scholarly journals Adenosine Receptor Agonists

2019 ◽  
Vol 18 ◽  
Author(s):  
Markus Wallner ◽  
Piotr Ponikowski
Keyword(s):  
Two Phase ◽  
Adenosine Receptor Agonists ◽  
Surface Receptors ◽  
Beneficial Effects ◽  
Phase Ii Studies ◽  
Clinical Models ◽  
Potential Benefits ◽  
Adenosine Agonists ◽  
G Protein Coupled ◽  
The Brain

Adenosine is a purine nucleoside that binds to adenosine cell surface receptors, which are widely expressed in heart and blood vessel cells as well as in the brain, kidney and adipose tissue.There are 4 subtypes of P1 (adenosine) G protein-coupled receptors (GPCR), named A1, A2A, A2B, and A3, which mediate a variety of cardioprotective and regenerative effects. In the heart, these effects are predominantly mediated through A1 receptors (A1R), which are expressed in atrial and ventricular cardiomyocytes and smooth muscle cells.  Pre-clinical studies have reported multiple potential benefits achievable by modulation of adenyl cyclase with beneficial effects in a variety of pre-clinical models of cardiovascular disease including chronic heart failure (HF). A1R blockade (e.g. rolofylline) was however not successful in the PROTECT trial, where 2033 patients with acute HF and renal dysfunction were randomized to rolofylline or placebo, showed no benefit on renal function, symptoms, rehospitalization, or mortality. Following this attention turned to partial adenosine agonists, capadenoson and neladenoson bialanate hydrochloride, which has two phase II studies underway, PANACHE (HFpEF) and PANTHEON (HFrEF).

scholarly journals The Retinoid and Non-Retinoid Ligands of the Rod Visual G Protein-Coupled Receptor

2019 ◽  
Vol 20 (24) ◽  
pp. 6218 ◽  
Author(s):  
Joseph T. Ortega ◽  
Beata Jastrzebska
Keyword(s):  
Drug Discovery ◽  
G Protein ◽  
Binding Sites ◽  
Binding Pocket ◽  
Biologically Active ◽  
Surface Receptors ◽  
Beneficial Effects ◽  
Light Sensing ◽  
Potential Binding ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) play a predominant role in the drug discovery effort. These cell surface receptors are activated by a variety of specific ligands that bind to the orthosteric binding pocket located in the extracellular part of the receptor. In addition, the potential binding sites located on the surface of the receptor enable their allosteric modulation with critical consequences for their function and pharmacology. For decades, drug discovery focused on targeting the GPCR orthosteric binding sites. However, finding that GPCRs can be modulated allosterically opened a new venue for developing novel pharmacological modulators with higher specificity. Alternatively, focus on discovering of non-retinoid small molecules beneficial in retinopathies associated with mutations in rhodopsin is currently a fast-growing pharmacological field. In this review, we summarize the accumulated knowledge on retinoid ligands and non-retinoid modulators of the light-sensing GPCR, rhodopsin and their potential in combating the specific vision-related pathologies. Also, recent findings reporting the potential of biologically active compounds derived from natural products as potent rod opsin modulators with beneficial effects against degenerative diseases related to this receptor are highlighted here.

Therapeutic Approaches to Alzheimer’s Type of Dementia: A Focus on FGF21 Mediated Neuroprotection

2019 ◽  
Vol 25 (23) ◽  
pp. 2555-2568 ◽  
Author(s):  
Rajeev Taliyan ◽  
Sarathlal K. Chandran ◽  
Violina Kakoty
Keyword(s):  
Diabetes Mellitus ◽  
Protein Trafficking ◽  
Metabolic Stress ◽  
Insulin Receptors ◽  
Metabolic Dysfunction ◽  
Beneficial Effects ◽  
Glucose And Lipid Metabolism ◽  
Endocrine Hormone ◽  
Metabolic Conditions ◽  
The Brain

