Regulation of Adrenergic, Serotonin, and Dopamine Receptors to Inhibit Diabetic Retinopathy: Monotherapies versus Combination Therapies

Kern, Timothy S.; Du, Yunpeng; Tang, Jie; Lee, Chieh Allen; Dreffs, Alyssa; Leinonen, Henri; Antonetti, David A.; Palczewski, Krzysztof

doi:10.1124/molpharm.121.000278

Cited by 9 publications

(9 citation statements)

References 68 publications

(80 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We were only able to find two studies that point to dopamine as an anti-angiogenic in the retina: a retrospective study showing that age-related macular degeneration was delayed by approximately 8 years in patients who were taking L-DOPA for Parkinson’s disease ( Brilliant et al, 2016 ) and an animal study showing that the dopamine agonist bromocriptine reduces vascular permeability in diabetic mice ( Kern et al, 2021 ). The research presented here suggests that treatments that target dopamine could be used as in the diabetic retina to reduce or prevent neovascularization and other vascular pathology, the clinical hallmark of DR and a cause of blindness.…”

Section: Discussionmentioning

confidence: 99%

Diabetic rats with high levels of endogenous dopamine do not show retinal vascular pathology

et al. 2023

Self Cite

View full text Add to dashboard Cite

PurposeLimited research exists on the time course of long-term retinal and cerebral deficits in diabetic rodents. Previously, we examined short term (4–8 weeks) deficits in the Goto-Kakizaki (GK) rat model of Type II diabetes. Here, we investigated the long-term (1–8 months) temporal appearance of functional deficits (retinal, cognitive, and motor), retinal vascular pathology, and retinal dopamine levels in the GK rat.MethodsIn GK rats and Wistar controls, retinal neuronal function (electroretinogram), cognitive function (Y-maze), and motor function (rotarod) were measured at 1, 2, 4, 6, and 8 months of age. In addition, we evaluated retinal vascular function (functional hyperemia) and glucose and insulin tolerance. Retinas from rats euthanized at ≥8 months were assessed for vascular pathology. Dopamine and DOPAC levels were measured via HPLC in retinas from rats euthanized at 1, 2, 8, and 12 months.ResultsGoto-Kakizaki rats exhibited significant glucose intolerance beginning at 4 weeks and worsening over time (p < 0.001). GK rats also showed significant delays in flicker and oscillatory potential implicit times (p < 0.05 to p < 0.001) beginning at 1 month. Cognitive deficits were observed beginning at 6 months (p < 0.05), but no motor deficits. GK rats showed no deficits in functional hyperemia and no increase in acellular retinal capillaries. Dopamine levels were twice as high in GK vs. Wistar retinas at 1, 2, 8, and 12 months (p < 0.001).ConclusionAs shown previously, retinal deficits were detectable prior to cognitive deficits in GK rats. While retinal neuronal function was compromised, retinal vascular pathology was not observed, even at 12+ months. High endogenous levels of dopamine in the GK rat may be acting as an anti-angiogenic and providing protection against vascular pathology.

show abstract

Section: Discussionmentioning

confidence: 99%

Diabetic rats with high levels of endogenous dopamine do not show retinal vascular pathology

et al. 2023

Self Cite

View full text Add to dashboard Cite

show abstract

“…These conclusions were supported by the following results: (1) TAM reduced a high glucose-induced expression of TNF-α, IL-6, IL-8, MMP-2 and MMP-9; (2) TAM inhibited the expression of VCAM-1 and ICAM-1, and a high glucose-induced expression of fibrosis factors such as COL-1 and TGF-β1; and (3) TAM reduced oxidative stress by inhibiting the generation of ROS, thus preventing the activation of p38. In addition, therapy involving the use of a combination of drugs that regulate G protein couple receptor (GPCR) signaling pathways including TAM was found to beneficially inhibit the development of early diabetic retinopathy [ 44 ] as well as retinal degeneration [ 45 , 46 ], as compared with the use of each drug individually. In the current study, using 2D and 3D cultures of ARPE 19 cells, we were able to successfully evaluate the drug-induced effects of TAM and obtained the following results: TAM significantly altered the distribution of ECM deposits and the energy balance between glycolysis and OXPHOS, and the increased barrier functions in the 2D ARPE 19 monolayers, and large and stiffer 3D ARPE 19 spheroids, and these effects were concentration dependent.…”

