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Cureus Dec 2023Diabetic retinopathy (DR) is a leading cause of global visual impairment, necessitating a comprehensive understanding of its vascular and neural components for effective... (Review)
Review
A Systematic Review of the Neuroprotective Effects of Vascular Endothelial Growth Factor (VEGF) in Diabetic Retinopathy and Diabetic Macular Edema: Unraveling the Molecular Mechanisms and Clinical Implications.
Diabetic retinopathy (DR) is a leading cause of global visual impairment, necessitating a comprehensive understanding of its vascular and neural components for effective therapeutic interventions. While vascular pathology is well-established, recent evidence suggests a neurodegenerative role in DR. Vascular endothelial growth factor (VEGF), traditionally implicated in angiogenesis, has emerged as a key player with neuroprotective potential. This systematic review evaluates the literature to shed light on molecular mechanisms and clinical implications in this regard. The review adheres to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, encompassing a thorough search strategy across multiple databases. Three in vitro studies met the inclusion criteria, highlighting the limited research in this evolving field. Findings suggest VEGF's neuroprotective effects on retinal ganglion cells (RGCs) and retinal neurons, unveiling potential therapeutic avenues. However, concerns arise regarding anti-VEGF therapies' impact on RGC survival. The review discusses the need for further research to delineate specific isoforms and signaling pathways responsible for VEGF-mediated neuroprotection. The delicate balance between angiogenesis and neuroprotection poses challenges in therapeutic development, emphasizing the importance of targeted interventions. Despite limitations, this review provides valuable insights into the intricate relationship between VEGF and neuroprotection in DR, paving the way for future investigations and redefining therapeutic strategies.
PubMed: 38288195
DOI: 10.7759/cureus.51351 -
The Cochrane Database of Systematic... Jan 2017Glaucoma is a heterogeneous group of conditions involving progressive damage to the optic nerve, deterioration of retinal ganglion cells, and ultimately visual field... (Review)
Review
BACKGROUND
Glaucoma is a heterogeneous group of conditions involving progressive damage to the optic nerve, deterioration of retinal ganglion cells, and ultimately visual field loss. It is a leading cause of blindness worldwide. Open angle glaucoma (OAG), the most common form of glaucoma, is a chronic condition that may or may not present with increased intraocular pressure (IOP). Neuroprotection for glaucoma refers to any intervention intended to prevent optic nerve damage or cell death.
OBJECTIVES
The objective of this review was to systematically examine the evidence regarding the effectiveness of neuroprotective agents for slowing the progression of OAG in adults compared with no neuroprotective agent, placebo, or other glaucoma treatment.
SEARCH METHODS
We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 7), Ovid MEDLINE, Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE Daily (January 1946 to August 2016), Embase (January 1980 to August 2016), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to August 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 16 August 2016.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) in which topical or oral treatments were used for neuroprotection in adults with OAG. Minimum follow-up time was four years.
DATA COLLECTION AND ANALYSIS
Two review authors independently reviewed titles and abstracts from the literature searches. We obtained full-text copies of potentially relevant studies and re-evaluated for inclusion. Two review authors independently extracted data related to study characteristics, risk of bias, and outcomes. We identified one trial for this review, thus we performed no meta-analysis. Two studies comparing memantine to placebo are currently awaiting classification until study investigators provide additional study details. We documented reasons for excluding studies from the review.
MAIN RESULTS
We included one multicenter RCT of adults with low-pressure glaucoma (Low-pressure Glaucoma Treatment Study, LoGTS) conducted in the USA. The primary outcome was progression of visual field loss after four years of treatment with either brimonidine or timolol. Of the 190 adults enrolled in the study, the investigators excluded 12 (6.3%) after randomization; 77 participants (40.5%) did not complete four years of follow-up. The rate of attrition was unbalanced between groups with more participants dropping out of the brimonidine group (55%) than the timolol group (29%).Of those remaining in the study at four years, participants assigned to brimonidine showed less progression of visual field loss than participants assigned to timolol (risk ratio (RR) 0.35, 95% confidence interval (CI) 0.14 to 0.86; 101 participants). Because of high risk of attrition bias and potential selective outcome reporting, we graded the certainty of evidence for this outcome as very low. At the four-year follow-up, the mean IOP was similar in both groups among those for whom data were available (mean difference 0.20 mmHg, 95% CI -0.73 to 1.13; 91 participants; very low-certainty evidence). The study authors did not report analyzable data for visual acuity or any data related to vertical cup-disc ratio, quality of life, or economic outcomes. The most frequent adverse event was ocular allergy to the study drug, which affected more participants in the brimonidine group than the timolol group (RR 5.32, 95% CI 1.64 to 17.26; 178 participants; very low-certainty evidence).