Neurodegenerative disorders are the most devastating disorder of the nervous system. The pathological basis of neurodegeneration is linked with dysfunctional protein trafficking, mitochondrial stress, environmental factors and aging. With the identification of insulin and insulin receptors in some parts of the brain, it has become evident that certain metabolic conditions associated with insulin dysfunction like Type 2 diabetes mellitus (T2DM), dyslipidemia, obesity etc., are also known to contribute to neurodegeneration mainly Alzheimer’s Disease (AD). Recently, a member of the fibroblast growth factor (FGF) superfamily, FGF21 has proved tremendous efficacy in diseases like diabetes mellitus, obesity and insulin resistance (IR). Increased levels of FGF21 have been reported to exert multiple beneficial effects in metabolic syndrome. FGF21 receptors are present in certain areas of the brain involved in learning and memory. However, despite extensive research, its function as a neuroprotectant in AD remains elusive. FGF21 is a circulating endocrine hormone which is mainly secreted by the liver primarily in fasting conditions. FGF21 exerts its effects after binding to FGFR1 and co-receptor, β-klotho (KLB). It is involved in regulating energy via glucose and lipid metabolism. It is believed that aberrant FGF21 signalling might account for various anomalies like neurodegeneration, cancer, metabolic dysfunction etc. Hence, this review will majorly focus on FGF21 role as a neuroprotectant and potential metabolic regulator. Moreover, we will also review its potential as an emerging candidate for combating metabolic stress induced neurodegenerative abnormalities.

Electromagnetic field in Alzheimer’s disease: a literature review of recent preclinical and clinical studies

2020 ◽  
Vol 17 ◽  
Author(s):  
Reem Habib Mohamad Ali Ahmad ◽  
Marc Fakhoury ◽  
Nada Lawand
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
In Vivo Studies ◽  
Key Factors ◽  
Potential Benefits ◽  
Preclinical And Clinical Studies ◽  
The Brain

: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the progressive loss of neurons leading to cognitive and memory decay. The main signs of AD include the irregular extracellular accumulation of amyloidbeta (Aβ) protein in the brain and the hyper-phosphorylation of tau protein inside neurons. Changes in Aβ expression or aggregation are considered key factors in the pathophysiology of sporadic and early-onset AD and correlate with the cognitive decline seen in patients with AD. Despite decades of research, current approaches in the treatment of AD are only symptomatic in nature and are not effective in slowing or reversing the course of the disease. Encouragingly, recent evidence revealed that exposure to electromagnetic fields (EMF) can delay the development of AD and improve memory. This review paper discusses findings from in vitro and in vivo studies that investigate the link between EMF and AD at the cellular and behavioural level, and highlights the potential benefits of EMF as an innovative approach for the treatment of AD.

The Effects of D-aspartate on Neurosteroids, Neurosteroid Receptors, and Inflammatory Mediators in Experimental Autoimmune Encephalomyelitis

2019 ◽  
Vol 19 (3) ◽  
pp. 316-325
Author(s):  
Mahdi Goudarzvand ◽  
Yaser Panahi ◽  
Reza Yazdani ◽  
Hosein Miladi ◽  
Saeed Tahmasebi ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Inflammatory Mediators ◽  
Mouse Serum ◽  
Enzyme Linked Immunosorbent Assay ◽  
Oral Gavage ◽  
Autoimmune Encephalomyelitis ◽  
Beneficial Effects ◽  
17Β Estradiol ◽  
The Brain ◽  
Experimental Autoimmune

Objective: Experimental autoimmune encephalomyelitis (EAE) is a widely used model for multiple sclerosis. The present study has been designed to compare the efficiencies of oral and intraperitoneal (IP) administration of D-aspartate (D-Asp) on the onset and severity of EAE, the production of neurosteroids, and the expression of neurosteroid receptors and inflammatory mediators in the brain of EAE mice. Methods: In this study, EAE was induced in C57BL/6 mice treated with D-Asp orally (D-Asp-Oral) or by IP injection (D-Asp-IP). On the 20th day, brains (cerebrums) and cerebellums of mice were evaluated by histological analyses. The brains of mice were analyzed for: 1) Neurosteroid (Progesterone, Testosterone, 17β-estradiol) concentrations; 2) gene expressions of cytokines and neurosteroid receptors by reverse transcription polymerase chain reaction, and 3) quantitative determination of D-Asp using liquid chromatography-tandem mass spectrometry. Further, some inflammatory cytokines and matrix metalloproteinase-2 (MMP-2) were identified in the mouse serum using enzyme-linked immunosorbent assay kits. Results: Our findings demonstrated that after D-Asp was administered, it was taken up and accumulated within the brain. Further, IP injection of D-Asp had more beneficial effects on EAE severity than oral gavage. The concentration of the testosterone and 17β-estradiol in D-Asp-IP group was significantly higher than that of the control group. There were no significant differences in the gene expression of cytokine and neurosteroid receptors between control, D-Asp-IP, and D-Asp-Oral groups. However, IP treatment with D-Asp significantly reduced C-C motif chemokine ligand 2 and MMP-2 serum levels compared to control mice. Conclusion: IP injection of D-Asp had more beneficial effects on EAE severity, neurosteroid induction and reduction of inflammatory mediators than oral gavage.

