Bax Contributes to Retinal Ganglion Cell Dendritic Degeneration During Glaucoma

Risner, Michael L.; Pasini, Silvia; McGrady, Nolan R; Calkins, David J.

doi:10.1007/s12035-021-02675-5

Cited by 15 publications

(25 citation statements)

References 59 publications

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“…We performed whole-cell recordings from whole-mount mouse retinas as previously described. 19–21 Animals were euthanized by cervical dislocation, eyes were enucleated, and retinas were dissected out under long-wavelength illumination (630 nm, 800 μW/cm 2 , FND/FG; Ushio, Cypress, CA, USA). Retinas were placed in carbogen-saturated Ames’ medium (US Biologic, Memphis, TN, USA) containing 20 mM glucose and 22.6 mM NaHCO 3 (pH 7.4, 290 Osm).…”

Section: Methodsmentioning

confidence: 99%

“…RGC dendritic morphologies were hand traced in Adobe Photoshop, and we measured cross-sectional soma area, dendritic area, total dendritic length and number of branching points. 19 , 1–3 The total dendritic length was defined as the sum of all dendritic lengths. A branch point was defined as the point of bifurcation of a dendrite from a parent dendrite.…”

Section: Methodsmentioning

confidence: 99%

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Axon hyperexcitability in the contralateral projection following unilateral optic nerve crush in mice

McGrady

Holden

Ribeiro

et al. 2022

Brain Communications

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Optic neuropathies are characterized by degeneration of retinal ganglion cell axonal projections to the brain, including acute conditions like optic nerve trauma and progressive conditions such as glaucoma. Despite different etiologies, retinal ganglion cell axon degeneration in traumatic optic neuropathy and glaucoma share common pathological signatures. We compared how early pathogenesis of optic nerve trauma and glaucoma influence axon function in the mouse optic projection. We assessed pathology by measuring anterograde axonal transport from retina to superior colliculus, current-evoked optic nerve compound action potential, and retinal ganglion cell density one week following unilateral optic nerve crush or intraocular pressure elevation. Nerve crush reduced axon transport, compound axon potential, and retinal ganglion cell density, which were unaffected by intraocular pressure elevation. Surprisingly, optic nerves contralateral to crush demonstrated 5-fold enhanced excitability in compound action potential compared to naïve nerves. Enhanced excitability in contralateral sham nerves is not due to increased accumulation of voltage-gated sodium channel 1.6, or ectopic voltage-gated sodium channel 1.2 expression within nodes of Ranvier. Our results indicate hyperexcitability is driven by intrinsic responses of αON-Sustained retinal ganglion cells. We found αON-Sustained retinal ganglion cells in contralateral, sham, eyes demonstrated increased responses to depolarizing currents compared to those from naïve eyes, while light-driven responses remained intact. Dendritic arbors of αON-Sustained retinal ganglion cells of the sham eye were like naïve, but soma area and non-phosphorylated neurofilament H increased. Current- and light-evoked responses of sham αOFF-Sustained retinal ganglion cells remained stable along with somato-dendritic morphologies. In retinas directly affected by crush, light responses of αON- and αOFF-Sustained retinal ganglion cells diminished compared to naïve cells along with decreased dendritic field area or branch points. Like light responses, αOFF-Sustained retinal ganglion cell current-evoked responses diminished, but surprisingly, αON-Sustained retinal ganglion cell responses were similar to those from naïve retinas. Optic nerve crush reduced dendritic length and area in αON-Sustained retinal ganglion cells in eyes ipsilateral to injury, while crush significantly reduced dendritic branching in αOFF-Sustained retinal ganglion cells. Interestingly, one week of intraocular pressure elevation only affected αOFF-Sustained retinal ganglion cell physiology, depolarizing resting membrane potential in cells of affected eyes and blunting current-evoked responses in cells of saline-injected eyes. Collectively, our results suggest that neither saline nor sham surgery provide a true control, chronic vs. acute optic neuropathies differentially affect retinal ganglion cells composing the ON and OFF pathways, and acute stress can have near-term effects on the contralateral projection.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Axon hyperexcitability in the contralateral projection following unilateral optic nerve crush in mice

McGrady

Holden

Ribeiro

et al. 2022

Brain Communications

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“…Its overexpression can promote mitochondria to increase the release of cytochrome c and apoptosis factors, which may antagonize the protective effect of Bcl-2 and make cells susceptible to apoptosis. 27 , 28 In fact, Bcl-2 and Bax proteins form heterodimers, and the ratio between Bcl-2 and Bax ultimately determines whether the cell undergoes apoptosis. Under normal conditions, the ratio of Bcl-2/Bax is close to 1.0 and does not initiate apoptosis.…”

Section: Resultsmentioning

confidence: 99%

Development and Evaluation of Puerarin Loaded-Albumin Nanoparticles Thermoresponsive in situ Gel for Ophthalmic Delivery

