Neuroprotection for glaucoma: Requirements for clinical translation

Levin, Leonard A.; Crowe, Megan E.; Quigley, Harry A.; Cordeiro, M. Francesca; Donoso, Larry A.; Liao, Yue; Libby, Richard T.; Masland, Richard H.; Nickells, Robert W.; Sieving, Paul A.; Sommer, Alfred

doi:10.1016/j.exer.2016.12.005

Cited by 53 publications

(35 citation statements)

References 46 publications

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“…Glaucoma is one of the leading causes of irreversible blindness worldwide, affecting nearly 60 million people (Quigley and Broman, 2006 ). As a neurodegenerative disorder caused by protein misfolding, glaucoma is characterized by retinal ganglion cell (RGC) death and axonal damage of the optic nerve (Levin et al, 2017 ; Nuzzi and Tridico, 2017 ). The degeneration of RGCs may be triggered by increased intraocular pressure (IOP), gene defects, high glucose levels, oxidative stress, and aging.…”

Section: Introductionmentioning

confidence: 99%

Reduced Annexin A1 Secretion by ABCA1 Causes Retinal Inflammation and Ganglion Cell Apoptosis in a Murine Glaucoma Model

Chen

et al. 2018

Front. Cell. Neurosci.

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Variants near the ATP-binding cassette transporter A1 (ABCA1) gene are associated with elevated intraocular pressure and newly discovered risk factors for glaucoma. Previous studies have shown an association between ABCA1 deficiency and retinal inflammation. Using a mouse model of ischemia-reperfusion (IR) induced by acute intraocular pressure elevation, we found that the retinal expression of ABCA1 protein was decreased. An induction of ABCA1 expression by liver X receptor agonist TO901317 reduced retinal ganglion cell (RGC) apoptosis after IR and promoted membrane translocation and secretion of the anti-inflammatory factor annexin A1 (ANXA1). Moreover, ABCA1 and ANXA1 co-localized in cell membranes, and the interaction domain is amino acid 196 to 274 of ANXA1 fragment. TO901317 also reduced microglia migration and activation and decreased the expression of pro-inflammatory cytokines interleukin (IL)-17A and IL-1β, which could be reversed by the ANXA1 receptor blocker Boc2. Overexpression of TANK-binding kinase 1 (TBK1) increased ABCA1 degradation, which was reversed by the proteasome inhibitor carbobenzoxy-L-leucyl-L-leucyl-L-leucinal (MG132). Silencing Tbk1 with siRNA increased ABCA1 expression and promoted ANXA1 membrane translocation. These results indicate a novel IR mechanism, that leads via TBK1 activation to ABCA1 ubiquitination. This degradation decreases ANXA1 secretion, thus facilitating retinal inflammation and RGC apoptosis. Our findings suggest a potential treatment strategy to prevent RGC apoptosis in retinal ischemia and glaucoma.

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Section: Introductionmentioning

confidence: 99%

Reduced Annexin A1 Secretion by ABCA1 Causes Retinal Inflammation and Ganglion Cell Apoptosis in a Murine Glaucoma Model

Chen

et al. 2018

Front. Cell. Neurosci.

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“…It has been proposed that the axoplasmic blocking and the oxidative stress caused by high IOP to RGCs, can lead to the pathogenesis of glaucoma (Moreno et al, 2004;Quigley et al, 2000). Glaucoma pathophysiological mechanisms, the various animal models, and future experimental treatments have already been extensively reviewed by others (Johnson & Tomarev, 2010;Munemasa & Kitaoka, 2012;Ishikawa, Yoshitomi, Zorumski, & Izumi, 2015;Levin et al, 2017;Nucci et al, 2018;Van de Velde, Groef, Stalmans, Moons, & Hove, 2015;Bucolo et al, 2018).…”

Section: Novel Treatment Optionsmentioning

confidence: 99%

Models and treatments for traumatic optic neuropathy and demyelinating optic neuritis

Bastakis

Ktena

Καραγωγεωσ

et al. 2019

Developmental Neurobiology

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Pathologies of the optic nerve could result as primary insults in the visual tract or as secondary deficits due to inflammation, demyelination, or compressing effects of the surrounding tissue. The extent of damage may vary from mild to severe, differently affecting patient vision, with the most severe forms leading to complete uni‐ or bilateral visual loss. The aim of researchers and clinicians in the field is to alleviate the symptoms of these, yet uncurable pathologies, taking advantage of known and novel potential therapeutic approaches, alone or in combinations, and applying them in a limited time window after the insult. In this review, we discuss the epidemiological and clinical profile as well as the pathophysiological mechanisms of two main categories of optic nerve pathologies, namely traumatic optic neuropathy and optic neuritis, focusing on the demyelinating form of the latter. Moreover, we report on the main rodent models mimicking these pathologies or some of their clinical aspects. The current treatment options will also be reviewed and novel approaches will be discussed.