The Effect of PAOPA, a Novel Allosteric Modulator of Dopamine D2 Receptors, on Select Signaling Proteins Following Sub-Chronic Administration in the Rat

2020 ◽  
Vol 13 ◽  
Author(s):  
Ritesh Daya ◽  
Joella Ho ◽  
Sharon Thomson ◽  
Jayant Bhandari ◽  
Ram K. Mishra
Keyword(s):  
Frontal Cortex ◽  
Mechanism Of Action ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Dorsal Striatum ◽  
D2 Receptors ◽  
Dopamine D2 ◽  
Therapeutic Mechanism ◽  
Clinical Models ◽  
G Protein Coupled

Background: Allosteric modulators of G-protein coupled receptors regulate receptor activity by binding to sites other than the active site and have emerged as a new and highly desirable class of drugs. PAOPA (3(R)-[(2(S)- pyrrolidinylcarbonyl)amino]-2-oxo-1-pyrrolidineacetamide), a peptidomimetic analog of Prolyl-Leucyl-Glycinamide, is a potent dopamine D2 receptor allosteric modulator. PAOPA has shown therapeutic effects in pre-clinical models of schizophrenia and extrapyramidal dysfunction. Objective: in this study, we sought to examine the biomolecular underpinnings of PAOPA‘s therapeutic outcomes in preclinical models of schizophrenia. Method: Following sub-chronic (daily for 7 days) administration of PAOPA, we assessed levels of dopamine D2 receptors, receptor kinases (GRK2 (G protein-coupled receptor kinase 2) and Arrestin-3), and phosphorylated mitogenactivated protein kinase (MAPKs), namely, extracellular signal-regulated kinases (ERK1/2) in the hippocampus, medial pre-frontal cortex, nucleus accumbens, pre-frontal cortex, and dorsal striatum via protein quantification. Results: Following 7 days of daily PAOPA treatment, we observed decreased GRK2 and increased dopamine D2 receptor expression in the dorsal striatum. These findings potentially underscore PAOPA’s therapeutic mechanism of action for the positive-like symptoms of schizophrenia in pre-clinical animal models. Additionally, we observed a decline in GRK2 in the hippocampus and an increase in phosphorylated ERK1 in the pre-frontal cortex, suggestive of a role for PAOPA in treating cognitive and/or affective dysfunction in pre-clinical models. Conclusion: While further studies are required to elucidate PAOPA’s mechanism of action, this study builds on prior investigations and develops an early framework to describe the therapeutic mechanism of action of PAOPA.

Boswellia serrata Oleo-Gum-Resin and its Effect on Memory Functions: A Review

2020 ◽  
Vol 10 (4) ◽  
pp. 355-363
Author(s):  
Mohaddese Mahboubi ◽  
Leila Mohammad Taghizadeh Kashani
Keyword(s):  
Memory Loss ◽  
Modern Medicine ◽  
Waste Materials ◽  
Boswellia Serrata ◽  
Memory Functions ◽  
Beneficial Effects ◽  
Waste Production ◽  
Nursing Mothers ◽  
Traditional Practitioners ◽  
The Brain

