Stress resilience-enhancing drugs (SREDs) have emerged as a promising class of therapeutics for retinopathies

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Chronic, progressive retinal diseases, including age-related macular degeneration (AMD), diabetic retinopathy, and retinitis pigmentosa, are characterized by genetic and environmental perturbations that disrupt cellular and tissue homeostasis.

Despite limited therapeutic options, preserving retinal structure and visual function at early disease stages remains critical. In this study, we employed a systems pharmacology platform to develop targeted therapies.

Through integrative single-cell transcriptomics, proteomics, and phosphoproteomics, we identified universal molecular mechanisms associated with impaired resilience to stress in retinal degenerations. Specifically, we discovered that selective inhibition of cyclic nucleotide phosphodiesterases (PDEs), critical regulators of intracellular signaling pathways, stabilized the retinal transcriptome, proteome, and phosphoproteome.

This intervention activated protective mechanisms and inhibited degenerative processes, enhancing resilience to acute and chronic stress in the degenerating retina. Consequently, tissue structure and function were preserved across models of age-related and inherited retinal disease. These findings demonstrate the potential clinical utility of this systems pharmacology approach in developing novel therapeutics for blinding retinal diseases.

Introduction

Chronic retinal diseases, such as AMD, diabetic retinopathy, and retinitis pigmentosa, pose significant challenges due to genetic and environmental perturbations that disrupt retinal homeostasis. Current therapeutic options are limited, emphasizing the need for innovative approaches to preserve retinal structure and visual function, particularly in the early stages of disease progression.

Methods

A systems pharmacology platform was employed, utilizing integrative single-cell transcriptomics, proteomics, and phosphoproteomics, to identify common molecular mechanisms associated with stress resilience impairment in retinal degenerations. Cyclic nucleotide phosphodiesterases (PDEs), critical regulators of intracellular signaling pathways, were identified as potential therapeutic targets.

Results

Selective pharmacological inhibition of PDEs was found to stabilize the retinal transcriptome, proteome, and phosphoproteome, thereby activating protective mechanisms and synergistically inhibiting degenerative processes. This intervention significantly enhanced resilience to acute and chronic stress in degenerating retinas, leading to the preservation of tissue structure and function in various models of retinal disease.

Discussion

The systems pharmacology approach employed in this study provides novel insights into the molecular mechanisms underlying retinal degenerations and identifies PDE inhibition as a promising therapeutic strategy. By targeting key regulatory nodes in intracellular signaling pathways, this approach offers a multifaceted approach to enhance stress resilience and mitigate retinal damage.

This study demonstrates the potential clinical utility of selective, targeted pharmacological inhibition of PDEs as a novel class of therapeutics for chronic, progressive retinal diseases. By preserving retinal structure and function, these interventions have the potential to address the unmet medical needs of millions of patients suffering from blinding retinal disorders.

Future Directions Further preclinical and clinical studies are warranted to validate the efficacy, safety, and long-term benefits of PDE inhibition as a therapeutic approach in retinal diseases. Additionally, the systems pharmacology platform utilized in this study can be extended to identify and evaluate other potential targets and drug candidates for retinal disease treatment.

In conclusion, this study highlights the significance of a systems pharmacology approach in identifying targeted interventions for chronic retinal diseases. By elucidating universal molecular mechanisms and employing selective pharmacological strategies, we provide a promising avenue for the development of novel therapeutics that can preserve retinal structure and function, ultimately improving the quality of life for individuals affected by these blinding conditions.


The mechanisms of action of Stress Resilience-Enhancing Drugs (SREDs) vary depending on the specific class of drugs.

Here, we provide a general overview of the mechanisms of action for different classes of SREDs:

  • Adaptogens: Adaptogens are a class of drugs derived from plants that help the body adapt to stressors and restore homeostasis. The exact mechanisms of action of adaptogens are complex and multifaceted. They are believed to modulate stress response systems, including the HPA axis, by regulating the release and activity of stress hormones such as cortisol. Adaptogens also enhance cellular energy production, promote antioxidant activity, and support neuroendocrine balance, thus improving stress resilience.
  • Serotonergic Agents: Serotonergic agents, such as selective serotonin reuptake inhibitors (SSRIs), work by increasing the availability of serotonin in the brain. Serotonin is a neurotransmitter involved in mood regulation and stress response. By inhibiting the reuptake of serotonin, SSRIs prolong its action, leading to increased neurotransmission and modulation of stress-related brain circuits. This modulation can help regulate mood, decrease anxiety, and enhance stress resilience.
  • GABA Modulators: Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter that plays a crucial role in reducing neuronal excitability and promoting relaxation. GABA modulators, such as benzodiazepines and GABA analogs, enhance GABAergic neurotransmission by binding to specific receptors in the brain. By increasing GABA activity, these drugs induce anxiolytic and sedative effects, thereby reducing stress and promoting stress resilience.
  • Cannabinoids: Cannabinoids, such as tetrahydrocannabinol (THC) and cannabidiol (CBD), interact with the endocannabinoid system (ECS) in the body. The ECS plays a role in regulating stress responses, mood, and emotional processing. Cannabinoids bind to cannabinoid receptors (CB1 and CB2) located in the brain and peripheral tissues, modulating neurotransmitter release and influencing stress-related circuits. This modulation can contribute to stress reduction and the enhancement of stress resilience.
  • Neuropeptide Modulators: Neuropeptide modulators, including oxytocin and vasopressin, act on specific neuropeptide receptors in the brain. These neuropeptides are involved in social bonding, trust, and stress regulation. By interacting with their respective receptors, neuropeptide modulators can influence stress response systems, emotional processing, and social behaviors, thereby enhancing stress resilience.
  • Corticotropin-Releasing Factor (CRF) Receptor Antagonists: Corticotropin-releasing factor (CRF) is a neuropeptide that plays a key role in initiating and regulating the stress response. CRF receptor antagonists, by blocking the action of CRF at its receptors, can modulate stress-related pathways. This modulation can help reduce the activation of the HPA axis and alleviate stress-related symptoms, leading to enhanced stress resilience.

It’s important to note that the mechanisms of action of SREDs are still an area of active research, and the understanding of their precise effects on stress resilience is continually evolving. The specific mechanisms may vary within each class of drugs, and there may be additional mechanisms involved that are not covered here. Further research is needed to elucidate the detailed mechanisms underlying the actions of SREDs and their impact on stress resilience.


reference link :

“Stress resilience-enhancing drugs preserve tissue structure and function in degenerating retina via phosphodiesterase inhibition” by Jennings C. Luu et al. PNAS

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