TrkB Receptor Signalling: Implications in Neurodegenerative,Psychiatric and Proliferative Disorders

The Trk family of receptors play a wide variety of roles in physiological and disease processes in both neuronal and non-neuronal tissues. Amongst these the TrkB receptor in particular has attracted major attention due to its critical role in signalling for brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT3) and neurotrophin-4 (NT4). TrkB signalling is indispensable for the survival, development and synaptic plasticity of several subtypes of neurons in the nervous system. Substantial evidence has emerged over the last decade about the involvement of aberrant TrkB signalling and its compromise in various neuropsychiatric and degenerative conditions. Unusual changes in TrkB signalling pathway have also been observed and implicated in a range of cancers. Variations in TrkB pathway have been observed in obesity and hyperphagia related disorders as well. Both BDNF and TrkB have been shown to play critical roles in the survival of retinal ganglion cells in the retina. The ability to specifically modulate TrkB signalling can be critical in various pathological scenarios associated with this pathway. In this review, we discuss the mechanisms underlying TrkB signalling, disease implications and explore plausible ameliorative or preventive approaches.     

Exploring the Molecular Interactions of 7,8-Dihydroxyflavone and Its Derivatives with TrkB and VEGFR2 Proteins

7,8-Dihydroxyflavone (7,8-DHF) is a TrkB receptor agonist, and treatment with this flavonoid derivative brings about an enhanced TrkB phosphorylation and promotes downstream cellular signalling. Flavonoids are also known to exert an inhibitory effect on the vascular endothelial growth factor receptor (VEGFR) family of tyrosine kinase receptors. VEGFR2 is one of the important receptors involved in the regulation of vasculogenesis and angiogenesis and has also been implicated to exhibit various neuroprotective roles. Its upregulation and uncontrolled activity is associated with a range of pathological conditions such as age-related macular degeneration and various proliferative disorders. In this study, we investigated molecular interactions of 7,8-DHF and its derivatives with both the TrkB receptor as well as VEGFR2. Using a combination of molecular docking and computational mapping tools involving molecular dynamics approaches we have elucidated additional residues and binding energies involved in 7,8-DHF interactions with the TrkB Ig2 domain and VEGFR2. Our investigations have revealed for the first time that 7,8-DHF has dual biochemical action and its treatment may have divergent effects on the TrkB via its extracellular Ig2 domain and on the VEGFR2 receptor through the intracellular kinase domain. Contrary to its agonistic effects on the TrkB receptor, 7,8-DHF was found to downregulate VEGFR2 phosphorylation both in 661W photoreceptor cells and in retinal tissue.     

Neuroprotection,Growth Factors and BDNF-TrkB Signalling in Retinal Degeneration

Neurotrophic factors play key roles in the development and survival of neurons. The potent neuroprotective effects of neurotrophic factors, including brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), glial cell-line derived neurotrophic factor (GDNF) and nerve growth factor (NGF), suggest that they are good therapeutic candidates for neurodegenerative diseases. Glaucoma is a neurodegenerative disease of the eye that causes irreversible blindness. It is characterized by damage to the optic nerve, usually due to high intraocular pressure (IOP), and progressive degeneration of retinal neurons called retinal ganglion cells (RGCs). Current therapy for glaucoma focuses on reduction of IOP, but neuroprotection may also be beneficial. BDNF is a powerful neuroprotective agent especially for RGCs. Exogenous application of BDNF to the retina and increased BDNF expression in retinal neurons using viral vector systems are both effective in protecting RGCs from damage. Furthermore, induction of BDNF expression by agents such as valproic acid has also been beneficial in promoting RGC survival. In this review, we discuss the therapeutic potential of neurotrophic factors in retinal diseases and focus on the differential roles of glial and neuronal TrkB in neuroprotection. We also discuss the role of neurotrophic factors in neuroregeneration.     

Dorzolamide nanoliposome as a long action ophthalmic delivery system in open angle glaucoma and ocular hypertension patients

Importance: To reduce the frequency of dorzolamide eye drop administration and increasing the duration of action.

