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Oral Scutellarin Treatment Ameliorates Retinal Thinning and Visual Deficits in Experimental Glaucoma.

ABSTRACT: Purpose: Intraocular pressure (IOP) is currently the only modifiable risk factor for glaucoma, yet glaucoma can continue to progress despite controlled IOP. Thus, development of glaucoma neurotherapeutics remains an unmet need. Scutellarin is a flavonoid that can exert neuroprotective effects in the eye and brain. Here, we investigated the neurobehavioral effects of scutellarin treatment in a chronic IOP elevation model. Methods: Ten adult C57BL/6J mice were unilaterally injected with an optically clear hydrogel into the anterior chamber to obstruct aqueous outflow and induce chronic IOP elevation. Eight other mice received unilateral intracameral injection of phosphate-buffered saline only. Another eight mice with hydrogel-induced unilateral chronic IOP elevation also received daily oral gavage of 300 mg/kg scutellarin. Tonometry, optical coherence tomography, and optokinetics were performed longitudinally for 4 weeks to monitor the IOP, retinal nerve fiber layer thickness, total retinal thickness, visual acuity, and contrast sensitivity of both eyes in all three groups. Results: Intracameral hydrogel injection resulted in unilateral chronic IOP elevation with no significant inter-eye IOP difference between scutellarin treatment and untreated groups. Upon scutellarin treatment, the hydrogel-injected eyes showed less retinal thinning and reduced visual behavioral deficits when compared to the untreated, hydrogel-injected eyes. No significant difference in retinal thickness or optokinetic measures was found in the contralateral, non-treated eyes over time or between all groups. Conclusion: Using the non-invasive measuring platform, oral scutellarin treatment appeared to preserve retinal structure and visual function upon chronic IOP elevation in mice. Scutellarin may be a novel neurotherapeutic agent for glaucoma treatment.

SUBMITTER: Zhu J

PROVIDER: S-EPMC8369066 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PurposeTo compare the rates of retinal nerve fiber layer (RNFL) loss in patients suspected of having glaucoma who developed visual field damage (VFD) with those who did not develop VFD and to determine whether the rate of RNFL loss can be used to predict the development of VFD.DesignProspective, observational cohort study.ParticipantsGlaucoma suspects, defined as having glaucomatous optic neuropathy or ocular hypertension (intraocular pressure, >21 mmHg) without repeatable VFD at baseline, from the Diagnostic Innovations in Glaucoma Study and the African Descent and Glaucoma Evaluation Study.MethodsGlobal and quadrant RNFL thickness (RNFLT) were measured with the Spectralis spectral-domain optical coherence tomography (SD-OCT; Spectralis HRA+OCT [Heidelberg Engineering, Heidelberg, Germany]). Visual field damage was defined as having 3 consecutive abnormal visual fields. The rate of RNFL loss in eyes developing VFD was compared to eyes not developing VFD using multivariate linear mixed-effects models. A joint longitudinal survival model used the estimated RNFLT slope to predict the risk of developing VFD, while adjusting for potential confounding variables.Main outcome measuresThe rate of RNFL thinning and the probability of developing VFD.ResultsFour hundred fifty-four eyes of 294 glaucoma suspects were included. The average number of SD-OCT examinations was 4.6 (range, 2-9), with median follow-up of 2.2 years (0.4-4.1 years). Forty eyes (8.8%) developed VFD. The estimated mean rate of global RNFL loss was significantly faster in eyes that developed VFD compared with eyes that did not develop VFD (-2.02 μm/year vs. -0.82 μm/year; P<0.001). The joint longitudinal survival model showed that each 1-μm/year faster rate of global RNFL loss corresponded to a 2.05-times higher risk of developing VFD (hazard ratio, 2.05; 95% confidence interval, 1.14-3.71; P = 0.017).ConclusionsThe rate of global RNFL loss was more than twice as fast in eyes that developed VFD compared with eyes that did not develop VFD. A joint longitudinal survival model showed that a 1-μm/year faster rate of RNFLT loss corresponded to a 2.05-times higher risk of developing VFD. These results suggest that measuring the rate of SD-OCT RNFL loss may be a useful tool to help identify patients who are at a high risk of developing visual field loss.

