scholarly journals Diabetes-Independent Retinal Phenotypes in an Aldose Reductase Transgenic Mouse Model

Metabolites ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 450
Author(s):  
Jonathan Mark Petrash ◽  
Biehuoy Shieh ◽  
David A. Ammar ◽  
Michelle G. Pedler ◽  
David J. Orlicky
Keyword(s):  
Aldose Reductase ◽  
Ganglion Cells ◽  
Polyol Pathway ◽  
Retinal Ganglion ◽  
Functional Changes ◽  
Age Related ◽  
Age Dependent ◽  
Diabetic Eye Disease ◽  
Retinal Inflammation ◽  
Rate Limiting

Aldose reductase (AR), the first and rate-limiting enzyme of the polyol pathway, has been implicated in the onset and development of the ocular complications of diabetes, including cataracts and retinopathy. Despite decades of research conducted to address possible mechanisms, questions still persist in understanding if or how AR contributes to imbalances leading to diabetic eye disease. To address these questions, we created a strain of transgenic mice engineered for the overexpression of human AR (AR-Tg). In the course of monitoring these animals for age-related retinal phenotypes, we observed signs of Müller cell gliosis characterized by strong immunostaining for glial fibrillary acidic protein. In addition, we observed increased staining for Iba1, consistent with an increase in the number of retinal microglia, a marker of retinal inflammation. Compared to age-matched nontransgenic controls, AR-Tg mice showed an age-dependent loss of Brn3a-positive retinal ganglion cells and an associated decrease in PERG amplitude. Both RGC-related phenotypes were rescued in animals treated with Sorbinil in drinking water. These results support the hypothesis that increased levels of AR may be a risk factor for structural and functional changes known to accompany retinopathy in humans.

scholarly journals Aldose Reductase and the Polyol Pathway in Schwann Cells: Old and New Problems

2021 ◽  
Vol 22 (3) ◽  
pp. 1031
Author(s):  
Naoko Niimi ◽  
Hideji Yako ◽  
Shizuka Takaku ◽  
Sookja K. Chung ◽  
Kazunori Sango
Keyword(s):  
Schwann Cells ◽  
Aldose Reductase ◽  
Critical Role ◽  
Polyol Pathway ◽  
Glucose Flux ◽  
Rate Limiting ◽  
Deficient Mice ◽  
Excess Glucose ◽  
Shed Light ◽  
Immortalized Schwann Cells

Aldose reductase (AR) is a member of the reduced nicotinamide adenosine dinucleotide phosphate (NADPH)-dependent aldo-keto reductase superfamily. It is also the rate-limiting enzyme of the polyol pathway, catalyzing the conversion of glucose to sorbitol, which is subsequently converted to fructose by sorbitol dehydrogenase. AR is highly expressed by Schwann cells in the peripheral nervous system (PNS). The excess glucose flux through AR of the polyol pathway under hyperglycemic conditions has been suggested to play a critical role in the development and progression of diabetic peripheral neuropathy (DPN). Despite the intensive basic and clinical studies over the past four decades, the significance of AR over-activation as the pathogenic mechanism of DPN remains to be elucidated. Moreover, the expected efficacy of some AR inhibitors in patients with DPN has been unsatisfactory, which prompted us to further investigate and review the understanding of the physiological and pathological roles of AR in the PNS. Particularly, the investigation of AR and the polyol pathway using immortalized Schwann cells established from normal and AR-deficient mice could shed light on the causal relationship between the metabolic abnormalities of Schwann cells and discordance of axon-Schwann cell interplay in DPN, and led to the development of better therapeutic strategies against DPN.

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.

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 Protective effect of endogenous apelin against age-related loss of retinal ganglion cells in mice

2020 ◽  
Vol 93 (0) ◽  
pp. 2-P-215
Author(s):  
Yuki Ishimaru ◽  
Akihide Sumino ◽  
Fumiya Shibagaki ◽  
Hikari Chitose ◽  
Reina Miura ◽  
...  
Keyword(s):  
Protective Effect ◽  
Retinal Ganglion Cells ◽  
Ganglion Cells ◽  
Retinal Ganglion ◽  
Age Related

scholarly journals Age-dependent neuroprotection of retinal ganglion cells by tempol-C8 acyl ester in a rat NMDA toxicity model

2014 ◽  
Vol 3 ◽  
pp. 291-297 ◽  
Author(s):  
Michal Fiedorowicz ◽  
Robert Rejdak ◽  
Frank Schuettauf ◽  
Michal Wozniak ◽  
Pawel Grieb ◽  
...  
Keyword(s):  
Retinal Ganglion Cells ◽  
Ganglion Cells ◽  
Retinal Ganglion ◽  
Age Dependent

Age-Related Losses of Retinal Ganglion Cells and Axons

2008 ◽  
Vol 49 (10) ◽  
pp. 4437 ◽  
Author(s):  
Ronald S. Harwerth ◽  
Joe L. Wheat ◽  
Nalini V. Rangaswamy
Keyword(s):  
Retinal Ganglion Cells ◽  
Ganglion Cells ◽  
Retinal Ganglion ◽  
Age Related

scholarly journals The Relevance of Oxidative Stress in the Pathogenesis and Therapy of Retinal Dystrophies

Antioxidants ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 347 ◽  
Author(s):  
Elena B. Domènech ◽  
Gemma Marfany
Keyword(s):  
Oxidative Stress ◽  
Ganglion Cells ◽  
Age Related Macular Degeneration ◽  
Retinal Cell ◽  
Retinal Ganglion ◽  
Leber Hereditary Optic Neuropathy ◽  
Stress Effects ◽  
Retinal Dystrophies ◽  
Age Related ◽  
Stress Damage

Retinal cell survival requires an equilibrium between oxygen, reactive oxygen species, and antioxidant molecules that counteract oxidative stress damage. Oxidative stress alters cell homeostasis and elicits a protective cell response, which is most relevant in photoreceptors and retinal ganglion cells, neurons with a high metabolic rate that are continuously subject to light/oxidative stress insults. We analyze how the alteration of cellular endogenous pathways for protection against oxidative stress leads to retinal dysfunction in prevalent (age-related macular degeneration, glaucoma) as well as in rare genetic visual disorders (Retinitis pigmentosa, Leber hereditary optic neuropathy). We also highlight some of the key molecular actors and discuss potential therapies using antioxidants agents, modulators of gene expression and inducers of cytoprotective signaling pathways to treat damaging oxidative stress effects and ameliorate severe phenotypic symptoms in multifactorial and rare retinal dystrophies.

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