Fabián Lerner - Academia.edu (original) (raw)

Papers by Fabián Lerner

Archives of Biochemistry and Biophysics, 2021

Glaucoma is a neurodegenerative disease that affects eye structures and brain areas related to th... more Glaucoma is a neurodegenerative disease that affects eye structures and brain areas related to the visual system. Oxidative stress plays a key role in the development and progression of the disease. The aims of the present study were to evaluate the mitochondrial function and its participation in the brain redox metabolism in an experimental glaucoma model. 3-month-old female Wistar rats were subjected to cauterization of two episcleral veins of the left eye to elevate the intraocular pressure. Seven days after surgery, animals were sacrificed, the brain was carefully removed and the primary visual cortex was dissected. Mitochondrial bioenergetics and ROS production, and the antioxidant enzyme defenses from both mitochondrial and cytosolic fractions were evaluated. When compared to control, glaucoma decreased mitochondrial ATP production (23%, p < 0.05), with an increase in superoxide and hydrogen peroxide production (30%, p < 0.01 and 28%, p < 0.05, respectively), whereas no changes were observed in membrane potential and oxygen consumption rate. In addition, the glaucoma group displayed a decrease in complex II activity (34%, p < 0.01). Moreover, NOX4 expression was increased in glaucoma compared to the control group (27%, p < 0.05). Regarding the activity of enzymes associated with the regulation of the redox status, glaucoma showed an increase in mitochondrial SOD activity (34%, p < 0.05), mostly due to an increase in Mn-SOD (50%, p < 0.05). A decrease in mitochondrial GST activity was observed (11%, p < 0.05). GR and TrxR activity were decreased in both mitochondrial (16%, p < 0.05 and 20%, p < 0.05 respectively) and cytosolic (21%, p < 0.01 and 50%, p < 0.01 respectively) fractions in the glaucoma group. Additionally, glaucoma showed an increase in cytoplasmatic GPx (50%, p < 0.01). In this scenario, redox imbalance took place resulting in damage to mitochondrial lipids (39%, p < 0.01) and proteins (70%, p < 0.05). These results suggest that glaucoma leads to mitochondrial function impairment in brain visual targets, that is accompanied by an alteration in both mitochondrial and cytoplasmatic enzymatic defenses. As a consequence of redox imbalance, oxidative damage to macromolecules takes place and can further affect vital cellular functions. Understanding the role of the mitochondria in the development and progression of the disease could bring up new neuroprotective therapies.

Clinical Ophthalmology, 2019

Introduction: Maximal medical therapy (MMT) is the use of ≥3 classes of topical antiglaucoma agen... more Introduction: Maximal medical therapy (MMT) is the use of ≥3 classes of topical antiglaucoma agents to achieve maximal intraocular pressure (IOP) reduction while minimizing adverse effects and compliance challenges. Purpose: To evaluate the additive IOP-lowering effect of twice-daily brinzolamide 1%/ brimonidine 0.2% fixed-dose combination (BBFC) used adjunctively with once daily travoprost 0.004%/timolol 0.5% fixed-dose combination (TTFC) in patients with open-angle glaucoma (OAG)/ocular hypertension (OHT). Methods: In this phase IV, double-masked study, patients on TTFC for ≥28 days, aged ≥18 years, with mean IOP ≥19 and ≤28 mmHg in at least 1 eye were randomized to receive BBFC+TTFC (n=67) or vehicle+TTFC (n=67) for 6 weeks. The primary endpoint was mean change in diurnal IOP from baseline (BL, averaged over 09:00 and 11:00) at Week 6. Results: The study was terminated prematurely due to recruitment challenges. BL mean IOP was similar in both groups (BBFC+TTFC: 21.6±1.78 mmHg; vehicle+TTFC: 21.8±1.90 mmHg). Mean change in diurnal IOP from BL at Week 6 was greater with BBFC+TTFC (−4.25 mmHg, 95% confidence interval [CI]: −4.7, −3.8) than with vehicle+TTFC (−2.11 mmHg, 95% CI: −2.6, −1.6, treatment difference, −2.15 mmHg (95% CI: −2.8, −1.5; P<0.001). Ocular adverse events (AEs) were reported in 11.9% of patients given BBFC+TTFC and 7.5% of patients given vehicle+TTFC. The AE with highest frequency was punctate keratitis (3%) in the BBFC+TTFC group; eye irritation (3%) in the vehicle+TTFC group. Conclusion: BBFC+TTFC as MMT demonstrated clinically relevant and statistically significant reductions in mean diurnal IOP in patients with OAG/OHT. AEs were consistent with known safety profiles of individual medications.

