scholarly journals Oral pyruvate prevents glaucomatous neurodegeneration

2020 ◽  
Author(s):  
Pete A Williams ◽  
Jeffrey M Harder ◽  
Chelsea Guymer ◽  
John P M Wood ◽  
Evangelia Daskalaki ◽  
...  
Keyword(s):  
Intraocular Pressure ◽  
Ganglion Cells ◽  
Nerve Degeneration ◽  
Columbia University ◽  
Retinal Ganglion ◽  
Cell Degeneration ◽  
Oral Supplementation ◽  
Pressure Sensitive ◽  
Age Related ◽  
Clinical Models

AbstractIntraocular pressure-sensitive retinal ganglion cell degeneration is a hallmark of glaucoma, the leading cause of irreversible blindness. Converging evidence indicates that age-related bioenergetic insufficiency increases the vulnerability of retinal ganglion cells to intraocular pressure. To investigate further, we used metabolomics and RNA-sequencing to examine early glaucoma in DBA/2J mice. We demonstrate an intraocular pressure-dependent decline in retinal pyruvate levels coupled to dysregulated glucose metabolism prior to detectable optic nerve degeneration. Oral supplementation of pyruvate strongly protected from neurodegeneration in pre-clinical models of glaucoma. We detected mTOR activation at the mechanistic nexus of neurodegeneration and metabolism. Rapamycin-induced inhibition of mTOR robustly prevented glaucomatous neurodegeneration. Bioenergetic enhancement, in combination with intraocular pressure reduction, therefore provides a readily translatable strategy that warrants investigation in clinical trials.FundingVetenskapsrådet 2018-02124 and StratNeuro StartUp grant (PAW). Pete Williams is supported by the Karolinska Institutet in the form of a Board of Research Faculty Funded Career Position and by St. Erik Eye Hospital philanthropic donations. EY011721 and the Barbra and Joseph Cohen Foundation and startup funds from Columbia University (SWMJ). Simon John is an Investigator of HHMI.

scholarly journals Disturbed glucose and pyruvate metabolism in glaucoma with neuroprotection by pyruvate or rapamycin

2020 ◽  
Vol 117 (52) ◽  
pp. 33619-33627
Author(s):  
Jeffrey M. Harder ◽  
Chelsea Guymer ◽  
John P. M. Wood ◽  
Evangelia Daskalaki ◽  
Glyn Chidlow ◽  
...  
Keyword(s):  
Intraocular Pressure ◽  
Nerve Degeneration ◽  
Retinal Ganglion ◽  
Metabolic Disturbances ◽  
Pyruvate Metabolism ◽  
Cell Degeneration ◽  
Oral Supplementation ◽  
Impact Pathways ◽  
Glucose Levels ◽  
Pressure Sensitive

Intraocular pressure-sensitive retinal ganglion cell degeneration is a hallmark of glaucoma, the leading cause of irreversible blindness. Here, we used RNA-sequencing and metabolomics to examine early glaucoma in DBA/2J mice. We demonstrate gene expression changes that significantly impact pathways mediating the metabolism and transport of glucose and pyruvate. Subsequent metabolic studies characterized an intraocular pressure (IOP)-dependent decline in retinal pyruvate levels coupled to dysregulated glucose metabolism prior to detectable optic nerve degeneration. Remarkably, retinal glucose levels were elevated 50-fold, consistent with decreased glycolysis but possibly including glycogen mobilization and other metabolic changes. Oral supplementation of the glycolytic product pyruvate strongly protected from neurodegeneration in both rat and mouse models of glaucoma. Investigating further, we detected mTOR activation at the mechanistic nexus of neurodegeneration and metabolism. Rapamycin-induced inhibition of mTOR robustly prevented glaucomatous neurodegeneration, supporting a damaging role for IOP-induced mTOR activation in perturbing metabolism and promoting glaucoma. Together, these findings support the use of treatments that limit metabolic disturbances and provide bioenergetic support. Such treatments provide a readily translatable strategy that warrants investigation in clinical trials.