Background: In Iranian Traditional Medicine, Boswellia serrata oleo-gum resins were used for the treatment of "Nisyan". "Nisyan" was equivalent to a reduction of memory or forgetfulness. Objective: This review evaluates the traditional believes of B. serrata and memory and its effectiveness on memory loss. Methods: We extracted all traditional and modern information on B. serrata oleo-gum resin preparations and memory from scientific accessible resources (Google Scholar, PubMed, Springer, Science direct, Wiley), non-accessible resources and traditional books. Results: In traditional manuscripts, "Nisyan" is equal to memory loss in modern medicine and was believed to happen as the result of pouring the waste materials into the brain. Traditional practitioners treated "Nisyan" by inhibition of waste production in the brain or cleaning the brain from waste materials. They recommended using the plants with warming effects on the brain. It was believed that B. serrata had beneficial effects on memory functions and its memory enhancing effects have been the subject of pharmacological and clinical trial studies. Conclusion: Despite some documents on the effectiveness of B. serrata oleo-gum-resin on memory functions, there is gap between these investigations, especially in pregnant and nursing mothers. More investigations with large clinical trials are required to complete flaw in order to improve the therapeutic applications of B. serrata on memory functions.

scholarly journals SARS-CoV-2: is there neuroinvasion?

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Conor McQuaid ◽  
Molly Brady ◽  
Rashid Deane
Keyword(s):  
Respiratory Distress ◽  
Vascular Dysfunction ◽  
Multiorgan Failure ◽  
Neurological Complications ◽  
Wide Distribution ◽  
The Body ◽  
Health Conditions ◽  
Main Body ◽  
Beneficial Effects ◽  
The Brain

Abstract Background SARS-CoV-2, a coronavirus (CoV), is known to cause acute respiratory distress syndrome, and a number of non-respiratory complications, particularly in older male patients with prior health conditions, such as obesity, diabetes and hypertension. These prior health conditions are associated with vascular dysfunction, and the CoV disease 2019 (COVID-19) complications include multiorgan failure and neurological problems. While the main route of entry into the body is inhalation, this virus has been found in many tissues, including the choroid plexus and meningeal vessels, and in neurons and CSF. Main body We reviewed SARS-CoV-2/COVID-19, ACE2 distribution and beneficial effects, the CNS vascular barriers, possible mechanisms by which the virus enters the brain, outlined prior health conditions (obesity, hypertension and diabetes), neurological COVID-19 manifestation and the aging cerebrovascualture. The overall aim is to provide the general reader with a breadth of information on this type of virus and the wide distribution of its main receptor so as to better understand the significance of neurological complications, uniqueness of the brain, and the pre-existing medical conditions that affect brain. The main issue is that there is no sound evidence for large flux of SARS-CoV-2 into brain, at present, compared to its invasion of the inhalation pathways. Conclusions While SARS-CoV-2 is detected in brains from severely infected patients, it is unclear on how it gets there. There is no sound evidence of SARS-CoV-2 flux into brain to significantly contribute to the overall outcomes once the respiratory system is invaded by the virus. The consensus, based on the normal route of infection and presence of SARS-CoV-2 in severely infected patients, is that the olfactory mucosa is a possible route into brain. Studies are needed to demonstrate flux of SARS-CoV-2 into brain, and its replication in the parenchyma to demonstrate neuroinvasion. It is possible that the neurological manifestations of COVID-19 are a consequence of mainly cardio-respiratory distress and multiorgan failure. Understanding potential SARS-CoV-2 neuroinvasion pathways could help to better define the non-respiratory neurological manifestation of COVID-19.

scholarly journals Molecular mechanisms of metabotropic GABAB receptor function

2021 ◽  
Vol 7 (22) ◽  
pp. eabg3362
Author(s):  
Hamidreza Shaye ◽  
Benjamin Stauch ◽  
Cornelius Gati ◽  
Vadim Cherezov
Keyword(s):  
G Protein ◽  
Molecular Mechanisms ◽  
Gabab Receptor ◽  
Neurological Diseases ◽  
Activation Mechanism ◽  
Allosteric Modulators ◽  
Inhibitory Neurotransmitter ◽  
Therapeutic Drugs ◽  
G Protein Coupled ◽  
The Brain

