scholarly journals Potential Therapeutic Roles for Inhibition of the PI3K/Akt/mTOR Pathway in the Pathophysiology of Diabetic Retinopathy

2011 ◽  
Vol 2011 ◽  
pp. 1-19 ◽  
Author(s):  
Jorge L. Jacot ◽  
David Sherris
Keyword(s):  
Diabetic Retinopathy ◽  
Mtor Inhibitors ◽  
Inhibitory Effect ◽  
Mtor Pathway ◽  
Blood Retinal Barrier ◽  
Pathological Angiogenesis ◽  
Dosing Frequency ◽  
Favorable Safety ◽  
Chronic Drug Administration ◽  
Chronic Use

Novel therapeutics such as inhibitors of PI3K/Akt/mTOR pathway presents a unique opportunity for the management of diabetic retinopathy (DR). Second generation mTOR inhibitors have the prospect to be efficacious in managing various stages of disease progression in DR. During early stages, the mTOR inhibitors suppress HIF-1α, VEGF, leakage, and breakdown of the blood-retinal barrier. These mTOR inhibitors impart a pronounced inhibitory effect on inflammation, an early component with diverse ramifications influencing the progression of DR. These inhibitors suppress IKK and NF-κB along with downstream inflammatory cytokines, chemokines, and adhesion molecules. In proliferative DR, mTOR inhibitors suppress several growth factors that play pivotal roles in the induction of pathological angiogenesis. Lead mTOR inhibitors in clinical trials for ocular indications present an attractive treatment option for chronic use in DR with favorable safety profile and sustained ocular pharmacokinetics following single dose. Thereby, reducing dosing frequency and risk associated with chronic drug administration.

Mechanistic Insights into Immunological Therapy for Targeting Diabetic Retinopathy

2021 ◽  
Vol 5 (3) ◽  
pp. 01-05
Author(s):  
Imteyaz Qamar
Keyword(s):  
Diabetic Retinopathy ◽  
Progressive Disease ◽  
Common Complication ◽  
Blood Retinal Barrier ◽  
Immunological Therapy ◽  
Tnf Α ◽  
Capillary Occlusion ◽  
Inflammatory Molecules ◽  
Inflammatory Effect

Diabetic retinopathy (DR) is a common complication amongst patients that have diabetes. It is a leading cause of blindness in middle age people. A large proportion of patients who have diabetes develop retinopathy. There are several immunological reasons associated with the pathophysiology of this disease. Role of several mediators that increase the oxidative stress and have a pro-inflammatory effect which leads to capillary occlusion and neovascularization (NV). Increased vasopermeability due to disruption of the blood-retinal barrier (BRB) leading to diabetic macular edema (DME). Immunotherapies utilise different compounds and target various inflammatory molecules like TNF-α and pathways such as PPARγ for treatment of this progressive disease. Inflammatory and pro-inflammatory pathways are found to have an essential role in promoting DR; therefore, targeting them provides a useful technique for curing DR.

mTOR Inhibitors as a New Therapeutic Strategy in Treatment Resistant Epilepsy in Hemimegalencephaly: A Case Report

2018 ◽  
Vol 34 (3) ◽  
pp. 132-138 ◽  
Author(s):  
Qi Xu ◽  
Shimrit Uliel-Sibony ◽  
Christopher Dunham ◽  
Harvey Sarnat ◽  
Laura Flores-Sarnat ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Mtor Inhibitor ◽  
De Novo ◽  
Mtor Inhibitors ◽  
Mtor Pathway ◽  
Definitive Treatment ◽  
Malformations Of Cortical Development ◽  
Treatment Resistant ◽  
Seizure Reduction ◽  
Functional Hemispherectomy

