Redistribution of metabolic resources through astrocyte networks mitigates neurodegenerative stress.

In the central nervous system, glycogen-derived bioenergetic resources in astrocytes help promote tissue survival in response to focal neuronal stress. However, our understanding of the extent to which these resources are mobilized and utilized during neurodegeneration, especially in nearby regions that are not actively degenerating, remains incomplete. Here we modeled neurodegeneration in glaucoma, the world's leading cause of irreversible blindness, and measured how metabolites mobilize through astrocyte gap junctions composed of connexin 43 (Cx43).

Of Mice and Monkeys: Neuroprotective Efficacy of the p38 Inhibitor BIRB 796 Depends on Model Duration in Experimental Glaucoma.

Glaucoma is a group of optic neuropathies associated with aging and sensitivity to intraocular pressure (IOP). Early progression involves retinal ganglion cell (RGC) axon dysfunction that precedes frank degeneration. Previously we demonstrated that p38 MAPK inhibition abates axonal dysfunction and slows degeneration in the inducible microbead occlusion model of glaucoma in rat.

Elevated ocular pressure reduces voltage-gated sodium channel NaV1.2 protein expression in retinal ganglion cell axons.

Glaucoma is an age-related neurodegenerative disease that is commonly associated with sensitivity to intraocular pressure. The disease selectively targets retinal ganglion cells (RGCs) and constituent axons. RGC axons are rich in voltage-gated sodium channels, which are essential for action potential initiation and regeneration.

Towards A Microbead Occlusion Model of Glaucoma for a Non-Human Primate.

Glaucoma is a group of optic neuropathies associated with aging and sensitivity to intraocular pressure (IOP). The disease causes vision loss through the degeneration of retinal ganglion cell neurons and their axons in the optic nerve. Using an inducible model of glaucoma, we elevated IOP in the squirrel monkey (Saimiri boliviensis) using intracameral injection of 35 μm polystyrene microbeads and measured common pathogenic outcomes in the optic projection.

Axogenic mechanism enhances retinal ganglion cell excitability during early progression in glaucoma.

Diseases of the brain involve early axon dysfunction that often precedes outright degeneration. Pruning of dendrites and their synapses represents a potential driver of axonopathy by reducing activity. Optic nerve degeneration in glaucoma, the world's leading cause of irreversible blindness, involves early stress to retinal ganglion cell (RGC) axons from sensitivity to intraocular pressure (IOP).

The Microbead Occlusion Model of Ocular Hypertension in Mice.

Glaucoma is a common optic neuropathy that leads to vision loss through the degeneration of retinal ganglion cells (RGCs) and their axons. RGC degeneration in glaucoma is associated with sensitivity to intraocular pressure (IOP) and elevated IOP (also known as ocular hypertension) is the primary modifiable risk factor. Ocular hypertension is the primary characteristic of rodent models for glaucoma research.

Imaging MS of Rodent Ocular Tissues and the Optic Nerve.

The visual system is comprised of many specialized cell types that are essential for relaying sensory information about an animal's surroundings to the brain. The cells present in ocular tissue are notoriously delicate, making it particularly challenging to section thin slices of unfixed tissue. Maintaining the morphology of the native tissue is crucial for accurate observations by either conventional staining techniques or in this instance matrix-assisted laser desorption ionization (MALDI IMS) or imaging using mass spectrometry.

Oral Delivery of a Synthetic Sterol Reduces Axonopathy and Inflammation in a Rodent Model of Glaucoma.

Glaucoma is a group of optic neuropathies associated with aging and sensitivity to intraocular pressure (IOP). The disease is the leading cause of irreversible blindness worldwide. Early progression in glaucoma involves dysfunction of retinal ganglion cell (RGC) axons, which comprise the optic nerve.

Nanosponge-Mediated Drug Delivery Lowers Intraocular Pressure.

Purpose: We examined the efficacy of an extended-release drug delivery system, nanosponge (NS) encapsulated compounds, administered intravitreally to lower intraocular pressure (IOP) in mice.