AUTHORS' CONCLUSIONS
Although the only trial we included in this review found less visual field loss in the brimonidine-treated group, the evidence was of such low certainty that we can draw no conclusions from this finding. Further clinical research is needed to determine whether neuroprotective agents may be beneficial for individuals with OAG. Such research should focus on outcomes important to patients, such as preservation of vision, and how these outcomes relate to cell death and optic nerve damage. As OAG is a chronic, progressive disease with variability in symptoms, RCTs designed to measure the effectiveness of neuroprotective agents require a long-term follow-up of five years or longer to detect clinically meaningful effects.
Topics: Adult; Antihypertensive Agents; Brimonidine Tartrate; Disease Progression; Glaucoma, Open-Angle; Humans; Neuroprotective Agents; Optic Nerve; Optic Nerve Diseases; Randomized Controlled Trials as Topic; Retinal Ganglion Cells; Timolol
PubMed: 28122126
DOI: 10.1002/14651858.CD006539.pub4 -
Aging and Disease Mar 2024Although researched extensively the understanding regarding mechanisms underlying glaucoma pathogenesis remains limited. Further, the exact mechanism behind neuronal... (Review)
Review
Although researched extensively the understanding regarding mechanisms underlying glaucoma pathogenesis remains limited. Further, the exact mechanism behind neuronal death remains elusive. The role of neuroinflammation in retinal ganglion cell (RGC) death has been prominently theorised. This review provides a comprehensive summary of neuroinflammatory responses in glaucoma. A systematic search of Medline and Embase for articles published up to 8th March 2023 yielded 32 studies using post-mortem tissues from glaucoma patients. The raw data were extracted from tables and text to calculate the standardized mean differences (SMDs). These studies utilized post-mortem tissues from glaucoma patients, totalling 490 samples, compared with 380 control samples. Among the included studies, 27 reported glial cell activation based on changes to cellular morphology and molecular staining. Molecular changes were predominantly attributed to astrocytes (62.5%) and microglia (15.6%), with some involvement of Muller cells. These glial cell changes included amoeboid microglial cells with increased CD45 or HLA-DR intensity and hypertrophied astrocytes with increased glial fibrillary acidic protein labelling. Further, changes to extracellular matrix proteins like collagen, galectin, and tenascin-C suggested glial cells' influence on structural changes in the optic nerve head. The activation of DAMPs-driven immune response and the classical complement cascade was reported and found to be associated with activated glial cells in glaucomatous tissue. Increased pro-inflammatory markers such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were also linked to glial cells. Glial cell activation was also associated with mitochondrial, vascular, metabolic and antioxidant component disruptions. Association of the activated glial cells with pro-inflammatory responses, dysregulation of homeostatic components and antigen presentation indicates that glial cell responses influence glaucoma progression. However, the exact mechanism triggering these responses and underlying interactions remains unexplored. This necessitates further research using human samples for an increased understanding of the precise role of neuroinflammation in glaucoma progression.
PubMed: 38502591
DOI: 10.14336/AD.2024.0103 -
Eye (London, England) May 2021To comprehensively assess diabetic retinopathy neurodegeneration (DRN) as quantified by retinal neuronal and axonal layers measured with spectral-domain optical... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
To comprehensively assess diabetic retinopathy neurodegeneration (DRN) as quantified by retinal neuronal and axonal layers measured with spectral-domain optical coherence tomography (SD-OCT) in subjects with diabetes mellitus (DM).
METHODS
Articles on the topic of examining macular ganglion cell-inner plexiform layer (m-GCIPL), macular retinal nerve fibre layer (m-RNFL), macular ganglion cell complex (m-GCC), and peripapillary RNFL (p-RNFL) measured with SD-OCT in DM subjects without DR (NDR) or with non-proliferative DR (NPDR) were searched in PubMed and Embase up to November 31, 2019. Standardized mean difference (SMD) as effect size were pooled using random-effects model.
RESULTS
Thirty-six studies searched from online databases and the CUHK DM cohort were included in the meta-analysis. In the comparison between NDR and control, macular measures including mean m-GCIPL (SMD = -0.26, p = 0.003), m-RNFL (SMD = -0.26, p = 0.046), and m-GCC (SMD = -0.28; p = 0.009) were significantly thinner in the NDR group. In the comparison between NPDR and NDR, only mean p-RNFL was significantly thinner in the NPDR group (SMD = -0.27; p = 0.03), but not other macular measures.
