Novel Insight of Histamine and Its Receptor Ligands in Glaucoma and Retina Neuroprotection.
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ABSTRACT:
SUBMITTER: Sgambellone S
PROVIDER: S-EPMC8392511 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The progressive death of retinal ganglion cells and resulting visual deficits are hallmarks of glaucoma, but the underlying mechanisms remain unclear. In many neurodegenerative diseases, cell death induced by primary insult is followed by a wave of secondary loss. Gap junctions (GJs), intercellular channels composed of subunit connexins, can play a major role in secondary cell death by forming conduits through which toxic molecules from dying cells pass to and injure coupled neighbors. Here we have shown that pharmacological blockade of GJs or genetic ablation of connexin 36 (Cx36) subunits, which are highly expressed by retinal neurons, markedly reduced loss of neurons and optic nerve axons in a mouse model of glaucoma. Further, functional parameters that are negatively affected in glaucoma, including the electroretinogram, visual evoked potential, visual spatial acuity, and contrast sensitivity, were maintained at control levels when Cx36 was ablated. Neuronal GJs may thus represent potential therapeutic targets to prevent the progressive neurodegeneration and visual impairment associated with glaucoma.
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Project description:Progressive neurodegeneration of the optic nerve and the loss of retinal ganglion cells is a hallmark of glaucoma, the leading cause of irreversible blindness worldwide, with primary open-angle glaucoma (POAG) being the most frequent form of glaucoma in the Western world. While some genetic mutations have been identified for some glaucomas, those associated with POAG are limited and for most POAG patients, the etiology is still unclear. Unfortunately, treatment of this neurodegenerative disease and other retinal degenerative diseases is lacking. For POAG, most of the treatments focus on reducing aqueous humor formation, enhancing uveoscleral or conventional outflow, or lowering intraocular pressure through surgical means. These efforts, in some cases, do not always lead to a prevention of vision loss and therefore other strategies are needed to reduce or reverse the progressive neurodegeneration. In this review, we will highlight some of the ocular pharmacological approaches that are being tested to reduce neurodegeneration and provide some form of neuroprotection.
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Project description:Glaucoma is a progressive neurodegenerative disease of retinal ganglion cells (RGCs) associated with characteristic axon degeneration in the optic nerve. Clinically, our only method of slowing glaucomatous loss of vision is to reduce intraocular pressure (IOP), but lowering IOP is only partially effective and does not address the underlying susceptibility of RGCs to degeneration. We review the recent steps forward in our understanding of the pathophysiology of glaucoma and discuss how this understanding has given us a next generation of therapeutic targets by which to maintain RGC survival, protect or rebuild RGC connections in the retina and brain, and enhance RGC function.
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Project description:In this article we report a combined experimental and computational study concerning the effects of deuteration on the binding of histamine and two other histaminergic agonists to 3H-tiotidine-labeled histamine H2 receptor in neonatal rat astrocytes. Binding affinities were measured by displacing radiolabeled tiotidine from H2 receptor binding sites present on cultured neonatal rat astrocytes. Quantum-chemical calculations were performed by employing the empirical quantization of nuclear motion within a cluster model of the receptor binding site extracted from the homology model of the entire H2 receptor. Structure of H2 receptor built by homology modelling is attached in the supporting information (S1 Table) Experiments clearly demonstrate that deuteration affects the binding by increasing the affinity for histamine and reducing it for 2-methylhistamine, while basically leaving it unchanged for 4-methylhistamine. Ab initio quantum-chemical calculations on the cluster system extracted from the homology H2 model along with the implicit quantization of the acidic N-H and O-H bonds demonstrate that these changes in the binding can be rationalized by the altered strength of the hydrogen bonding upon deuteration known as the Ubbelohde effect. Our computational analysis also reveals a new mechanism of histamine binding, which underlines an important role of Tyr250 residue. The present work is, to our best knowledge, the first study of nuclear quantum effects on ligand receptor binding. The ligand H/D substitution is relevant for therapy in the context of perdeuterated and thus more stable drugs that are expected to enter therapeutic practice in the near future. Moreover, presented approach may contribute towards understanding receptor activation, while a distant goal remains in silico discrimination between agonists and antagonists based on the receptor structure.