Methods: Bilateral ocular hypertension was induced in mice by injecting microbeads into the anterior chamber. Hypertensive mice received NS loaded with ocular hypotensive drugs via intravitreal injection and IOP was monitored.

Short-term increases in transient receptor potential vanilloid-1 mediate stress-induced enhancement of neuronal excitation.

Progression of neurodegeneration in disease and injury is influenced by the response of individual neurons to stressful stimuli and whether this response includes mechanisms to counter declining function. Transient receptor potential (TRP) cation channels transduce a variety of disease-relevant stimuli and can mediate diverse stress-dependent changes in physiology, both presynaptic and postsynaptic. Recently, we demonstrated that knock-out or pharmacological inhibition of the TRP vanilloid-1 (TRPV1) capsaicin-sensitive subunit accelerates degeneration of retinal ganglion cell neurons and their axons with elevated ocular pressure, the critical stressor in the most common optic neuropathy, glaucoma.

Activation of the TRPV1 cation channel contributes to stress-induced astrocyte migration.

Astrocytes provide metabolic, structural, and synaptic support to neurons in normal physiology and also contribute widely to pathogenic processes in response to stress or injury. Reactive astrocytes can undergo cytoskeletal reorganization and increase migration through changes in intracellular Ca(2+) mediated by a variety of potential modulators. Here we tested whether migration of isolated retinal astrocytes following mechanical injury (scratch wound) involves the transient receptor potential vanilloid-1 channel (TRPV1), which contributes to Ca(2+)-mediated cytoskeletal rearrangement and migration in other systems.

Absence of transient receptor potential vanilloid-1 accelerates stress-induced axonopathy in the optic projection.

How neurons respond to stress in degenerative disease is of fundamental importance for identifying mechanisms of progression and new therapeutic targets. Members of the transient receptor potential (TRP) family of cation-selective ion channels are candidates for mediating stress signals, since different subunits transduce a variety of stimuli relevant in both normal and pathogenic physiology. We addressed this possibility for the TRP vanilloid-1 (TRPV1) subunit by comparing how the optic projection of Trpv1(-/-) mice and age-matched C57 controls responds to stress from elevated ocular pressure, the critical stressor in the most common optic neuropathy, glaucoma.

α-Lipoic acid antioxidant treatment limits glaucoma-related retinal ganglion cell death and dysfunction.

Oxidative stress has been implicated in neurodegenerative diseases, including glaucoma. However, due to the lack of clinically relevant models and expense of long-term testing, few studies have modeled antioxidant therapy for prevention of neurodegeneration. We investigated the contribution of oxidative stress to the pathogenesis of glaucoma in the DBA/2J mouse model of glaucoma.

High-resolution matrix-assisted laser desorption ionization-imaging mass spectrometry of lipids in rodent optic nerve tissue.

Purpose: To develop a method for generating high spatial resolution (10 µm) matrix-assisted laser desorption ionization (MALDI) images of lipids in rodent optic nerve tissue.

Methods: Ice-embedded optic nerve tissue from rats and mice were cryosectioned across the coronal and sagittal axes of the nerve fiber. Sections were thaw mounted on gold-coated MALDI plates and were washed with ammonium acetate to remove biologic salts before being coated in 2,5-dihydroxybenzoic acid by sublimation.

Brimonidine prevents axonal and somatic degeneration of retinal ganglion cell neurons.

Background: Brimonidine is a common drug for lowering ocular pressure and may directly protect retinal ganglion cells in glaucoma. The disease involves early loss of retinal ganglion cell transport to brain targets followed by axonal and somatic degeneration. We examined whether brimonidine preserves ganglion cell axonal transport and abates degeneration in rats with elevated ocular pressure induced by laser cauterization of the episcleral veins.

Cell proliferation and interleukin-6-type cytokine signaling are implicated by gene expression responses in early optic nerve head injury in rat glaucoma.