Inherited glaucoma in DBA/2J mice: Pertinent disease features for studying the neurodegeneration

2005 ◽  
Vol 22 (5) ◽  
pp. 637-648 ◽  
Author(s):  
RICHARD T. LIBBY ◽  
MICHAEL G. ANDERSON ◽  
IOK-HOU PANG ◽  
ZACHARY H. ROBINSON ◽  
OLGA V. SAVINOVA ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Ganglion Cells ◽  
The Elderly ◽  
Nerve Degeneration ◽  
Retinal Ganglion ◽  
Cell Degeneration ◽  
Future Studies ◽  
Age Related ◽  
Iop Elevation ◽  
Mechanistic Basis

The glaucomas are neurodegenerative diseases involving death of retinal ganglion cells and optic nerve head excavation. A major risk factor for this neurodegeneration is a harmfully elevated intraocular pressure (IOP). Human glaucomas are typically complex, progressive diseases that are prevalent in the elderly. Family history and genetic factors are clearly important in human glaucoma. Mouse studies have proven helpful for investigating the genetic and mechanistic basis of complex diseases. We previously reported inherited, age-related progressive glaucoma in DBA/2J mice. Here, we report our updated findings from studying the disease in a large number of DBA/2J mice. The period when mice have elevated IOP extends from 6 months to 16 months, with 8–9 months representing an important transition to high IOP for many mice. Optic nerve degeneration follows IOP elevation, with the majority of optic nerves being severely damaged by 12 months of age. This information should help with the design of experiments, and we present the data in a manner that will be useful for future studies of retinal ganglion cell degeneration and optic neuropathy.

scholarly journals Role of Heat Shock Proteins in Glaucoma

2019 ◽  
Vol 20 (20) ◽  
pp. 5160 ◽  
Author(s):  
Teresa Tsai ◽  
Pia Grotegut ◽  
Sabrina Reinehr ◽  
Stephanie C. Joachim
Keyword(s):  
Heat Shock ◽  
Heat Shock Proteins ◽  
Retinal Ganglion Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Ganglion Cells ◽  
Nerve Degeneration ◽  
Retinal Ganglion ◽  
Cell Degeneration ◽  
Shock Proteins

Glaucoma, one of the most common causes of blindness worldwide, is a multifactorial neurodegenerative disease characterized by damage of retinal ganglion cells and optic nerve degeneration. However, the exact mechanism leading to glaucoma is still not understood. Evidences suggest an immunological involvement in the pathogenesis. Among other immune responses, altered autoantibody patterns were found in glaucoma patients. Especially elevated antibody levels against heat shock proteins (HSPs), like HSP27 or HSP60, were identified. In an animal model, an immunization with these HSPs induced a pressure-independent retinal ganglion cell degeneration and axon loss, hence mimicking glaucoma-like damage. In addition, development of autoreactive antibodies, as well as a glia and T-cell activation, were described in these animals. Recently, we noted that intravitreal HSP27 injection likewise led to a degeneration of retinal ganglion cells and their axons. Therefore, HSP27 might have a direct damaging effect on retinal cells, and might play a key role in glaucoma.

scholarly journals Cytoprotective Effect of Astaxanthin in a Model of Normal Intraocular Pressure Glaucoma

2020 ◽  
Vol 2020 ◽  
pp. 1-6
Author(s):  
Kasumi Kikuchi ◽  
Zhenyu Dong ◽  
Yasuhiro Shinmei ◽  
Miyuki Murata ◽  
Atsuhiro Kanda ◽  
...  
Keyword(s):  
Intraocular Pressure ◽  
Ganglion Cells ◽  
Normal Tension Glaucoma ◽  
Nerve Degeneration ◽  
Retinal Ganglion ◽  
Cytoprotective Effect ◽  
Littermate Control ◽  
Stress Effects ◽  
Antioxidative Stress ◽  
Hematoxylin And Eosin

Glaucoma is characterized by axonal degeneration of retinal ganglion cells (RGCs) and apoptotic death of their cell bodies. Lowering intraocular pressure is currently the only way to treat glaucoma, but it is often insufficient to inhibit the progression of the disease. Glaucoma is a multifactorial disease, and the involvement of oxidative stress has recently received much attention. In the present study, we investigated the cytoprotective effect of astaxanthin (AST) on RGC degeneration using a normal-tension glaucoma (NTG) mouse model, which lacks the glutamate/aspartate transporter (Glast) and demonstrates spontaneous RGC and optic nerve degeneration without elevated intraocular pressure. Three-week-old Glast± mice were given intraperitoneal injections of AST at 10, 30, or 60 mg/kg/day or vehicle alone, and littermate control mice were given vehicle alone for 14 days, respectively. Five weeks after birth, the number of RGCs was counted in paraffin sections of retinal tissues stained with hematoxylin and eosin. We also used a retrograde labeling technique to quantify the number of RGCs. Additionally, the phosphorylated (p) IκB/total IκB ratio and the 4-hydroxynonenal (HNE) were measured in retinal tissues. The number of RGCs in Glast± mice was significantly decreased compared with that in control mice. RGC loss was suppressed by the administration of AST at 60 mg/kg/day, compared with vehicle alone. Following AST administration, the concentration of 4-HNE in the retina was also suppressed, but the pIκB/IκB ratio did not change. Our study revealed that the antioxidative stress effects of AST inhibit RGC degeneration in the retina and may be useful in the treatment of NTG.