Background: This study aims to compare the effect of dorzolamide loaded-nanoliposome with marketed dorzolamide HCl eye drop on intraocular pressure in primary open angle glaucoma and ocular hypertension patients.

Design: A randomized study was conducted in a hospital.

Participants: Twenty patients with primary open angle glaucoma or ocular hypertension (in both eyes) diagnosis were recruited as participants.

Methods: Dorzolamide loaded-nanoliposome was prepared by thin layer hydration method and characterized. Intra ocular pressure were compared between the two groups who received marketed dorzolamide solution or dorzolamide-loaded nanoliposome.

Main outcome measures: The main outcome measures include intraocular pressure initially (day 0) and on days 14 and 28 and adverse effect of dorzolamide-loaded nanoliposome eye drop.

Results: Based on the results of repeated measure, intra ocular pressure was seen to decrease in both the groups. But these reductions in the intervention group (dorzolamide-loaded eye drop) were significantly higher than those in control group (p?Conclusion: This study confirmed safety and long-lasting efficacy of dorzolamide loaded-nanoliposome eye drop. The highly enhanced permeation through the cornea can be attributed to similarity of phospholipid bilayer of liposomes to the biological membrane and their small particle size and positive zeta potential.     

The Latest Evidence of Erythropoietin in the Treatment of Glaucoma

Erythropoietin (EPO) is a circulating hormone conventionally considered to be responsible for erythropoiesis. In addition to facilitating red blood cell production, EPO has pluripotent potential, such as for cognition improvement, neurogenesis, and anti-fibrotic, anti-apoptotic, anti-oxidative, and anti-inflammatory effects. In human retinal tissues, EPO receptors (EPORs) are expressed in the photoreceptor cells, retinal pigment epithelium, and retinal ganglion cell layer. Studies have suggested its potential therapeutic effects in many neurodegenerative diseases, including glaucoma. In this review, we discuss the correlation between glaucoma and EPO, physiology and potential neuroprotective function of the EPO/EPOR system, and latest evidence for the treatment of glaucoma with EPO.     

Retina disease prediction using modified convolutional neural network based on Inception-ResNet model with support vector machine classifier

Artificial intelligence and deep learning have aided ocular disease through experiments including automatic illness recognition from images of the iris, fundus, or retina. Automated diagnosis systems (ADSs) provide services for the benefit of humanity and are essential in the early detection of harmful diseases. In fact, early detection is essential to avoid total blindness. In real life, several diagnostic tests such as visual ocular tonometry, retinal exam, and acuity test are performed, but they are conclusively time demanding and stressful for the patient. To consume time and detect the retinal disease earlier, an efficient prediction method is designed. In this proposed model, the first process is data collection that consists of a retinal disease dataset for testing and training. The second process is pre-processing, which executes image resizing and noise filter for feature extraction. The third step is feature extraction, which extracts the image's form, size, color, and texture for classification with CNN based on Inception-ResNet V2. The classification process is done by using the SVM with the extracted features. The prediction of diseases is classified such as normal, cataract, glaucoma, and retinal disease. The suggested model's performance is assessed using performance indicators such as accuracy, error, sensitivity, precision, and so forth. The suggested model's accuracy, error, sensitivity, and precision are 0.96, 0.962, 0.964, and 0.04, respectively, higher than existing techniques such as VGG16, Mobilenet V1, ResNet, and AlexNet. Thus, the proposed model instantly predicts retinal disease.     

基于多相Mumford-Shah模型最小图分割的视乳头杯盘分割*

为了有效地解决血管遮挡、噪声污染、光照不均、对比度小以及个体间差异大等视乳头图像分割中固有 的难题,提出采用基于图论的多相分段常数水平集ＭｕｍｆｏｒｄＳｈａｈ图像分割模型及其相应的图分割最优化方法。实验表明,该方法能够比经典的多相分段常数水平集ＭｕｍｆｏｒｄＳｈａｈ模型更快更精准地分割青光眼病人视乳头图像中的视杯和视盘形态。