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Project description:Glaucoma is the second leading cause of blindness worldwide and is most notably characterized by progressive optic nerve atrophy and advancing loss of retinal ganglion cells (RGCs). The main concomitant factor is the elevated intraocular pressure (IOP). Existing treatments are focused generally on lowering IOP. However, both RGC loss and optic nerve atrophy can independently occur with IOP at normal levels. In recent years, there has been substantial progress in the development of neuroprotective therapies for glaucoma in order to restore vital visual function. The present review intends to offer a brief insight into conventional glaucoma treatments and discuss exciting current developments of mostly preclinical data in novel neuroprotective strategies for glaucoma that include recent advances in noninvasive diagnostics going beyond IOP maintenance for an enhanced global view. Such strategies now target RGC loss and optic nerve damage, opening a critical therapeutic window for preventative monitoring and treatment.
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Project description:Virtual screening offers an efficient alternative to high-throughput screening in the identification of pharmacological tools and lead compounds. Virtual screening is typically based on the matching of target structures or ligand pharmacophores to commercial or in-house compound catalogues. This study provides the first proof-of-concept for our recently reported method where pharmacophores are instead constructed based on the inference of residue-ligand fragments from crystal structures. We demonstrate its unique utility for G protein-coupled receptors, which represent the largest families of human membrane proteins and drug targets. We identified five neutral antagonists and one inverse agonist for the histamine H3 receptor with potencies of 0.7-8.5??M in a recombinant receptor cell-based inositol phosphate accumulation assay and validated their activity using a radioligand competition binding assay. H3 receptor antagonism is of large therapeutic value and our ligands could serve as starting points for further lead optimisation. The six ligands exhibit four chemical scaffolds, whereof three have high novelty in comparison to the known H3 receptor ligands in the ChEMBL database. The complete pharmacophore fragment library is freely available through the GPCR database, GPCRdb, allowing the successful application herein to be repeated for most of the 285 class A GPCR targets. The method could also easily be adapted to other protein families.
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Project description:BACKGROUND:Glaucoma is a heterogeneous group of conditions involving progressive damage to the optic nerve, deterioration of retinal ganglion cells and ultimately visual field loss. It is a leading cause of blindness worldwide. Open angle glaucoma (OAG), the commonest form of glaucoma, is a chronic condition that may or may not present with increased intraocular pressure (IOP). Neuroprotection for glaucoma refers to any intervention intended to prevent optic nerve damage or cell death. The treatment can target extracellular factors such as reducing IOP, or cellular factors derived from the optic nerve itself such as blocking intracellular death signals. OBJECTIVES:The objective of this review was to systematically examine the evidence regarding the effectiveness of neuroprotective agents, either topical or oral, for slowing the progression of OAG in adults. SEARCH STRATEGY:We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library, Issue 4, 2009), MEDLINE (January 1960 to January 2010), EMBASE (January 1980 to January 2010), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to January 2010) and ClinicalTrials.gov (http://clinicaltrials.gov). (5 January 2010). There were no language or date restrictions in the search for trials. The electronic databases were last searched on 5 January 2010. SELECTION CRITERIA:This review was limited to randomized controlled trials (RCTs) in which topical or oral treatments were used to prevent retinal ganglion cell death. Our population of interest was adults with OAG. As the primary outcome for this review was the proportion of participants who developed any progression of visual field loss at five years post intervention, only trials with at least five years of follow-up were included. DATA COLLECTION AND ANALYSIS:Two review authors independently reviewed titles and abstracts from the literature searches. Full text copies of relevant or potentially relevant studies were obtained and re-evaluated for inclusion. There were no trials identified for this review, thus we performed no data extraction or meta-analysis. Two studies comparing memantine to placebo are currently awaiting classification until additional study details are provided. Reasons for excluding studies from the review were documented. MAIN RESULTS:In accordance with the selection criteria for inclusion, we identified no studies relevant for this review. The results of short-term trials and other studies are discussed in this review. AUTHORS' CONCLUSIONS:Although neuroprotective agents are intended to act as pharmacological antagonists to prevent cell death, the evidence that they are effective in preventing retinal ganglion cell death, and thus preserving vision in patients with OAG, has not been demonstrated. Long-term RCTs are needed to determine whether or not neuroprotective agents may be beneficial for individuals with OAG.
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| S-EPMC3431845 | biostudies-literature