Section: Discussionmentioning

confidence: 99%

The Selective α1 Antagonist Tamsulosin Alters ECM Distributions and Cellular Metabolic Functions of ARPE 19 Cells in a Concentration-Dependent Manner

et al. 2022

View full text Add to dashboard Cite

The purpose of the present study was to examine the effect of the selective α1 antagonist tamsulosin (TAM) on human retinal pigment epithelium cells, ARPE 19. Two-dimension (2D) and three-dimension (3D) cultured ARPE 19 cells were used in the following characterizations: (1) ultrastructure by scanning electron microscopy (SEM) (2D); (2) barrier functions by transepithelial electrical resistance (TEER) measurements, and FITC-dextran permeability (2D); (3) real time cellular metabolisms by Seahorse Bioanalyzer (2D); (4) physical properties, size and stiffness measurements (3D); and (5) expression of extracellular matrix (ECM) proteins, including collagen1 (COL1), COL4, COL6 and fibronectin (FN) by qPCR and immunohistochemistry (2D and 3D). TAM induced significant effects including: (1) alteration of the localization of the ECM deposits; (2) increase and decrease of the TEER values and FITC-dextran permeability, respectively; (3) energy shift from glycolysis into mitochondrial oxidative phosphorylation (OXPHOS); (4) large and stiffened 3D spheroids; and (5) down-regulations of the mRNA expressions and immune labeling of most ECM proteins in a concentration-dependent manner. However, in some ECM proteins, COL1 and COL6, their immunolabeling intensities were increased at the lowest concentration (1 μM) of TAM. Such a discrepancy between the gene expressions and immunolabeling of ECM proteins may support alterations of ECM localizations as observed by SEM. The findings reported herein indicate that the selective α1 antagonist, TAM, significantly influenced ECM production and distribution as well as cellular metabolism levels in a concentration-dependent manner.

show abstract

“…Among these, serotonin is a crucial monoamine neurotransmitter that regulates central neurotransmission and intestinal physiological functions. Given that serotonin levels in patients with proliferative diabetic retinopathy (PDR) are significantly lower than in healthy subjects, and that the incidence of DR is lower in diabetic patients taking serotonin reuptake inhibitors compared to controls, it is possible that gut microbiota influences DR by regulating the production of tryptophan and serotonin ( Kern et al, 2021 ).…”

Section: Function and Application Of Postbiotics In Dr Treatmentmentioning

confidence: 99%

Postbiotics: emerging therapeutic approach in diabetic retinopathy

Chen,

Li,

Xie

et al. 2024

Front. Microbiol.

View full text Add to dashboard Cite

Diabetic retinopathy (DR) is a prevalent microvascular complication in diabetic patients that poses a serious risk as it can cause substantial visual impairment and even vision loss. Due to the prolonged onset of DR, lengthy treatment duration, and limited therapeutic effectiveness, it is extremely important to find a new strategy for the treatment of DR. Postbiotic is an emerging dietary supplement which consists of the inactivate microbiota and its metabolites. Numerous animal experiments have demonstrated that intervention with postbiotics reduces hyperglycemia, attenuates retinal peripapillary and endothelial cell damage, improves retinal microcirculatory dysfunction, and consequently delays the progression of DR. More strikingly, unlike conventional probiotics and prebiotics, postbiotics with small molecules can directly colonize the intestinal epithelial cells, and exert heat-resistant, acid-resistant, and durable for storage. Despite few clinical significance, oral administration with postbiotics might become the effective management for the prevention and treatment of DR. In this review, we summarized the basic conception, classification, molecular mechanisms, and the advances in the therapeutic implications of postbiotics in the pathogenesis of DR. Postbiotics present great potential as a viable adjunctive therapy for DR.

show abstract

Regulation of Adrenergic, Serotonin, and Dopamine Receptors to Inhibit Diabetic Retinopathy: Monotherapies versus Combination Therapies

Cited by 9 publications

References 68 publications

Diabetic rats with high levels of endogenous dopamine do not show retinal vascular pathology

Diabetic rats with high levels of endogenous dopamine do not show retinal vascular pathology

The Selective α1 Antagonist Tamsulosin Alters ECM Distributions and Cellular Metabolic Functions of ARPE 19 Cells in a Concentration-Dependent Manner

Postbiotics: emerging therapeutic approach in diabetic retinopathy

Contact Info

Product

Resources

About