scholarly journals Hop flower extracts mitigate retinal ganglion cell degeneration in a glaucoma mouse model

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Tomoko Hasegawa ◽  
Hanako O. Ikeda ◽  
Sachiko Iwai ◽  
Norio Sasaoka ◽  
Akira Kakizuka ◽  
...  
Keyword(s):  
Intraocular Pressure ◽  
Visual Field ◽  
Ganglion Cell ◽  
Retinal Ganglion Cells ◽  
Ganglion Cells ◽  
Amyloid Β ◽  
Visual Field Loss ◽  
Retinal Ganglion ◽  
Cell Degeneration ◽  
Novel Therapeutic

AbstractIn glaucoma, retinal ganglion cells degenerate progressively, leading to visual field loss and blindness. Presently, the only treatment strategy for glaucoma is lowering the intraocular pressure. However, there are cases in which patients develop progressive visual field loss even though their intraocular pressures are within normal ranges. Therefore, the development of novel therapeutic strategies is an urgent endeavor. Besides high intraocular pressure, several other factors have been proposed to be associated with glaucoma progression, e.g., myopia, blood flow impairment, and amyloid β accumulation. We have previously reported that hop flower extracts possess γ-secretase inhibitory activities and reduce amyloid β deposition in the brains of Alzheimer’s disease model mice. In the current study, we showed that administration of hop flower extracts to glutamate-aspartate transporter (GLAST) knockout mice, the glaucoma model mice, attenuated glaucomatous retinal ganglion cell degeneration. Preservation of retinal ganglion cells in hop flower extract-administered mice was confirmed using optical coherence tomography, confocal scanning laser ophthalmoscopy, and retinal flatmount and histological evaluations. Hop flower extracts are, therefore, deemed a possible candidate as a novel therapeutic agent to treat glaucoma.

scholarly journals Neuroprotection of retinal ganglion cells by the sigma-1 receptor agonist pridopidine in models of experimental glaucoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Michal Geva ◽  
Noga Gershoni-Emek ◽  
Luana Naia ◽  
Philip Ly ◽  
Sandra Mota ◽  
...  
Keyword(s):  
Ganglion Cell ◽  
Retinal Degeneration ◽  
Retinal Ganglion Cells ◽  
Retinal Ganglion Cell ◽  
Ganglion Cells ◽  
Neuroprotective Effect ◽  
Retinal Ganglion ◽  
Cell Degeneration ◽  
Sigma 1 Receptor ◽  
Sigma 1

AbstractOptic neuropathies such as glaucoma are characterized by retinal ganglion cell (RGC) degeneration and death. The sigma-1 receptor (S1R) is an attractive target for treating optic neuropathies as it is highly expressed in RGCs, and its absence causes retinal degeneration. Activation of the S1R exerts neuroprotective effects in models of retinal degeneration. Pridopidine is a highly selective and potent S1R agonist in clinical development. We show that pridopidine exerts neuroprotection of retinal ganglion cells in two different rat models of glaucoma. Pridopidine strongly binds melanin, which is highly expressed in the retina. This feature of pridopidine has implications to its ocular distribution, bioavailability, and effective dose. Mitochondria dysfunction is a key contributor to retinal ganglion cell degeneration. Pridopidine rescues mitochondrial function via activation of the S1R, providing support for the potential mechanism driving its neuroprotective effect in retinal ganglion cells.