CONCLUSIONS
Thinning of retinal neuronal and axonal layers at macula as measured by SD-OCT are presented in eyes with NDR, supporting DRN may be the early pathogenesis in the DM patients without the presence of clinical signs of DR. In the future, these SD-OCT measures may be used as surrogates of DRN to stratify DM patients with a high risk of DR, and may be used as a therapeutic target if neuroprotection treatment for DR is available.
Topics: Humans; Macula Lutea; Nerve Fibers; Retina; Retinal Ganglion Cells; Tomography, Optical Coherence
PubMed: 32581390
DOI: 10.1038/s41433-020-1020-z -
Current Neuropharmacology 2024Tauroursodeoxycholic acid (TUDCA) is a naturally produced hydrophilic bile acid that has been used for centuries in Chinese medicine. Numerous recent and studies have...
BACKGROUND
Tauroursodeoxycholic acid (TUDCA) is a naturally produced hydrophilic bile acid that has been used for centuries in Chinese medicine. Numerous recent and studies have shown that TUDCA has neuroprotective action in various models of retinal disorders.
OBJECTIVE
To systematically review the scientific literature and provide a comprehensive summary on the neuroprotective action and the mechanisms involved in the cytoprotective effects of TUDCA.
METHODS
A systematic review was conducted in accordance with the PRISMA (The Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Systematic literature search of United States National Library of Medicine (PubMed), Web of Science, Embase, Scopus and Cochrane Library was performed, which covered all original articles published up to July 2022. The terms, "TUDCA" in combination with "retina", "retinal protection", "neuroprotection" were searched. Possible biases were identified with the adopted SYRCLE's tool.
RESULTS
Of the 423 initially gathered studies, 24 articles met inclusion/exclusion criteria for full-text review. Six of them were experiments, 17 studies reported data and one study described both and data. The results revealed the effect of TUDCA on different retinal diseases, such as retinitis pigmentosa (RP), diabetic retinopathy (DR), retinal degeneration (RD), retinal ganglion cell (RGC) injury, Leber's hereditary optic neuropathy (LHON), choroidal neovascularization (CNV), and retinal detachment (RDT). The quality scores of the studies were ranged from 5 to 7 points (total 10 points), according to SYRCLE's risk of bias tool. Both and data suggested that TUDCA could effectively delay degeneration and apoptosis of retinal neurons, preserve retinal structure and function, and its mechanism of actions might be related with inhibiting apoptosis, decreasing inflammation, attenuating oxidative stress, suppressing endoplasmic reticulum (ER) stress, and reducing angiogenesis.
CONCLUSION
This systematic review demonstrated that TUDCA has neuroprotective effect on and models of retinal disorders, reinforcing the currently available evidence that TUDCA could be a promising therapeutic agent in retinal diseases treatment. However, well designed clinical trials are necessary to appraise the efficacy of TUDCA in clinical setting.
Topics: Taurochenodeoxycholic Acid; Animals; Neuroprotective Agents; Humans; Retinal Diseases; Disease Models, Animal
PubMed: 37691227
DOI: 10.2174/1570159X21666230907152207 -
Frontiers in Medicine 2022Parkinson's disease (PD) is a multifaceted neurodegenerative disease. The optic nerve, as a window into the central nervous system (CNS), is known to be an important...
BACKGROUND
Parkinson's disease (PD) is a multifaceted neurodegenerative disease. The optic nerve, as a window into the central nervous system (CNS), is known to be an important part of the CNS and can be detected non-invasively. With the widespread availability of optical coherence tomography (OCT) devices, an increasing number of studies have paid attention to the neuropathological disorders in the retina of PD patients in recent years. However, it is still controversial whether OCT can be used as a complementary tool for PD diagnosis.
METHODS
This review is registered with PROSPERO, number CRD42022301258. The Embase, PUBMED, and The Cochrane Library databases were independently retrieved by 2 investigators to identify relevant papers published from 1 January 2017 to 24 January 2022. These studies used OCT or OCTA to evaluate the difference in the retinal nerve fiber layer (RNFL) thickness, ganglion cell layer(GCL) thickness, macula thickness, Cup and disk area superficial retinal capillary plexus (SCP), and deep retinal capillary plexus(DCP). The standard mean difference (SMD) with the 95% confidence interval (CI) was pooled for continuous outcomes.
RESULTS
In total, 26 studies had been enrolled in this meta-analysis with a total number of 2,790 eyes, including 1,343 eyes from the PD group along with 1,447 eyes from the HC group. The results revealed that the RNFL thickness (SMD: -0.53; 95%CI, -0.71∼-0.35; < 0.00001), GCL thickness (SMD: -0.43; 95%CI, -0.66 to -0.19; = 0.0003), macula thickness (SMD: -0.22; 95%CI, -0.22 to -0.11; < 0.0001) were significantly thinner in patients with PD. The SCP (SMD: -0.61; 95%CI, -1.31to -0.10; = 0.02) was significantly lower in PD patients. The DCP (SMD: -0.48; 95%CI, -1.02 to -0.06; = 0.08) is lower in PD patients, but the difference was statistically insignificant.