Purpose: In glaucoma, the optic nerve head (ONH) is the principal site of initial axonal injury, and elevated intraocular pressure (IOP) is the predominant risk factor. However, the initial responses of the ONH to elevated IOP are unknown. Here the authors use a rat glaucoma model to characterize ONH gene expression changes associated with early optic nerve injury.

Progressive ganglion cell degeneration precedes neuronal loss in a mouse model of glaucoma.

Glaucoma is characterized by retinal ganglion cell (RGC) pathology and a progressive loss of vision. Previous studies suggest RGC death is responsible for vision loss in glaucoma, yet evidence from other neurodegenerative diseases suggests axonal degeneration, in the absence of neuronal loss, can significantly affect neuronal function. To characterize RGC degeneration in the DBA/2 mouse model of glaucoma, we quantified RGCs in mice of various ages using neuronal-specific nuclear protein (NeuN) immunolabeling, retrograde labeling, and optic nerve axon counts.

Neurotrophin and Trk expression by cells of the human lamina cribrosa following oxygen-glucose deprivation.

Background: Ischemia within the optic nerve head (ONH) may contribute to retinal ganglion cell (RGC) loss in primary open angle glaucoma (POAG). Ischemia has been reported to increase neurotrophin and high affinity Trk receptor expression by CNS neurons and glial cells. We have previously demonstrated neurotrophin and Trk expression within the lamina cribrosa (LC) region of the ONH.

Effect of exogenous neurotrophins on Trk receptor phosphorylation, cell proliferation, and neurotrophin secretion by cells isolated from the human lamina cribrosa.

Purpose: Glaucoma is the number one cause of preventable blindness in the United States. The lamina cribrosa (LC) region of the optic nerve head (ONH) is a major site of injury in glaucomatous optic neuropathy. Neurotrophins (NTs), which include NGF, BDNF, NT-3, and NT-4, are growth factors involved in the development and support of neurons and in non-neuronal interactions.

Cells of the human optic nerve head express glial cell line-derived neurotrophic factor (GDNF) and the GDNF receptor complex.

Purpose: Glial cell-line derived neurotrophic factor (GDNF) is a distant member of the TGFbeta family of growth factors and has wide ranging effects within the central nervous system. In the present study we profile the expression of GDNF and its receptor complex (Ret and GFRalpha-1) in cells isolated from the human optic nerve head (ONH).

Methods: Lamina cribrosa (LC) cells and ONH astrocytes were used from normal donors of various ages.

Expression of bone morphogenetic proteins (BMP), BMP receptors, and BMP associated proteins in human trabecular meshwork and optic nerve head cells and tissues.

Purpose: Bone morphogenetic proteins (BMPs) are multi-functional cytokines that have wide ranging effects on a variety of cells and tissues. In the present study, we profile the expression of BMPs, BMP receptors, and BMP associated proteins in the human trabecular meshwork (TM) and optic nerve head (ONH), two tissues involved in glaucoma pathogenesis.

Methods: Total RNA was isolated and subjected to reverse transcriptase-polymerase chain reaction (RT-PCR) to examine the expression of BMP, BMP receptor, and BMP associated proteins in tissues and cultured cells from the human TM and ONH (ONH astrocytes and lamina cribrosa cells).

Expression of p75(NTR) in photoreceptor cells of dystrophic rat retinas.

Although a gene mutation in the Royal College of Surgeons (RCS) dystrophic rat results in defective phagocytosis and in accumulation of debris in the subretinal space, the molecular mechanisms leading to photoreceptor cell death remain unclear. In this study, the expression of p75(NTR), the low-affinity neurotrophin receptor incriminated in the apoptosis of developing neurons, was investigated at various stages of retinal degeneration in dystrophic rats using immunohistochemistry, in situ reverse transcription polymerase chain reaction (RT-PCR), Western blot, and relative RT-PCR. In normal adult retinas, p75(NTR) immunolabeling was observed mainly in the outer limiting membrane, with punctate labeling in the inner nuclear and ganglion cell layers.