Project description:PurposeTo determine if oral losartan treatment decreases the retinal ganglion cell (RGC) death caused by experimental intraocular pressure (IOP) elevation in mice.MethodsWe produced IOP increase in CD1 mice and performed unilateral optic nerve crush. Mice received oral losartan, spironolactone, enalapril, or no drug to test effects of inhibiting angiotensin receptors. IOP was monitored by Tonolab, and blood pressure was monitored by tail cuff device. RGC loss was measured in masked axon counts and RGC bodies by ?-tubulin labeling. Scleral changes that could modulate RGC injury were measured including axial length, scleral thickness, and retinal layer thicknesses, pressure-strain behavior in inflation testing, and study of angiotensin receptors and pathways by reverse transcription polymerase chain reaction, Western blot, and immunohistochemistry.ResultsLosartan treatment prevented significant RGC loss (median loss = 2.5%, p = 0.13), while median loss with water, spironolactone, and enalapril treatments were 26%, 28% and 43%; p < 0.0001). The lower RGC loss with losartan was significantly less than the loss with spironolactone or enalapril (regression model p = 0.001; drug treatment group term p = 0.01). Both losartan and enalapril significantly lowered blood pressure (p< 0.001), but losartan was protective, while enalapril led to worse than water-treated RGC loss. RGC loss after crush injury was unaffected by losartan treatment (difference from control p = 0.9). Survival of RGC in cell culture was not prolonged by sartan treatment. Axonal transport blockade after 3 day IOP elevations was less in losartan-treated than in control glaucoma eyes (p = 0.007). Losartan inhibited effects of glaucoma, including reduction in extracellular signal-related kinase activity and modification of glaucoma-related changes in scleral thickness and creep under controlled IOP.ConclusionsThe neuroprotective effect of losartan in mouse glaucoma is associated with adaptive changes in the sclera expressed at the optic nerve head.

Project description:ImportanceHigher intraocular pressure variability may be associated with faster structural changes in patients with glaucoma.ObjectivesTo investigate the association of mean intraocular pressure and intraocular pressure variability (defined as the SD of intraocular pressure and the intraocular pressure range) with the rate of retinal nerve fiber layer thinning over time in patients with glaucoma.Design, setting, and participantsIn this retrospective analysis of a longitudinal cohort, patients were enrolled from the Diagnostic Innovations in Glaucoma Study and the African Descent and Glaucoma Evaluation study. A total of 815 eyes (564 with perimetric glaucoma and 251 with preperimetric glaucoma) from 508 patients with imaging follow-up for a mean of 6.3 years from December 2008 to October 2020 were studied. Data were analyzed from November 2021 to March 2022.Main outcomes and measuresIn this longitudinal study, eyes with at least 4 visits and 2 years of follow-up optical coherence tomography and intraocular pressure measurement were included. A linear mixed-effect model was used to investigate the association of intraocular pressure parameters with the rates of retinal nerve fiber layer thinning. Dominance analysis was performed to determine the relative importance of the intraocular pressure parameters.ResultsOf 508 included patients, 280 (55.1%) were female, 195 (38.4%) were African American, 24 (4.7%) were Asian, 281 (55.3%) were White, and 8 (1.6%) were another race or ethnicity; the mean (SD) age was 65.5 (11.0) years. The mean rate of retinal nerve fiber layer change was -0.67 (95% CI, -0.73 to -0.60) μm per year. In multivariable models adjusted for mean intraocular pressure and other confounding factors, faster annual rate of retinal nerve fiber layer thinning was associated with a higher SD of intraocular pressure (-0.20[ 95% CI, -0.26 to -0.15] μm per 1-mm Hg higher; P < .001) or higher intraocular pressure range (-0.05 [95% CI, -0.06 to -0.03] μm per 1-mm Hg higher; P < .001).Conclusions and relevanceIn this study, intraocular pressure variability was independently associated with structural change in patients with glaucoma, even after adjustment for mean intraocular pressure, supporting its potential value in clinical management.

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Oral Scutellarin Treatment Ameliorates Retinal Thinning and Visual Deficits in Experimental Glaucoma.

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