposure rapidly induces identical inclusions in cultured, immature astroglia. CSH induces a cellular stress response prior to astrocyte granulation. To determine whether stress proteins are actual constituents of the autofluorescent granules, 12-week-old rat brain sections and CSH-treated astroglial cultures were immunostained with various anti-stress protein antibodies and evaluated by laser scanning confocal microscopy. We observed intense co-localization of heat shock protein (HSP) 27 and ubiquitin (Ub) to the autofluorescent astrocyte granules in situ and in CSH-treated glial cultures. In both preparations, glucose regulated protein (GRP) 94 consistently exhibited partial co-localization to the granule periphery and adjacent cytoplasm. In contrast, HSP72 co-localization to these inclusions was only occasionally seen and the granules appeared entirely devoid of HSP90 and alpha B-crystallin. Acute exposure of cultured astroglia to CSH induced intense cytoplasmic Ub staining, suggesting that activation of the Ub pathway may be an early event in the biogenesis of these astrocytic granules. Taken together, our results support the notion that the autofluorescent astrocyte inclusions are stress or heat shock granules which progressively accumulate in the aging periventricular brain. Moreover, CSH greatly accelerates the appearance of this senescent astrocyte phenotype in primary culture.
Cysteamine (CSH; 2-mercaptoethylamine) stimulates the accumulation of peroxidase-positive inclusions in cultured astroglia akin to those observed in the aging periventricular brain. Because CSH ...induces the synthesis of a stress protein (heme oxygenase) in rat liver, we hypothesized that aspects of the cellular stress response may play a role in the biogenesis of CSH-induced astrocyte granules. In the present study, we performed indirect immunofluorescent staining and immunoblotting for various stress proteins in rat neuroglial cultures. Exposure of astrocyte cultures to CSH enhanced immunostaining for heme oxygenase-1 (HO-1) and heat-shock proteins 27, 72, and 90, but not glucose-regulated protein 94, relative to untreated cultures. CSH-pretreated astrocytes exhibited enhanced tolerance to H2O2 toxicity relative to untreated cells, providing physiological evidence of an antecedent stress response in the former. In addition, exposure for 12 days to H2O2, a known inducer of the stress response, elicited astrocyte granulation similar to that observed with CSH. Chronic induction of HO-1 and other stress proteins may participate in the biogenesis of metalloporphyrin-rich inclusions in CSH-treated astroglial cultures and in astrocytes of the aging periventricular brain.
In aging vertebrates, subpopulations of limbic and periventricular astrocytes accumulate peroxidase-positive cytoplasmic inclusions distinct from lipofuscin. In rodent brain, chronic estrogenization ...accelerates the appearance of this senescent glial phenotype. Identical inclusions are rapidly induced in primary neuroglial cultures by cysteamine exposure. Abnormal mitochondria replete with redox-active iron and other transition metals are the subcellular precursors of the inclusions in situ and in cysteamine-treated cultures. The objective of this thesis was to elucidate mechanisms responsible for the biogenesis of these glial inclusions in the aging nervous system.
We determined that the accumulation of astrocytic inclusions in cysteamine-treated rat glial cultures occurs in the context of an antecedent cellular stress response characterized by (i) the upregulation of heat shock proteins (HSP) 27, 72, 90, ubiquitin and heme oxygenase-1, and (ii) enhanced resistance of cysteamine-stressed astroglia to subsequent oxidative injury. Furthermore, multiple injections of cysteamine or estradiol valerate in adult male rats induced robust overexpression of stress proteins and an accretion of identical peroxidase-positive granules in GFAP-positive astroglia. Both in situ and in cysteamine-treated cultures, HSP27, ubiquitin, glucose-regulated protein 94 and to a lesser extent, HSP72 (but not HSP90 or $ alpha$B-crystallin) exhibited immunolocalization to these astrocytic "stress" inclusions. We observed that exogenous $ rm H sb2O sb2$ induces identical inclusions in cultured astroglia and that cysteamine-derived $ rm H sb2O sb2$ promotes lipid peroxidation in isolated astroglial mitochondria. These data indicate that sustained oxidative stress may represent a "final common pathway" leading to the transformation of normal mitochondria to peroxidase-positive astrocytic inclusions in the aging nervous system.
The metal-dependent peroxidase activity of these glial inclusions has been shown to oxidize dopamine and other catechols to neurotoxic free radicals in vitro, implicating these cells in the pathogenesis of parkinsonism and other free radical-related neurodegenerations. Since peroxidase-positive astroglia have been identified in aging human striatum, the findings presented here suggest that antioxidant therapy coupled with pharmacological inhibition of metal sequestration by "stressed" astroglial mitochondria may prove useful in the management of Parkinson's disease and other age-associated neurodegenerative afflictions.
In aging vertebrates, subpopulations of limbic and periventricular astrocytes accumulate peroxidase-positive cytoplasmic inclusions distinct from lipofuscin. In rodent brain, chronic estrogenization ...accelerates the appearance of this senescent glial phenotype. Identical inclusions are rapidly induced in primary neuroglial cultures by cysteamine exposure. Abnormal mitochondria replete with redox-active iron and other transition metals are the subcellular precursors of the inclusions in situ and in cysteamine-treated cultures. The objective of this thesis was to elucidate mechanisms responsible for the biogenesis of these glial inclusions in the aging nervous system. We determined that the accumulation of astrocytic inclusions in cysteamine-treated rat glial cultures occurs in the context of an antecedent cellular stress response characterized by (i) the upregulation of heat shock proteins (HSP) 27, 72, 90, ubiquitin and heme oxygenase-1, and (ii) enhanced resistance of cysteamine-stressed astroglia to subsequent oxidative injury. Furthermore, multiple injections of cysteamine or estradiol valerate in adult male rats induced robust overexpression of stress proteins and an accretion of identical peroxidase-positive granules in GFAP-positive astroglia. Both in situ and in cysteamine-treated cultures, HSP27, ubiquitin, glucose-regulated protein 94 and to a lesser extent, HSP72 (but not HSP90 or $\alpha$B-crystallin) exhibited immunolocalization to these astrocytic "stress" inclusions. We observed that exogenous $\rm H\sb2O\sb2$ induces identical inclusions in cultured astroglia and that cysteamine-derived $\rm H\sb2O\sb2$ promotes lipid peroxidation in isolated astroglial mitochondria. These data indicate that sustained oxidative stress may represent a "final common pathway" leading to the transformation of normal mitochondria to peroxidase-positive astrocytic inclusions in the aging nervous system. The metal-dependent peroxidase activity of these glial inclusions has been shown to oxidize dopamine and other catechols to neurotoxic free radicals in vitro, implicating these cells in the pathogenesis of parkinsonism and other free radical-related neurodegenerations. Since peroxidase-positive astroglia have been identified in aging human striatum, the findings presented here suggest that antioxidant therapy coupled with pharmacological inhibition of metal sequestration by "stressed" astroglial mitochondria may prove useful in the management of Parkinson's disease and other age-associated neurodegenerative afflictions.
