Optic Nerve Head Astrocytes Display Axon-Dependent and -Independent Reactivity in Response to Acutely Elevated Intraocular Pressure

Tehrani, Shandiz; Davis, Lauren; Cepurna, William O.; Delf, R. Katherine; Lozano, Diana C; Choe, Tiffany E.; Johnson, Elaine C.; Morrison, John C.

doi:10.1167/iovs.18-25447

Cited by 25 publications

(13 citation statements)

References 67 publications

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“…The F-to-G actin ratio (F-actin fiber length over G-actin fluorescence) significantly decreased during reactive astrocytosis ( Figure 1E). Altogether, these data are consistent with in vitro studies using 3D culture models [38], in vivo models using an acute controlled elevation of intraocular pressure (CEI) [39], and with the generally accepted notion that mechanical forces exerted on the human optic nerve head cause disruption of the actin cytoskeleton (reviewed in [40]).…”

Section: Discussionsupporting

confidence: 80%

Differential Activation of Glioprotective Intracellular Signaling Pathways in Primary Optic Nerve Head Astrocytes after Treatment with Different Classes of Antioxidants

et al. 2020

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Optic nerve head astrocytes are the specialized glia cells that provide structural and trophic support to the optic nerve head. In response to cellular injury, optic nerve head astrocytes undergo reactive astrocytosis, the process of cellular activation associated with cytoskeletal remodeling, increases in the rate of proliferation and motility, and the generation of Reactive Oxygen Species. Antioxidant intervention has previously been proposed as a therapeutic approach for glaucomatous optic neuropathy, however, little is known regarding the response of optic nerve head astrocytes to antioxidants under physiological versus pathological conditions. The goal of this study was to determine the effects of three different antioxidants, manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin (Mn-TM-2-PyP), resveratrol and xanthohumol in primary optic nerve head astrocytes. Effects on the expression of the master regulator nuclear factor erythroid 2-related factor 2 (Nrf2), the antioxidant enzyme, manganese-dependent superoxide dismutase 2 (SOD2), and the pro-oxidant enzyme, nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4), were determined by quantitative immunoblotting. Furthermore, efficacy in preventing chemically and reactive astrocytosis-induced increases in cellular oxidative stress was quantified using cell viability assays. The results were compared to the effects of the prototypic antioxidant, Trolox. Antioxidants elicited highly differential changes in the expression levels of Nrf2, SOD2, and NOX4. Notably, Mn-TM-2-PyP increased SOD2 expression eight-fold, while resveratrol increased Nrf2 expression three-fold. In contrast, xanthohumol exerted no statistically significant changes in expression levels. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) uptake and lactate dehydrogenase (LDH) release assays were performed to assess cell viability after chemically and reactive astrocytosis-induced oxidative stress. Mn-TM-2-PyP exerted the most potent glioprotection by fully preventing the loss of cell viability, whereas resveratrol and xanthohumol partially restored cell viability. Our data provide the first evidence for a well-developed antioxidant defense system in optic nerve head astrocytes, which can be pharmacologically targeted by different classes of antioxidants.

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Section: Discussionsupporting

confidence: 80%

Differential Activation of Glioprotective Intracellular Signaling Pathways in Primary Optic Nerve Head Astrocytes after Treatment with Different Classes of Antioxidants

et al. 2020

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“…Retinal astrocytes, also called astroglia, link neurons to blood vessels and are located almost exclusively in the retinal nerve fiber layer ( 84 ). They have been found to provide structural and physiological support to optic nerve head axons ( 85 ) and modulate remodeling of the extracellular matrix in response to IOP elevation ( 86 , 87 ). During retinal injury or in response to elevated IOP, astrocytes are activated, followed by morphological changes, such as cell body hypertrophy and loss of thick processes ( 17 , 87 ).…”

Section: Astrocytes and Their Role In Retinal Ganglion Cell Homeostasmentioning

confidence: 99%

Glial Cells in Glaucoma: Friends, Foes, and Potential Therapeutic Targets

et al. 2021

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Glaucoma is the second leading cause of blindness worldwide, affecting ~80 million people by 2020 (1, 2). The condition is characterized by a progressive loss of retinal ganglion cells (RGCs) and their axons accompanied by visual field loss. The underlying pathophysiology of glaucoma remains elusive. Glaucoma is recognized as a multifactorial disease, and lowering intraocular pressure (IOP) is the only treatment that has been shown to slow the progression of the condition. However, a significant number of glaucoma patients continue to go blind despite intraocular pressure-lowering treatment (2). Thus, the need for alternative treatment strategies is indisputable. Accumulating evidence suggests that glial cells play a significant role in supporting RGC function and that glial dysfunction may contribute to optic nerve disease. Here, we review recent advances in understanding the role of glial cells in the pathophysiology of glaucoma. A particular focus is on the dynamic and essential interactions between glial cells and RGCs and potential therapeutic approaches to glaucoma by targeting glial cells.

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“…The pressure insult in acute models is fairly short (hours) by comparison since the animal must be maintained under anesthesia during the cannulation procedure. Nevertheless, a single insult was found to reduce inner retina components of the electroretinogram [30][31][32] , alter molecular and structural responses of astrocytes and retinal neurons [31][32][33][34] , and induce focal axonal degeneration 32 within 2 weeks of the exposure. The overall injury to the optic nerve was mild in grade, not unlike this study at the 2-week time point.…”

Section: Discussionmentioning

confidence: 99%

Experimental glaucoma model with controllable intraocular pressure history

Ficarrotta

Mohamed

Passaglia

2020

Sci Rep

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Glaucoma-like neuropathies can be experimentally induced by disturbing aqueous outflow from the eye, resulting in intraocular pressure (iop) changes that are variable in magnitude and time course and permanent in duration. This study introduces a novel method of glaucoma induction that offers researchers round-the-clock measurement and reversible control of IOP for the first time. One eye of Brown-norway rats was implanted with a cannula tethered to a pressure sensor and aqueous reservoir. IOP was raised 10 mmHg for weeks-to-months in treated animals and unaltered in control animals. Counts of Brn3a-expressing retinal ganglion cells (RGCs) in implanted eyes were indistinguishable from non-implanted eyes in control animals and 15 ± 2%, 23 ± 4%, and 38 ± 4% lower in animals exposed to 2, 4, and 9 weeks of IOP elevation. RGC loss was greater in peripheral retina at 2 weeks and widespread at longer durations. optic nerves also showed progressive degeneration with exposure duration, yet conventional outflow facility of implanted eyes was normal (24.1 ± 2.9 nl/min/mmHg) even after 9-weeks elevation. Hence, this infusion-based glaucoma model exhibits graded neural damage with unimpaired outflow pathways. The model further revealed a potentially-significant finding that outflow properties of rat eyes do not remodel in response to chronic ocular hypertension.

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Optic Nerve Head Astrocytes Display Axon-Dependent and -Independent Reactivity in Response to Acutely Elevated Intraocular Pressure

Abstract: WO, et al. Optic nerve head astrocytes display axon-dependent and-independent reactivity in response to acutely elevated intraocular pressure.

Cited by 25 publications

References 67 publications

Differential Activation of Glioprotective Intracellular Signaling Pathways in Primary Optic Nerve Head Astrocytes after Treatment with Different Classes of Antioxidants

Differential Activation of Glioprotective Intracellular Signaling Pathways in Primary Optic Nerve Head Astrocytes after Treatment with Different Classes of Antioxidants

Glial Cells in Glaucoma: Friends, Foes, and Potential Therapeutic Targets

Experimental glaucoma model with controllable intraocular pressure history

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