All roads lead to glaucoma: Induced retinal injury cascades contribute to a common neurodegenerative outcome

Alqawlaq, Samih; Flanagan, John G.; Sivak, Jeremy M.

doi:10.1016/j.exer.2018.11.005

Cited by 81 publications

(83 citation statements)

References 171 publications

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“…Glaucoma represents a group of irreversible, progressive optic neuropathies often leading to severe visual field loss and blindness [1]. Even though intraocular pressure (IOP) elevation is not pathognomonic of glaucoma, its therapeutic management has been considered the standard of care in glaucomatous patients as it is the most modifiable parameter [1].…”

Section: Introductionmentioning

confidence: 99%

In vivo confocal microscopy: qualitative investigation of the conjunctival and corneal surface in open angle glaucomatous patients undergoing the XEN-Gel implant, trabeculectomy or medical therapy

et al. 2020

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Purpose: Assessing the quality of the ocular surface by in vivo scanning laser confocal microscopy (IVCM) in primary open angle glaucoma (POAG) patients treated by Xen 45 Gel Stent, medical therapy and trabeculectomy. Methods: Retrospective, single-center, single-masked, comparative study including 60 eyes of 30 patients (mean age 61.16 ± 10 years) affected by POAG. Eyes were divided into 3 groups: Group 1 eyes underwent the Xen 45 Gel Stent procedure, Group 2 eyes were under medical therapy, Group 3 eyes were surgically treated by trabeculectomy. All patients underwent HRT II IVCM analysis of cornea, limbus, conjunctiva, sub-tenionian space and sclera. Results: The Xen 45 Gel stent, if properly positioned in the sub-conjunctival space preserves goblet cells and limits ocular surface inflammation. Regular corneal epithelial cells with micro-cysts, and normo-reflective sub-epithelial nerve plexus are documented by IVCM. In sub Tenon's implants an alternative lamellar intra-scleral filtration is detectable. Combined surgical procedures show a noticeable number of inflammatory cells with rare micro-cysts. Post-trabeculectomy inflammatory reaction is more evident than Xen 45 Gel Stent associated surgical procedures, but less than medical therapy where a conspicuous presence of Langerhans cells, peri-neural infiltrates, marked loss of goblet cells and fibrosis is visible. Conclusion: Ocular surface inflammation was more notable in topical therapy than after trabeculectomy, which itself causes more inflammation than XEN Gel stents.

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Section: Introductionmentioning

confidence: 99%

In vivo confocal microscopy: qualitative investigation of the conjunctival and corneal surface in open angle glaucomatous patients undergoing the XEN-Gel implant, trabeculectomy or medical therapy

et al. 2020

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“…Studies assessing LXs in the CNS have generally focused on their proresolution roles. However, recent findings from our laboratory and others have also intriguingly uncovered a direct neuronal activity . Previously, neuroprotective effects have been described for the structurally distinct DHA product NPD1 .…”

Section: Lipoxins Can Mediate Direct Neuronal Actionsmentioning

confidence: 82%

“…However, recent findings from our laboratory and others have also intriguingly uncovered a direct neuronal activity. [51,86,87] Previously, neuroprotective effects have been described for the structurally distinct DHA product NPD1. [88][89][90] But, such activity had not been identified for LXs.…”

Section: Lipoxins Can Mediate Direct Neuronal Actionsmentioning

confidence: 99%

Fair‐Weather Friends: Evidence of Lipoxin Dysregulation in Neurodegeneration

Kim

Livne‐Bar

Gronert

et al. 2020

Molecular Nutrition Food Res

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Lipoxins (LXs) are autacoids, specialized proresolving lipid mediators (SPMs) acting locally in a paracrine or autocrine fashion. They belong to a complex superfamily of dietary small polyunsaturated fatty acid (PUFA)–metabolites, which direct potent cellular responses to resolve inflammation and restore tissue homeostasis. Together, these SPM activities have been intensely studied in systemic inflammation and acute injury or infection, but less is known about LX signaling and activities in the central nervous system. LXs are derived from arachidonic acid, an omega‐6 PUFA. In addition to well‐established roles in systemic inflammation resolution, they have increasingly become implicated in regulating neuroinflammatory and neurodegenerative processes. In particular, chronic inflammation plays a central role in Alzheimer's disease (AD) etiology, and dysregulated LX production and activities have been reported in a variety of AD rodent models and clinical tissue samples, yet with complex and sometimes conflicting results. In addition, reduced LX production following retinal injury has been reported recently by the authors, and an intriguing direct neuronal activity promoting survival and homeostasis in retinal and cortical neurons is demonstrated. Here, the authors review and clarify this growing literature and suggest new research directions to further elaborate the role of lipoxins in neurodegeneration.