Hu¹,

Xu²,

Meng³

2022

DDDT

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Puerarin (PUR) is a major bioactive ingredient extracted from the root of Pueraria lobata (Willd.) Ohwi, which is known as Gegen in traditional Chinese medicine. Conventional PUR ophthalmic dosage forms such as solutions and suspensions have many drawbacks, including-rapid precorneal elimination of the drug mainly due to lacrimal duct drainage. The purpose of this study is to develop a thermal responsive in situ gel system containing PUR-loaded human albumin nanoparticles (PUR-HSA-NPs ISG). Methods: The system has the required sol-gel phase transition temperature, and therefore can be used for local ocular administration to treat glaucoma. The formulation was evaluated for its sol-gel transition temperature, viscosity and in vitro release. In vivo eye irritation was evaluated in rabbits. In this study, the animal model of glaucoma was used to evaluate the pharmacodynamics of PUR-HSA-NPs ISG in vivo. Results: Morphologically, the PUR-HSA-NPs ISG exhibited a normal spherical shape with no aggregation or degradation. It had a mean size of 64.8 nm, and the drug-loading and encapsulation efficiency were 7.1%±0.3% and 80.7%±7.4%, respectively. The gelation temperature of the prepared PUR-HSA-NPs ISG thermogelling solutions was 37°C. Meanwhile, the PUR-HSA-NPs ISG showed thixotropic behavior with the downward curve exhibiting lower shear stress values as compared to corresponding points on the upward curve. The pharmacological results showed a continuous reduction of the IOP value for a long time and that the value remained in a lower-level range compared to that in the PUR eye drop group. According to the pharmacodynamic results, the Bcl-2/Bax ratio of the PUR-HSA-NPs ISG group was closest to 1 (0.8798, 24 h), with obvious reduction of tissue cell apoptosis. Conclusion: Through this study, it was found that PUR-HSA-NPs ISG is an ideal ocular drug delivery system. It is hoped that this product could be further promoted for clinical applications in the future.

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“…The Vanderbilt University Institutional Animal Care and Use Committee approved all experimental procedures. We used microbead occlusion to elevate intraocular pressure (IOP) unilaterally in 6- to 8-week-old male C57BL/6 mice (n = 7 per cohort; Charles River Laboratory, Wilmington, MA), following our published protocol [ 20 , 21 , 43 , 44 , 45 , 67 , 68 ]. We obtained bilateral IOP measurements 2–3 days prior to elevation in anesthetized (2.5% isoflurane) mice using TonoPen XL (Medtronic Solan, Minneapolis, MN, USA) and averaged these to obtain a baseline measure (day 0).…”

Section: Methodsmentioning

confidence: 99%

Intraocular Delivery of a Collagen Mimetic Peptide Repairs Retinal Ganglion Cell Axons in Chronic and Acute Injury Models

Ribeiro

McGrady

Baratta³

et al. 2022

IJMS

Self Cite

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Vision loss through the degeneration of retinal ganglion cell (RGC) axons occurs in both chronic and acute conditions that target the optic nerve. These include glaucoma, in which sensitivity to intraocular pressure (IOP) causes early RGC axonal dysfunction, and optic nerve trauma, which causes rapid axon degeneration from the site of injury. In each case, degeneration is irreversible, necessitating new therapeutics that protect, repair, and regenerate RGC axons. Recently, we demonstrated the reparative capacity of using collagen mimetic peptides (CMPs) to heal fragmented collagen in the neuronal extracellular milieu. This was an important step in the development of neuronal-based therapies since neurodegeneration involves matrix metalloproteinase (MMP)-mediated remodeling of the collagen-rich environment in which neurons and their axons exist. We found that intraocular delivery of a CMP comprising single-strand fractions of triple helix human type I collagen prevented early RGC axon dysfunction in an inducible glaucoma model. Additionally, CMPs also promoted neurite outgrowth from dorsal root ganglia, challenged in vitro by partial digestion of collagen. Here, we compared the ability of a CMP sequence to protect RGC axons in both inducible glaucoma and optic nerve crush. A three-week +40% elevation in IOP caused a 67% degradation in anterograde transport to the superior colliculus, the primary retinal projection target in rodents. We found that a single intravitreal injection of CMP during the period of IOP elevation significantly reduced this degradation. The same CMP delivered shortly after optic nerve crush promoted significant axonal recovery during the two-week period following injury. Together, these findings support a novel protective and reparative role for the use of CMPs in both chronic and acute conditions affecting the survival of RGC axons in the optic projection to the brain.

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Bax Contributes to Retinal Ganglion Cell Dendritic Degeneration During Glaucoma

Cited by 15 publications

References 59 publications

Axon hyperexcitability in the contralateral projection following unilateral optic nerve crush in mice

Axon hyperexcitability in the contralateral projection following unilateral optic nerve crush in mice

Development and Evaluation of Puerarin Loaded-Albumin Nanoparticles Thermoresponsive in situ Gel for Ophthalmic Delivery

Intraocular Delivery of a Collagen Mimetic Peptide Repairs Retinal Ganglion Cell Axons in Chronic and Acute Injury Models

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