Glaucoma, the second leading cause of irreversible blindness worldwide, is associated with age and sensitivity to intraocular pressure (IOP). We have shown that elevated IOP causes an early increase in levels of reactive oxygen species (ROS) in the microbead occlusion mouse model. We also detected an endogenous antioxidant response mediated by Nuclear factor erythroid 2-Related Factor 2 (NRF2), a transcription factor that binds to the antioxidant response element (ARE) and increases transcription of antioxidant genes. Our previous studies show that inhibiting this pathway results in earlier and greater glaucoma pathology. In this study, we sought to determine if this endogenous antioxidant response is driven by the retinal ganglion cells (RGCs) or glial cells. We used Nrf2^fl/fl mice and cell-type specific adeno-associated viruses (AAVs) expressing Cre to alter Nrf2 levels in either the RGCs or glial cells. Then, we quantified the endogenous antioxidant response, visual function and optic nerve histology after IOP elevation. We found that knock-down of Nrf2 in either cell type blunts the antioxidant response and results in earlier pathology and vision loss. Further, we show that delivery of Nrf2 to the RGCs is sufficient to provide neuroprotection. In summary, both the RGCs and glial cells contribute to the antioxidant response, but treatment of the RGCs alone with increased Nrf2 is sufficient to delay onset of vision loss and axon degeneration in this induced model of glaucoma.

Glaucoma is a progressive age-related disease of the visual system and the leading cause of irreversible blindness worldwide. Currently, intraocular pressure (IOP) is the only modifiable risk factor for the disease, but even as IOP is lowered, the pathology of the disease often progresses. Hence, effective clinical targets for the treatment of glaucoma remain elusive. Glaucoma shares comorbidities with a multitude of vascular diseases, and evidence in humans and animal models demonstrates an association between vascular dysfunction of the retina and glaucoma pathology. Integral to the survival of retinal ganglion cells (RGCs) is functional neurovascular coupling (NVC), providing RGCs with metabolic support in response to neuronal activity. NVC is mediated by cells of the neurovascular unit (NVU), which include vascular cells, glial cells, and neurons. Nitric oxide-cyclic guanosine monophosphate (NO-cGMP) signaling is a prime mediator of NVC between endothelial cells and neurons, but emerging evidence suggests that cGMP signaling is also important in the physiology of other cells of the NVU. NO-cGMP signaling has been implicated in glaucomatous neurodegeneration in humans and mice. In this review, we explore the role of cGMP signaling in the different cell types of the NVU and investigate the potential links between cGMP signaling, breakdown of neurovascular function, and glaucoma pathology.

Erythropoietin (EPO) is neuroprotective in multiple models of neurodegenerative diseases, including glaucoma. EPO-R76E retains the neuroprotective effects of EPO but diminishes the effects on hematocrit. Treatment with EPO-R76E in a glaucoma model increases expression of antioxidant proteins and is neuroprotective. A major pathway that controls the expression of antioxidant proteins is the NRF2/ARE pathway. This pathway is activated endogenously after elevation of intraocular pressure (IOP) and contributes to the slow onset of pathology in glaucoma. In this study, we explored if sustained release of EPO-R76E in the eye would activate the NRF2/ARE pathway and if this pathway was key to its neuroprotective activity. Treatment with PLGA.EPO-E76E prevented increases in retinal superoxide levels in vivo, and caused phosphorylation of NRF2 and upregulation of antioxidants. Further, EPO-R76E activates NRF2 via phosphorylation by the MAPK pathway rather than the PI3K/Akt pathway, used by the endogenous antioxidant response to elevated IOP.

Background: Meniscal allograft transplantation (MAT) has been established as a safe, effective treatment for meniscal deficiency. However, questions remain regarding pre- and perioperative factors that affect MAT outcomes. Purpose: To assess predictive factors for preoperative to postoperative change in Lysholm score (ΔLysholm) and nonfailure reoperations after MAT. Study Design: Systematic review and meta-analysis; Level of evidence, 4. Methods: The Ovid Medline, Embase, Scopus, and Clinicaltrials.gov databases were systematically searched for studies investigating clinical outcomes after MAT, including Lysholm scores, failure, complications, or reoperations. Study characteristics, predictive factors, and outcomes were extracted. The primary outcomes included ΔLysholm scores and nonfailure reoperations. Nonfailure reoperation was defined as any nonfailure meniscus-related procedure after primary MAT aiming to improve knee function. Failure was defined as conversion to total/unilateral knee arthroplasty, total or subtotal meniscectomy/allograft removal, or revision MAT. Relationships between predictive factors and outcomes were analyzed by meta-analysis or by weighted linear regression. Significant factors were included in a multivariable meta-regression. Results: Of 2347 screened titles, 154 met inclusion criteria. A total of 11,413 patients and 11,548 transplanted menisci were identified. The estimated pooled ΔLysholm score was 24.2 (SD, 6.08), and the nonfailure reoperation incidence rate was 3.36% (SD, 7.46%). No prognostic factors were significantly associated with differing ΔLysholm scores from meta-analysis. Lateral MATs had greater risk of nonfailure reoperation than medial MATs (ln[RR], −0.74; 95% CI, −1.37 to −0.108; P = .022). From multivariable regression, shorter time between meniscectomy and MAT ( P = .007) and older age ( P = .02) predicted less favorable cohort ΔLysholm scores. Longer intervals between injury and MAT ( P = .039) and bone-bridge graft fixation for medial MAT compared with bone-plug fixation ( P < .001) predicted higher risk of nonfailure reoperation. Conclusion: This systematic review and meta-analysis identified lateral MAT as a significant risk factor for nonfailure reoperation. Older age and shorter time interval between meniscectomy and MAT were significantly associated with less favorable ΔLysholm scores. A longer meniscal injury-MAT time interval and bone-bridge compared with bone-plug fixation technique for medial MAT were significantly associated with higher reoperation risk.