Archivos de la Sociedad Española de Oftalmología (English Edition), 2018

Objective: To report the results using Micropulse ® transscleral cyclophotocoagulation (Iridex) i... more Objective: To report the results using Micropulse ® transscleral cyclophotocoagulation (Iridex) in the treatment of glaucoma. Methods: Retrospective study in adult patients with glaucoma with at least 6 months of follow-up, and only one session of Micropulse ®. The same surgical technique was used in all cases. The only laser parameter that could vary was the total treatment duration (in seconds). The remaining parameters were fixed at 2 Watts of power and 0.5 ms (31.3%) of active cycle. Results: A total of 22 eyes of 17 patients with glaucoma of various types and stages were included (mainly congenital and pseudoexfoliation). The mean follow-up time was 7.9 months. The total treatment duration varied from 100 to 180 s. Definition of success: 5 mmHg < Intraocular pressure (IOP) < 21 mmHg and a reduction of ≥20% of the baseline value and no addition of oral carbonic anhydrase inhibitors, and no re-operation. The overall success rate was 72.7% in the first month, 54% at 4 months, 41% at 6 months, and 27.3% at final follow-up. Patients with longer treatment durations (180 s) achieved better results. The mean reduction in IOP in successful eyes was 36% (from 26.3 to 16.7 mmHg, SD 4.58, p = 0.028). No complications were reported. Conclusions: In a heterogeneous population of glaucoma (mostly congenital and pseudoexfoliation types), a low success rate (27.3%) was obtained in the medium-term with a single session of Micropulse ® .

International Ophthalmology, 2015

The objective of this study is to evaluate the efficacy and safety of a second Ahmed glaucoma val... more The objective of this study is to evaluate the efficacy and safety of a second Ahmed glaucoma valve (AGV) in eyes with refractory glaucoma that had undergone prior Ahmed device implantation. This multicenter, retrospective study evaluated 58 eyes (58 patients) that underwent a second AGV (model S2-n = 50, model FP7-n = 8) due to uncontrolled IOP under maximal medical therapy. Outcome measures included IOP, visual acuity, number of glaucoma medications, and postoperative complications. Success was defined as IOP &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;21 mmHg (criterion 1) or 30 % reduction of IOP (criterion 2) with or without hypotensive medications. Persistent hypotony (IOP &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;5 mmHg after 3 months of follow-up), loss of light perception, and reintervention for IOP control were defined as failure. Mean preoperative IOP and mean IOPs at 12 and 30 months were 27.55 ± 1.16 mmHg (n = 58), 14.45 ± 0.83 mmHg (n = 42), and 14.81 ± 0.87 mmHg (n = 16), respectively. The mean numbers of glaucoma medications preoperatively at 12 and 30 months were 3.17 ± 0.16 (n = 58), 1.81 ± 0.2 (n = 42), and 1.83 ± 0.35 (n = 18), respectively. The reductions in mean IOP and number of medications were statistically significant at all time intervals (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001). According to criterion 1, Kaplan-Meier survival curves disclosed success rates of 62.9 % at 12 months and 56.6 % at 30 months. According to criterion 2, Kaplan-Meier survival curves disclosed success rates of 43.9 % at 12 months and 32.9 % at 30 months. The most frequent early complication was hypertensive phase (10.3 %) and the most frequent late complication was corneal edema (17.2 %). Second AGV implantation may effectively reduce IOP in eyes with uncontrolled glaucoma, and is associated with relatively few complications.

