Posters
Presentation Type
Poster
Discipline Track
Biomedical Science
Abstract Type
Research/Clinical
Abstract
Background: Diabetic retinopathy (DR) remains the leading cause of blindness in working age Americans. There has yet to be any effective treatment to prevent the onset of the condition, only to treat late-stage disease. Research on early signs of disease have shown that changes in neural layers of the retina are the earliest signs of disease, preceding the vascular changes that currently define DR. This has sparked interest in the pathogenesis of the neurodegeneration involved in DR. This review explains the current understanding of the cellular and molecular mechanisms of neuronal degeneration in DR, as well as the potential pharmacological interventions that are being researched for each mechanism.
Methods: A literature review was performed to look at each major cellular and molecular pathway that has been defined and associated with DR-related neurodegeneration, the most current research regarding pharmacological interventions, and the relationship between the retinal neural cells and the microvasculature in diabetes to promote neurodegeneration. Articles have been sourced from either PubMed or Up-To-Date.
Results: The polyol, PKC, hexosamine, and AGEs pathways have been shown to be upregulated in hyperglycemia. The polyol pathway descreases NADPH, which is necessary for glutathione regeneration. Neural cells become unable to tolerate ROS. Fructose and sorbitol accumulate in cells, causing swelling. Epalrestat, FDA approved for diabetic neuropathy to target aldose reductase, has potential for DR. The PKC and RAGEs pathways promotes NADPH oxidase which produces ROS. PKC-β inhibitor Ruboxistaurin has been in clinical trials to treat Diabetic Retinopathy. The hexosamine pathway intermediate glucosamine is toxic to mitochondria and promotes peroxide production. Benfotiamine, a B1 derivative, may inhibit AGEs, PKC, and hexosamine pathways. DM causes an imbalance of the pro-NGF/NGF ratio, promoting apoptosis. NGF eye drops show promise at treating DME by normalizing ratio. The BDNF ratio is also affected the same way. Constant supplementation of BDNF inhibits photoreceptor death, however routine injections are not effective.
Elevated TNF-α is seen in retinal tissue one week after DM onset, stimulating extrinsic apoptosis. Etanercept, TNF-αβ inhibitor, appears to slow progression of DR. Hyperglycemia downregulates PI3K/Akt pathway, used for neuronal survival. Insulin promotes this pathway which protects from apoptosis, yet simultaneously promotes apoptosis. Muller cells and microglia are activated by hyperglycemia and release inflammatory mediators and cause glutamate excitotoxcity. Muller cell activation can be seen 1.5 months after DM onset, transient BBB breakdown within 6 weeks, and increased glial reactivity. Tau regulation is mediated by astrocytes. Abnormal tau causes astrocyte dysfunction and leads to neuron death.
Nitric Oxide gets inactivated by ROS forming peroyxnitrite and creating a neurotoxic environment. VEGF promotes neuron survival at low levels, but apoptosis by degradation of BDNF and GNDF at high levels. Elevated ROS promotes VEGF and inhibits its protective effects.
Conclusion: Several mechanisms for neurodegeneration preceding diabetic retinal vasculopathy have been described, both cellular and molecular. Many studies detail the potential for neurodegenerative pathway to lead to retinal vasculopathy. Continued research on which mechanisms predominate is necessary to develop effective treatments to prevent the onset of DR.
Academic/Professional Position
Medical Student
Recommended Citation
Callan, Andrew; Jha, Sonal V.; Valdez, Laura; and Tsin, Andrew, "Cellular and Molecular Mechanisms of Neurodegeneration in Early-Stage Diabetic Retinopathy" (2024). Research Symposium. 53.
https://scholarworks.utrgv.edu/somrs/2023/posters/53
Included in
Cellular and Molecular Mechanisms of Neurodegeneration in Early-Stage Diabetic Retinopathy
Background: Diabetic retinopathy (DR) remains the leading cause of blindness in working age Americans. There has yet to be any effective treatment to prevent the onset of the condition, only to treat late-stage disease. Research on early signs of disease have shown that changes in neural layers of the retina are the earliest signs of disease, preceding the vascular changes that currently define DR. This has sparked interest in the pathogenesis of the neurodegeneration involved in DR. This review explains the current understanding of the cellular and molecular mechanisms of neuronal degeneration in DR, as well as the potential pharmacological interventions that are being researched for each mechanism.
Methods: A literature review was performed to look at each major cellular and molecular pathway that has been defined and associated with DR-related neurodegeneration, the most current research regarding pharmacological interventions, and the relationship between the retinal neural cells and the microvasculature in diabetes to promote neurodegeneration. Articles have been sourced from either PubMed or Up-To-Date.
Results: The polyol, PKC, hexosamine, and AGEs pathways have been shown to be upregulated in hyperglycemia. The polyol pathway descreases NADPH, which is necessary for glutathione regeneration. Neural cells become unable to tolerate ROS. Fructose and sorbitol accumulate in cells, causing swelling. Epalrestat, FDA approved for diabetic neuropathy to target aldose reductase, has potential for DR. The PKC and RAGEs pathways promotes NADPH oxidase which produces ROS. PKC-β inhibitor Ruboxistaurin has been in clinical trials to treat Diabetic Retinopathy. The hexosamine pathway intermediate glucosamine is toxic to mitochondria and promotes peroxide production. Benfotiamine, a B1 derivative, may inhibit AGEs, PKC, and hexosamine pathways. DM causes an imbalance of the pro-NGF/NGF ratio, promoting apoptosis. NGF eye drops show promise at treating DME by normalizing ratio. The BDNF ratio is also affected the same way. Constant supplementation of BDNF inhibits photoreceptor death, however routine injections are not effective.
Elevated TNF-α is seen in retinal tissue one week after DM onset, stimulating extrinsic apoptosis. Etanercept, TNF-αβ inhibitor, appears to slow progression of DR. Hyperglycemia downregulates PI3K/Akt pathway, used for neuronal survival. Insulin promotes this pathway which protects from apoptosis, yet simultaneously promotes apoptosis. Muller cells and microglia are activated by hyperglycemia and release inflammatory mediators and cause glutamate excitotoxcity. Muller cell activation can be seen 1.5 months after DM onset, transient BBB breakdown within 6 weeks, and increased glial reactivity. Tau regulation is mediated by astrocytes. Abnormal tau causes astrocyte dysfunction and leads to neuron death.
Nitric Oxide gets inactivated by ROS forming peroyxnitrite and creating a neurotoxic environment. VEGF promotes neuron survival at low levels, but apoptosis by degradation of BDNF and GNDF at high levels. Elevated ROS promotes VEGF and inhibits its protective effects.
Conclusion: Several mechanisms for neurodegeneration preceding diabetic retinal vasculopathy have been described, both cellular and molecular. Many studies detail the potential for neurodegenerative pathway to lead to retinal vasculopathy. Continued research on which mechanisms predominate is necessary to develop effective treatments to prevent the onset of DR.