Hemimegalencephaly is a hamartomatous malformation of one hemisphere. Functional hemispherectomy, the definitive treatment, is associated with significant morbidity and mortality in early infancy. Dysregulation of the mTOR pathway can result in malformations of cortical development, and mTOR inhibitors can effectively reduce seizures in tuberous sclerosis complex. We report a 6-day-old female with hemimegalencephaly and frequent seizures despite 9 antiseizure medications. At 3 months of age, while awaiting hemispherectomy, an mTOR inhibitor, rapamycin, was initiated by the neurologist. After 1 week of treatment, there was >50% reduction in seizures and total seizure burden, and after 2 weeks, development improved, resulting in deferral of surgery by 2.5 months with an increased body weight. Pathology demonstrated cortical dysplasia with upregulation of the mTOR pathway. Deep-sequencing of brain tissue demonstrated 16% mosaicism for a pathogenic de novo MTOR gene mutation. This case exemplifies how mTOR inhibitors could be considered for seizure reduction in patients with hemimegalencephaly while awaiting surgery.

scholarly journals Lipoprotein-associated phospholipase A2 (Lp-PLA2) as a therapeutic target to prevent retinal vasopermeability during diabetes

2016 ◽  
Vol 113 (26) ◽  
pp. 7213-7218 ◽  
Author(s):  
Paul Canning ◽  
Bridget-Ann Kenny ◽  
Vivien Prise ◽  
Josephine Glenn ◽  
Mosharraf H. Sarker ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
Vascular Function ◽  
Specific Inhibitor ◽  
Inhibitory Effect ◽  
Diabetic Rats ◽  
Brown Norway ◽  
Vegf Receptor ◽  
Blood Retinal Barrier ◽  
Species Specific ◽  
Brb Breakdown

Lipoprotein-associated phospholipase A2 (Lp-PLA2) hydrolyses oxidized low-density lipoproteins into proinflammatory products, which can have detrimental effects on vascular function. As a specific inhibitor of Lp-PLA2, darapladib has been shown to be protective against atherogenesis and vascular leakage in diabetic and hypercholesterolemic animal models. This study has investigated whether Lp-PLA2 and its major enzymatic product, lysophosphatidylcholine (LPC), are involved in blood–retinal barrier (BRB) damage during diabetic retinopathy. We assessed BRB protection in diabetic rats through use of species-specific analogs of darapladib. Systemic Lp-PLA2 inhibition using SB-435495 at 10 mg/kg (i.p.) effectively suppressed BRB breakdown in streptozotocin-diabetic Brown Norway rats. This inhibitory effect was comparable to intravitreal VEGF neutralization, and the protection against BRB dysfunction was additive when both targets were inhibited simultaneously. Mechanistic studies in primary brain and retinal microvascular endothelial cells, as well as occluded rat pial microvessels, showed that luminal but not abluminal LPC potently induced permeability, and that this required signaling by the VEGF receptor 2 (VEGFR2). Taken together, this study demonstrates that Lp-PLA2 inhibition can effectively prevent diabetes-mediated BRB dysfunction and that LPC impacts on the retinal vascular endothelium to induce vasopermeability via VEGFR2. Thus, Lp-PLA2 may be a useful therapeutic target for patients with diabetic macular edema (DME), perhaps in combination with currently administered anti-VEGF agents.

Erythropoietin protects outer blood‐retinal barrier in experimental diabetic retinopathy by up‐regulating ZO‐1 and occludin

2019 ◽  
Vol 47 (9) ◽  
pp. 1182-1197 ◽  
Author(s):  
Chaoyang Zhang ◽  
Hai Xie ◽  
Qian Yang ◽  
Yiting Yang ◽  
Weiye Li ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Blood Retinal Barrier

scholarly journals A Potential Role for Angiopoietin 2 in the Regulation of the Blood–Retinal Barrier in Diabetic Retinopathy

2011 ◽  
Vol 52 (6) ◽  
pp. 3784 ◽  
Author(s):  
Sampathkumar Rangasamy ◽  
Ramprasad Srinivasan ◽  
Joann Maestas ◽  
Paul G. McGuire ◽  
Arup Das
Keyword(s):  
Diabetic Retinopathy ◽  
Potential Role ◽  
Blood Retinal Barrier ◽  
Angiopoietin 2
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