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“…We hypothesise that NAM supplementation may benefit eyes with elevated IOP, which is associated with increased RGC metabolic stress and dysfunction. 2,34 The NAM dosage used in our study was derived empirically from preclinical work and clinical trials of the supplement for other indications.…”

Section: Discussionmentioning

confidence: 99%

Improvement in Inner Retinal Function in Glaucoma with Nicotinamide (Vitamin B₃) Supplementation: A Crossover Randomised Clinical Trial

Hui

Tang

Williams

et al. 2020

Preprint

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Importance: Retinal ganglion cells endure significant metabolic stress with ageing and glaucoma-related stressors. Injured cells require increased energy for repair but maintain capacity to recover function despite periods of functional loss. Nicotinamide, a precursor of redox co-factor and metabolite, NAD+, is low in serum of patients with primary open-angle glaucoma and its supplementation provides robust protection of retinal ganglion cells by targeting mitochondrial health in glaucoma models. However, the potential of nicotinamide to improve retinal ganglion cell function in humans with glaucoma is yet unknown. Objective: To determine whether nicotinamide supplementation taken in conjunction with conventional IOP-lowering therapy leads to early improvement in retinal ganglion cell function in people with glaucoma. Design: Crossover, double-masked, randomized clinical trial conducted between October 2017 to January 2019. Setting: Study participants recruited from two tertiary care centers in Melbourne, Australia. Participants: Adults diagnosed and treated for primary glaucoma. Ninety-four participants assessed for study eligibility. Intervention: Participants randomized to first receive oral placebo or nicotinamide and reviewed six-weekly. Accelerated dosing method utilized; participants commenced 6-week course of 1.5 grams/day followed by 6 weeks of 3.0 grams/day. After 12 weeks, participants crossed over to other intervention for 12 weeks without washout. At each visit, visual function measured using full-field flash electroretinography and white-on-white perimetry. Main outcome measures: Primary endpoint was change in inner retinal function determined a-priori as change in photopic negative response (PhNR) parameters: saturated PhNR amplitude (Vmax), ratio of PhNR/b-wave amplitude (Vmax ratio). Results: Fifty-seven participants (65.5±10.0 years, 39% female) enrolled. PhNR Vmax improved beyond 95% coefficient of repeatability (COR) in 23% of participants following 12 weeks of nicotinamide versus 9% on placebo. Conversely, PhNR Vmax deteriorated in 9% on placebo and 7% on nicotinamide. Overall, Vmax improved by 14.8% [95% CI: 2.8%, 26.9%], (p=0.02) on nicotinamide and 5.2% [-4.2%, 14.6%], (p=0.27) on placebo. Vmax ratio improved on average by 12.6% [5.0%, 20.2%], (p=0.002) following nicotinamide and 3.6% [-3.4%, 10.5%], (p=0.30) on placebo. A concomitant trend for improved visual field mean deviation was observed with 27% improving ≥1dB on nicotinamide and fewer deteriorating ≥1dB (4%) compared to placebo (p=0.02). Moderate correlation was observed between PhNR and visual field change with treatment. Participants demonstrated excellent treatment adherence rates (>94%) and nicotinamide was well tolerated with minimal side effects. Conclusions and Relevance: Nicotinamide supplementation can improve inner retinal function in patients receiving concurrent IOP-lowering glaucoma therapy. Further studies are underway to elucidate the effects of long-term nicotinamide supplementation on glaucoma progression.

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All roads lead to glaucoma: Induced retinal injury cascades contribute to a common neurodegenerative outcome

Cited by 81 publications

References 171 publications

In vivo confocal microscopy: qualitative investigation of the conjunctival and corneal surface in open angle glaucomatous patients undergoing the XEN-Gel implant, trabeculectomy or medical therapy

In vivo confocal microscopy: qualitative investigation of the conjunctival and corneal surface in open angle glaucomatous patients undergoing the XEN-Gel implant, trabeculectomy or medical therapy

Fair‐Weather Friends: Evidence of Lipoxin Dysregulation in Neurodegeneration

Improvement in Inner Retinal Function in Glaucoma with Nicotinamide (Vitamin B₃) Supplementation: A Crossover Randomised Clinical Trial

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All roads lead to glaucoma: Induced retinal injury cascades contribute to a common neurodegenerative outcome

Cited by 81 publications

References 171 publications

In vivo confocal microscopy: qualitative investigation of the conjunctival and corneal surface in open angle glaucomatous patients undergoing the XEN-Gel implant, trabeculectomy or medical therapy

In vivo confocal microscopy: qualitative investigation of the conjunctival and corneal surface in open angle glaucomatous patients undergoing the XEN-Gel implant, trabeculectomy or medical therapy

Fair‐Weather Friends: Evidence of Lipoxin Dysregulation in Neurodegeneration

Improvement in Inner Retinal Function in Glaucoma with Nicotinamide (Vitamin B3) Supplementation: A Crossover Randomised Clinical Trial

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Improvement in Inner Retinal Function in Glaucoma with Nicotinamide (Vitamin B₃) Supplementation: A Crossover Randomised Clinical Trial