Metabotropic γ-aminobutyric acid G protein–coupled receptors (GABAB) represent one of the two main types of inhibitory neurotransmitter receptors in the brain. These receptors act both pre- and postsynaptically by modulating the transmission of neuronal signals and are involved in a range of neurological diseases, from alcohol addiction to epilepsy. A series of recent cryo-EM studies revealed critical details of the activation mechanism of GABAB. Structures are now available for the receptor bound to ligands with different modes of action, including antagonists, agonists, and positive allosteric modulators, and captured in different conformational states from the inactive apo to the fully active state bound to a G protein. These discoveries provide comprehensive insights into the activation of the GABAB receptor, which not only broaden our understanding of its structure, pharmacology, and physiological effects but also will ultimately facilitate the discovery of new therapeutic drugs and neuromodulators.

scholarly journals From Exercise to Cognitive Performance: Role of Irisin

2021 ◽  
Vol 11 (15) ◽  
pp. 7120
Author(s):  
Mirko Pesce ◽  
Irene La Fratta ◽  
Teresa Paolucci ◽  
Alfredo Grilli ◽  
Antonia Patruno ◽  
...  
Keyword(s):  
The Elderly ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Beneficial Effects ◽  
General Exercise ◽  
Fibronectin Type Iii ◽  
Exercise Induced ◽  
Fibronectin Type Iii Domain ◽  
The Brain

The beneficial effects of exercise on the brain are well known. In general, exercise offers an effective way to improve cognitive function in all ages, particularly in the elderly, who are considered the most vulnerable to neurodegenerative disorders. In this regard, myokines, hormones secreted by muscle in response to exercise, have recently gained attention as beneficial mediators. Irisin is a novel exercise-induced myokine, that modulates several bodily processes, such as glucose homeostasis, and reduces systemic inflammation. Irisin is cleaved from fibronectin type III domain containing 5 (FNDC5), a transmembrane precursor protein expressed in muscle under the control of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). The FNDC5/irisin system is also expressed in the hippocampus, where it stimulates the expression of the neurotrophin brain-derived neurotrophic factor in this area that is associated with learning and memory. In this review, we aimed to discuss the role of irisin as a key mediator of the beneficial effects of exercise on synaptic plasticity and memory in the elderly, suggesting its roles within the main promoters of the beneficial effects of exercise on the brain.

scholarly journals Potential for imaging the high-affinity state of the 5-HT1B receptor: a comparison of three PET radioligands with differing intrinsic activity

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Anton Lindberg ◽  
Ryosuke Arakawa ◽  
Tsuyoshi Nogami ◽  
Sangram Nag ◽  
Magnus Schou ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Specific Binding ◽  
Occipital Cortex ◽  
Intrinsic Activity ◽  
High Affinity ◽  
G Protein Coupled ◽  
Dose Dependent ◽  
The Brain ◽  
Agonist Affinity States ◽  
Different Doses

Abstract Background Over the last decade, a few radioligands have been developed for PET imaging of brain 5-HT1B receptors. The 5-HT1B receptor is a G-protein-coupled receptor (GPCR) that exists in two different agonist affinity states. An agonist ligand is expected to be more sensitive towards competition from another agonist, such as endogenous 5-HT, than an antagonist ligand. It is of interest to know whether the intrinsic activity of a PET radioligand for the 5-HT1B receptor impacts on its ability to detect changes in endogenous synaptic 5-HT density. Three high-affinity 11C-labeled 5-HT1B PET radioligands with differing intrinsic activity were applied to PET measurements in cynomolgus monkey to evaluate their sensitivity to be displaced within the brain by endogenous 5-HT. For these experiments, fenfluramine was pre-administered at two different doses (1.0 and 5.0 mg/kg, i.v.) to induce synaptic 5-HT release. Results A dose-dependent response to fenfluramine was detected for all three radioligands. At the highest dose of fenfluramine (5.0 mg/kg, i.v.), reductions in specific binding in the occipital cortex increased with radioligand agonist efficacy, reaching 61% for [11C]3. The most antagonistic radioligand showed the lowest reduction in specific binding. Conclusions Three 5-HT1B PET radioligands were identified with differing intrinsic activity that could be used in imaging high- and low-affinity states of 5-HT1B receptors using PET. From this limited study, radioligand sensitivity to endogenous 5-HT appears to depend on agonist efficacy. More extensive studies are required to substantiate this suggestion.

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