The Mystery of Glaucoma, 2011

Investigative Opthalmology & Visual Science, 2010

PURPOSE. To evaluate the relationship between oxidative stress markers and increased intraocular ... more PURPOSE. To evaluate the relationship between oxidative stress markers and increased intraocular pressure in experimental glaucoma. METHODS. In vivo chemiluminescence (CL), total antioxidant capacity (TRAP), nitrite concentration (NC), and lipid peroxidation markers (TBARS) were evaluated. Wistar rats (n ϭ 18 for each time point) underwent operation, and two episcleral veins were cauterized. RESULTS. Decreases of 22%, 35%, and 27% at 7, 15, and 30 days and an increase of 22% at 60 days in CL were observed in glaucomatous eyes. In optic nerve, TBARS values were 6.9 Ϯ 0.5 nmol/mg protein (7 days), 9.4 Ϯ 0.4 nmol/mg protein (15 days), 18.0 Ϯ 1.2 nmol/mg protein (30 days), and 43.1 Ϯ 5.3 nmol/mg protein (60 days) (control, 6.2 Ϯ 0.4 nmol/mg protein; P Ͻ 0.001). NC was 37.0 Ϯ 1.8 M (7 days), 31.4 Ϯ 1.2 M (15 days), 39.6 Ϯ 1.3 M (30 days), and 40.0 Ϯ 1.3 M (60 days) (control, 21.1 Ϯ 1.7 M; P Ͻ 0.001). In glaucomatous vitreous humor, TRAP decreased by 42% at 15 days and 78% at 60 days (control, 414 Ϯ 29 M; P Ͻ 0.001). In glaucomatous aqueous humor, TRAP values were 75 Ϯ 7 M (7 days), 54 Ϯ 4 M (15 days), 25 Ϯ 4 M (30 days), and 50 Ϯ 3 M (60 days) (control, 90 Ϯ 10 M; P Ͻ 0.001). CONCLUSIONS. Reactive species were increased in glaucoma, as evidenced by the increases in CL, TBARS, and NC. The decrease in the antioxidant levels may be a consequence of an increase in oxidative processes.

American Journal of Ophthalmology, 2004

Acta Ophthalmologica, 2012

The goal of the present study is to establish the antioxidant status in the brain of a high press... more The goal of the present study is to establish the antioxidant status in the brain of a high pressure-induced rat model. Methods: Ocular hypertension was induced in rats (n = 12) cauterizing two episcleral veins under a surgical microscope. A sham procedure (n = 12) was performed in the control group. The markers evaluated in the brain 7 days after surgery were as follows: spontaneous chemiluminescence, protein carbonylation, nitrite concentration, total reactive antioxidant potential (TRAP), ascorbic acid, glutathione, vitamin E and activities of superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase. Results: Chemiluminescence in glaucoma was 55% higher than in controls (393 ± 20 cpm ⁄ mg protein, p < 0.001). Protein carbonylation in glaucoma was 93% higher than in controls (1.15 ± 0.18 nmol ⁄ mg protein, p < 0.001). Nitrite concentration was 5.30 ± 0.25 lM for glaucoma (controls 4.41 ± 0.24 lM, p < 0.05). Total reactive antioxidant potential decreased by 42% in glaucoma (controls 153 ± 14 lM Trolox, p < 0.001). Ascorbic acid was 67 ± 26 lM for glaucoma (controls 275 ± 22 lM, p < 0.001). Vitamin E was 0.58 ± 0.05 lmol ⁄ g organ for glaucoma (controls 1.10 ± 0.06 lmol ⁄ g organ, p < 0.01). Glutathione was 1.98 ± 0.13 lmol ⁄ g organ for glaucoma (controls 8.19 ± 0.71 lmol ⁄ g organ, p < 0.001). Superoxide dismutase and GPx were increased in glaucoma by 42 and 59%, respectively (p < 0.05). Conclusions: Reactive oxygen and nitrogen species were increased in glaucoma, the increase in chemiluminescence, protein carbonylation and nitrite levels could be evidenced by this situation. The decrease in nonenzymatic antioxidants and a compensatory increase in SOD and GPx activity may have been a consequence of an increase in oxidative processes.