CONCLUSION
Retinal nerve fiber layer thickness, GCL thickness, macular thickness, and SVD of PD patients are lower than those of healthy control. OCT and OCTA could detect morphological retinal changes in PD and might be objective and reproducible auxiliary tools to assist clinician diagnosis.
SYSTEMATIC REVIEW REGISTRATION
[https://www.crd.york.ac.uk/prospero/], identifier [CRD42022301258].
PubMed: 36186761
DOI: 10.3389/fmed.2022.957700 -
Advances in Ophthalmology Practice and... Nov 2021To evaluate the feature of different retinal layer segmentation in neuromyelitis optica spectrum disorders (NMOSD) with spectral-domain optical coherence tomography... (Review)
Review
BACKGROUND
To evaluate the feature of different retinal layer segmentation in neuromyelitis optica spectrum disorders (NMOSD) with spectral-domain optical coherence tomography (SD-OCT) and to compare it with that in multiple sclerosis (MS), healthy controls (HC), and idiopathic optic neuritis (ION).
METHODS
We retrieved four electronic databases, including Pubmed, Embase, Cochrane Library, and Web of Science from inception to September 1st, 2021. A meta-analysis was performed to compare different retinal layer segmentation thicknesses between patients with or without a history of optic neuritis (ON) in NMOSD and the control group, including patients with MS, HC, and ION.
RESULTS
Forty-two studies were included and the interval between the last ON onset and examination was greater than 3 months. Compared with that in HC eyes, the loss of retinal nerve fiber layer (RNFL) and macular ganglion cell and inner plexiform layer (GC-IPL) was serious in NMOSD eye especially after ON. Moreover, compared with that in ION eyes or MS-related-ON eyes, the injury to the peripapillary retinal nerve fiber layer (pRNFL) was severe in NMOSD-related-ON eyes. In addition, the correlation coefficient between pRNFL and prognostic visual acuity was 0.43. However, the one-arm study revealed the inner nuclear layer (INL) was thickened in NMOSD-related-ON eyes compared with HC eyes.
CONCLUSIONS
Inclusion of the RNFL and macular GC-IPL is recommended for monitoring disease progression and attention should be paid to changes in the INL.
PubMed: 37846392
DOI: 10.1016/j.aopr.2021.100007 -
Progress in Brain Research 2020glaucoma is a remarkable social issue being the leading cause of irreversible blindness worldwide. It is a progressive neuropathy characterized by the death of the...
BACKGROUND
glaucoma is a remarkable social issue being the leading cause of irreversible blindness worldwide. It is a progressive neuropathy characterized by the death of the retinal ganglion cells, of which the most important risk factor is represented by the increase of intraocular pressure (IOP). The role of nutraceutical supplementations with anti-oxidant activity has been extensively tested in preclinical models of glaucoma. The clinical efficacy of nutraceuticals in glaucoma is still controversial.
OBJECTIVES
the aim of this systematic review is to assess the efficacy of nutraceuticals with anti-oxidant activity in glaucoma through the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) rigorous criteria.
DATA SOURCES
the literature search has been performed on the electronic databases currently recognized of most relevance for medical scientific literature, i.e. PubMed, MEDLINE, The Cochrane Central Register of Controlled Trials (CENTRAL) with access to EMBASE, ClinicalTrials.gov and Scopus. The date of last search is April 8th, 2020. Study eligibility criteria, participants, and interventions: prospective randomized clinical trials assessing the effects of nutraceuticals and anti-oxidants on IOP and/or visual field in patients with glaucoma. The eligible papers must be published in English and available in full text.
STUDY APPRAISAL AND SYNTHESIS METHODS
the evaluation of the eligibility of the studies has been carried out independently by two authors. The selection process has followed the PRISMA flow diagram, assessing the quality of the body of evidence and the risk of bias.
RESULTS
the search of literature has retrieved 1615 papers and 2 clinical trials with results, among which only 6 are eligible for inclusion in the present systematic review to address the preset participants, interventions, comparisons, outcomes and study design (PICOS) "are the nutraceuticals effective in glaucoma?". In 5 out of 6 studies the nutraceutical supplementation is effective in providing additional decrease of IOP to current usual therapy, without the occurrence of side effects. However, all the studies present high heterogeneity and some concerns in terms of risk of bias, apart from one trial for which the risk of bias is low.