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“…And higher intraocular pressure could damage the optic nerve and cause its function loss. Recently, many neuroprotectants have been used for treatment of glaucoma by the means of lowering the intraocular pressure to improve the nerve function . Hence, neuroprotection has become an important method for the management of glaucoma.…”

Section: Introductionmentioning

confidence: 99%

5‐[2‐(N‐(Substituted phenyl)acetamide)]amino‐1,3,4‐thiadiazole‐2‐sulfonamides as Selective Carbonic Anhydrase II Inhibitors with Neuroprotective Effects

et al. 2020

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In this study, 22 novel compounds were designed and synthesized by acetamide bridge chains, among which 5 a-5 k were monosubstituted compounds, and 6 a-6 k were disubstituted. A series of biological evaluations was then carried out to determine the carbonic anhydrase inhibitory activity, neuroprotective effects and cytotoxicity of 5 a-5 k and 6 a-6 k. The results showed that some compounds could protect PC12 cells from sodium nitroprusside (SNP)-induced damage. In terms of the neuroprotection and inhibitory activity against carbonic anhydrase II, monosubstituted compounds were better than disubstituted. Compound 5 c exhibited better protective effect in PC12 cells than that of edaravone, and 5 c also showed less cytotoxicity. In addition, compound 5 c was found to be the most effective selective carbonic anhydrase II inhibitor (IC 50 = 16.7 nM, CAI/CAII = 54.3), which was similar to the inhibitory effect of acetazolamide. Moreover, the selectivity of compound 5 c was better than that of acetazolamide (IC 50 = 12.0 nM, CAI/ CAII = 20.8). Molecular docking presented that the binding effect of compound 5 c with carbonic anhydrase II was superior to that of 5 c with carbonic anhydrase I and IX, which was consistent with the inhibitory results. Based on above findings, compound 5 c may be a potential candidate for selective carbonic anhydrase II inhibitor, and it had obviously neuroprotective effect and great advantages in drug safety.[a] Dr. Chemistry Optimization of reaction conditionsAccording to previous literature, [26,27] mono-or disubstituted products cannot be obtained simultaneously in a reaction. After optimizing the reaction conditions by the study, mono-and disubstituted compounds were obtained in a reaction. The synthetic route was shown in Scheme 1. First, 5-amino-1,3,4thiadiazole-2-sulfonamide (2) and 2-bromo-N-(4-fluorophenyl) acetamide (4 c) served as reactants, with DMF as solvent, [28,29] and reaction was carried out at room temperature. Results discovered that only disubstituted products were formed. Thus, the reaction conditions were optimized by controlling the reaction temperature, equivalent ratio of substrates, type and amount of alkali to improve the yield of monosubstituted product. The analysis was performed by using HPLC (Figure 1).(i) Temperature: Reactions were carried out at 25, 0, À 20 and À 40°C, with 1 equiv. K 2 CO 3 and the equivalent ratio of 4 c:2 of 1 : 1. Results found that the lower the temperature was, the slower the reaction proceed. At 25°C, although reaction was completed in 2 h, only 3 % monosubstituted product was produced. At 0°C, the reaction obtained 5 % of monosubstituted products and the remaining 59 % of raw materials. At À 20°C, it obtained 21 % of monosubstituted products and the remaining 56 % of raw materials, and no products were formed at À 40°C. As the data of the reaction shown, the reaction would control the temperature at À 20°C and simultaneously control other conditions to maximize production of monosubstituted and disubstituted products (Table 1, entri...

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Neuroprotection for glaucoma: Requirements for clinical translation

Cited by 53 publications

References 46 publications

Reduced Annexin A1 Secretion by ABCA1 Causes Retinal Inflammation and Ganglion Cell Apoptosis in a Murine Glaucoma Model

Reduced Annexin A1 Secretion by ABCA1 Causes Retinal Inflammation and Ganglion Cell Apoptosis in a Murine Glaucoma Model

Models and treatments for traumatic optic neuropathy and demyelinating optic neuritis

5‐[2‐(N‐(Substituted phenyl)acetamide)]amino‐1,3,4‐thiadiazole‐2‐sulfonamides as Selective Carbonic Anhydrase II Inhibitors with Neuroprotective Effects

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