Pathways of regenerated retinotectal axons in goldfish

Development ◽  
1986 ◽  
Vol 93 (1) ◽  
pp. 1-28
Author(s):  
Claudia A. O. Stuermer
Keyword(s):  
Optic Nerve ◽  
Retinal Ganglion Cells ◽  
Normal Development ◽  
Ganglion Cells ◽  
Optic Tract ◽  
Spatiotemporal Pattern ◽  
Retinal Ganglion ◽  
Retinal Axons ◽  
Age Related ◽  
Regenerated Fibres

This study investigates the order of regenerating retinal axons in the goldfish. The spatiotemporal pattern of axon regrowth was assessed by applying horseradish peroxidase (HRP) to regenerating axons in the optic tract at various times after optic nerve section and by analysing the distribution of retrogradely labelled ganglion cells in retina. At all regeneration stages labelled ganglion cells were widely distributed over the retina. There was no hint that axons from central (older) ganglion cells might regrow earlier, and peripheral (younger) ganglion cells later, as occurs in normal development. The absence of an age-related ordering in the regenerated optic nerve was demonstrated by labelling a few axon bundles intraorbitally with HRP (Easter, Rusoff & Kish, 1981) caudal to the previous cut. The retrogradely labelled cells in retina were randomly distributed in regenerates andnot clustered in annuli as in normals. Tracing regenerating axons which were stained anterogradelyfrom intraretinal HRP applications or retrogradely from single labelled tectal fascicles illustrated the fact that the regenerating axons coursed in abnormal routes in the optic nerve and tract. On the surface of the tectum regenerated fibres re-established a fascicle fan. The retinal origin of tectal fascicles was assessed by labelling individual peripheral, intermediate and rostral fascicles with HRP. The retrogradely labelled ganglion cells in the retina were often more widely distributed than in normals, but were mostly found in peripheral, intermediate and central retina, respectively. The order of fibre departure from each tectal fascicle was revealed by placing HRP either on the fascicle's proximal or on its distal half. With proximal labelling sites labelled ganglion cells were found in the temporal and nasal retina, and with distal labelling sites labelled ganglion cells were confined to nasal retina only. Further, the axonal trajectories of anterogradely labelled dorsotemporal retinal ganglion cells were compared to those of dorsonasal retinal ganglion cells in tectal whole mounts. Dorsotemporal axons were confined to the rostral tectal half, whereas dorsonasal axons followed fascicular routes into the fascicles' distal end and reached into caudal tectum. This suggests that the fibres exited along their fascicle's course in a temporonasal sequence. Thus in the tectum, fibres in fascicles restore a gross spatial and age-related order and tend to follow their normal temporonasal sequence of exit.

scholarly journals Effect of Acupuncture on Intraocular Pressure in Glaucoma Patients: A Single-Blinded, Randomized, Controlled Trial

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Shu-Yuan Chen ◽  
Feng-Shuen Yieh ◽  
Wen-Ling Liao ◽  
Tsai-Chung Li ◽  
Ching-Liang Hsieh
Keyword(s):  
Randomized Controlled Trial ◽  
Intraocular Pressure ◽  
Sham Group ◽  
Ganglion Cells ◽  
Controlled Trial ◽  
Ocular Blood Flow ◽  
Retinal Ganglion ◽  
Randomized Controlled ◽  
Ocular Perfusion ◽  
The Difference

Glaucoma is characterized by the degeneration of retinal ganglion cells that cause progressive optic neuropathy, finally resulting in changes to the optic nerve head. Lowering intraocular pressure (IOP) is the only method proven for treating glaucoma. Several studies have discovered that acupuncture can reduce IOP and also increase ocular perfusion and ocular blood flow. Therefore, the present study investigated the effect of acupuncture on IOP in glaucoma patients. We conducted a single-blinded, randomized, controlled trial involving 45 glaucoma patients. The results indicated that the difference between the IOP 60 min after the intervention and IOP immediately before the intervention was greater in the acupuncture group (AG) and electroacupuncture group (EG) than in the sham group (SG) for all four of the interventions performed and in both eyes (all p<0.05). The IOP difference between immediately before the first intervention and after finishing the final intervention was also greater in the AG and EG than in the SG in both eyes (all p<0.05). In conclusion, IOP was reduced at 60 min after acupuncture or electroacupuncture was performed at BL1 and EX-HN7. Additionally, IOP was reduced after finishing four acupuncture or electroacupuncture sessions. Therefore, our results suggest that acupuncture and electroacupuncture are beneficial for lowering IOP in glaucoma patients. This trial is registered with NCT04157530.

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