Nature genetics, Jan 23, 2015

Exfoliation syndrome (XFS) is the most common recognizable cause of open-angle glaucoma worldwide... more Exfoliation syndrome (XFS) is the most common recognizable cause of open-angle glaucoma worldwide. To better understand the etiology of XFS, we conducted a genome-wide association study (GWAS) of 1,484 cases and 1,188 controls from Japan and followed up the most significant findings in a further 6,901 cases and 20,727 controls from 17 countries across 6 continents. We discovered a genome-wide significant association between a new locus (CACNA1A rs4926244) and increased susceptibility to XFS (odds ratio (OR) = 1.16, P = 3.36 × 10(-11)). Although we also confirmed overwhelming association at the LOXL1 locus, the key SNP marker (LOXL1 rs4886776) demonstrated allelic reversal depending on the ancestry group (Japanese: ORA allele = 9.87, P = 2.13 × 10(-217); non-Japanese: ORA allele = 0.49, P = 2.35 × 10(-31)). Our findings represent the first genetic locus outside of LOXL1 surpassing genome-wide significance for XFS and provide insight into the biology and pathogenesis of the disease.

Ophthalmology, 2003

To compare the efficacy and safety of topical bimatoprost (LUMIGAN; Allergan, Inc., Irvine, CA) o... more To compare the efficacy and safety of topical bimatoprost (LUMIGAN; Allergan, Inc., Irvine, CA) once daily with that of topical combined timolol and dorzolamide (Cosopt; Merck and Co, Inc., Whitehouse Station, NJ) twice daily. Prospective, randomized, double-masked, multicenter clinical trial. One hundred seventy-seven patients with a diagnosis of glaucoma or ocular hypertension and inadequate control of intraocular pressure (IOP) after at least 2 weeks of topical timolol maleate 0.5% monotherapy. Patients were randomized to receive bimatoprost 0.03% once daily (n = 90) or combined timolol 0.5% and dorzolamide 2% twice daily (n = 87) over a 3-month period. Intraocular pressure, the primary end point, was measured at 8 AM and 10 AM at baseline, week 1, and months 1, 2, and 3, and also at 4 PM and 8 PM at baseline and month 3. Bimatoprost provided significantly greater IOP lowering compared with combined timolol and dorzolamide. At the 8 AM measurements, bimatoprost lowered mean IOP 6.8 mmHg to 7.6 mmHg from baseline, whereas combined timolol and dorzolamide lowered mean IOP 4.4 to 5.0 mmHg from baseline (P&amp;amp;amp;amp;amp;amp;amp;lt;0.001). At the last follow-up, patients had better diurnal IOP control with bimatoprost than combined timolol and dorzolamide. At 8 AM at the 3-month visit, the percentages of patients achieving IOPs of &amp;amp;amp;amp;amp;amp;amp;lt;or =13 mmHg, &amp;amp;amp;amp;amp;amp;amp;lt; or =14 mmHg, &amp;amp;amp;amp;amp;amp;amp;lt; or =15 mmHg, or &amp;amp;amp;amp;amp;amp;amp;lt; or =16 mmHg were more than twice as high for bimatoprost than for combined timolol and dorzolamide (all P&amp;amp;amp;amp;amp;amp;amp;lt; or =0.008). Taste perversion, ocular burning, and stinging with instillation were more common with combined timolol and dorzolamide, whereas conjunctival hyperemia was more common with bimatoprost. In individuals with glaucoma or ocular hypertension, uncontrolled on a topical beta-blocker alone, bimatoprost lowered IOP more consistently than did combined timolol and dorzolamide.

International ophthalmology, Jan 3, 2015