CONCLUSIONS
the evidence of effectiveness of nutraceutical formulations is still uncertain and inconclusive. Therefore, large double-blind randomized clinical trials with adequate design, methodology and statistical power are needed to support the use of nutraceuticals in glaucoma.
Topics: Dietary Supplements; Glaucoma; Humans; Intraocular Pressure; Prospective Studies; Randomized Controlled Trials as Topic; Visual Fields
PubMed: 32988469
DOI: 10.1016/bs.pbr.2020.07.014 -
EClinicalMedicine Apr 2022Statins, the first-line therapy for hyperlipidemia, have received considerable attention as candidates for glaucoma treatments given its neuroprotective effects. In this...
BACKGROUND
Statins, the first-line therapy for hyperlipidemia, have received considerable attention as candidates for glaucoma treatments given its neuroprotective effects. In this systematic review and meta-analysis, we intended to assess the association of statin use with the onset and progression of open-angle glaucoma (OAG).
METHODS
Databases including PubMed, Embase and Web of Science Core Collection were searched for longitudinal studies reporting the association between statin use and OAG onset or progression on Feb 3, 2021. A meta-analysis was performed for the association between statin use and OAG onset. Relative risks (RRs) with 95% confidential intervals (CIs) were retrieved from included studies and pooled using random-effects models. Potential risks of bias were evaluated by the Newcastle-Ottawa Quality Assessment Scale for all eligible studies. This study had been registered on PROSPERO (CRD 42021232172).
FINDINGS
515,788 participants (mean age 68.7 years, 62.3% female) from ten studies were included in the systematic review of the association between statin use and OAG onset, and 26,347 OAG patients (mean age 67.3 years, 52.2% female) from seven studies were included for the association between statin use and OAG progression. Potential risks of bias were detected in 12 studies, which were mainly attributed to selection and confounding bias. In addition, 515,600 participants from eight studies were included in the meta-analysis which collectively showed that statin use was associated with a reduced risk of OAG onset (Pooled RR: 0.95; 95%CI: 0.93-0.98; I=0.199;). No significant heterogeneity or publication bias was found for studies included in the meta-analysis. There were inconsistent evidences for the association between statin use and OAG progression.
INTERPRETATION
Statin use is associated with a slightly lower risk of OAG onset based on existing evidences from longitudinal observational studies, the association between statin use and OAG progression remains inconclusive. The included evidences were typically weak due to poor study design and under-powered studies. Current findings should be interpreted cautiously and still need to be validated in further research.
FUNDING
The National Key R&D Program of China (2018YFC0116500), Science and Technology Planning Project of Guangdong Province (2013B20400003), the China Postdoctoral Science Foundation (2019TQ0365), the National Natural Science Foundation of China (82000901 and 82101171).
PubMed: 35399812
DOI: 10.1016/j.eclinm.2022.101364 -
Brain Research Oct 2023Light is detected in the eye by three classes of photoreceptors (rods, cones, and intrinsically photosensitive retinal ganglion cells (ipRGCs)) that are each optimized... (Meta-Analysis)
Meta-Analysis Review
Light is detected in the eye by three classes of photoreceptors (rods, cones, and intrinsically photosensitive retinal ganglion cells (ipRGCs)) that are each optimized for a specific function and express a particular light-detecting photopigment. The significant role of short-wavelength light and ipRGCs in improving alertness has been well-established; however, few reviews have been undertaken to assess the other wavelengths' effects regarding timing and intensity. This study aims to evaluate the impact of different narrowband light wavelengths on subjective and objective alertness among the 36 studies included in this systematic review, 17 of which were meta-analyzed. Short-wavelength light (∼460-480 nm) significantly improves subjective alertness, cognitive function, and neurological brain activities at night, even for a sustained period (∼6h) (for λmax: 470/475 nm, 0.4 < |Hedges's g| < 0.6, p < 0.05), but except early morning, it almost does not show this effect during the day when melatonin level is lowest. Long-wavelength light (∼600-640 nm) has little effect at night, but significantly increases several measures of alertness at lower irradiance during the daytime (∼1h), particularly when there is homeostatic sleep drive (for λmax: ∼630 nm, 0.5 < |Hedges's g| < 0.8, p < 0.05). The results further suggest that melanopic illuminance may not always be sufficient to measure the alerting effect of light.
Topics: Circadian Rhythm; Sleep; Retinal Cone Photoreceptor Cells; Retinal Ganglion Cells; Retinal Rod Photoreceptor Cells
PubMed: 37364848
DOI: 10.1016/j.brainres.2023.148470