Pathophysiological Role and Medicinal Chemistry of A2A Adenosine Receptor Antagonists in Alzheimer's Disease

The A(2A) adenosine receptor is a protein belonging to a family of four GPCR adenosine receptors. It is involved in the regulation of several pathophysiological conditions in both the central nervous system and periphery. In the brain, its localization at pre- and postsynaptic level in striatum, cortex, hippocampus and its effects on glutamate release, microglia and astrocyte activation account for a crucial role in neurodegenerative diseases, including Alzheimer's disease (AD). This ailment is considered the main form of dementia and is expected to exponentially increase in coming years. The pathological tracts of AD include amyloid peptide-beta extracellular accumulation and tau hyperphosphorylation, causing neuronal cell death, cognitive deficit, and memory loss. Interestingly, in vitro and in vivo studies have demonstrated that A(2A) adenosine receptor antagonists may counteract each of these clinical signs, representing an important new strategy to fight a disease for which unfortunately only symptomatic drugs are available. This review offers a brief overview of the biological effects mediated by A(2A) adenosine receptors in AD animal and human studies and reports the state of the art of A(2A) adenosine receptor antagonists currently in clinical trials. As an original approach, it focuses on the crucial role of pharmacokinetics and ability to pass the blood-brain barrier in the discovery of new agents for treating CNS disorders. Considering that A(2A) receptor antagonist istradefylline is already commercially available for Parkinson's disease treatment, if the proof of concept of these ligands in AD is confirmed and reinforced, it will be easier to offer a new hope for AD patients

Short-Term Exposure to Bisphenol A Does Not Impact Gonadal Cell Steroidogenesis In Vitro

: Bisphenol A (BPA) is a ubiquitous, synthetic chemical proven to induce reproductive disorders in both men and women. The available studies investigated the effects of BPA on male and female steroidogenesis following long-term exposure to the compound at relatively high environmental concentrations. However, the impact of short-term exposure to BPA on reproduction is poorly studied. We evaluated if 8 and 24 h exposure to 1 nM and 1 µM BPA perturbs luteinizing hormone/choriogonadotropin (LH/hCG)-mediated signalling in two steroidogenic cell models, i.e., the mouse tumour Leydig cell line mLTC1, and human primary granulosa lutein cells (hGLC). Cell signalling studies were performed using a homogeneous time-resolved fluorescence (HTRF) assay and Western blotting, while gene expression analysis was carried out using real-time PCR. Immunostainings and an immunoassay were used for intracellular protein expression and steroidogenesis analyses, respectively. The presence of BPA leads to no significant changes in gonadotropin-induced cAMP accumulation, alongside phosphorylation of downstream molecules, such as ERK1/2, CREB and p38 MAPK, in both the cell models. BPA did not impact STARD1, CYP11A1 and CYP19A1 gene expression in hGLC, nor Stard1 and Cyp17a1 expression in mLTC1 treated with LH/hCG. Additionally, the StAR protein expression was unchanged upon exposure to BPA. Progesterone and oestradiol levels in the culture medium, measured by hGLC, as well as the testosterone and progesterone levels in the culture medium, measured by mLTC1, did not change in the presence of BPA combined with LH/hCG. These data suggest that short-term exposure to environmental concentrations of BPA does not compromise the LH/hCG-induced steroidogenic potential of either human granulosa or mouse Leydig cells

Electromagnetic fields (EMFs) and adenosine receptors modulate prostaglandin E2 and cytokine production in human osteoarthritic synovial fibroblasts

Objective. Synovial fibroblasts (SFs) contribute to the development of osteoarthritis (OA) by the secretion of a wide range of pro-inflammatory mediators, including cytokines and lipid mediators of inflammation (1). Previous studies show that electromagnetic fields (EMFs) may represent a potential therapeutical approach to limit cartilage degradation and to control inflammation associated to OA, and that they may act through the adenosine pathway (2). On this basis the aim of this study was to investigate if EMFs might modulate inflammatory activities of human SFs derived from OA patients (OASFs) and the possible involvement of adenosine receptors (ARs) in mediating EMF effects. Design. SFs obtained from OA patients, undergoing total hip joint replacement surgery, were exposed to EMFs (1.5 mT; 75 Hz) for 24 hours. In control and EMF-exposed cells, ARs were evaluated by western blotting, quantitative real-time RT-PCR and saturation binding experiments and cAMP levels were measured by a specific assay. In the absence and in the presence of interleukin-1β (IL-1β), used as a pro-inflammatory stimulus, prostaglandin E2 (PGE2), cytokine and matrix degrading enzyme production was evaluated in OASFs exposed to EMFs and treated with selective adenosine receptor agonists and antagonists. Results. EMF exposure induced a selective increase in A2A and A3 ARs. These increases were associated to changes in cAMP levels, indicating that ARs were functionally active in EMF-exposed cells. In IL-1β-treated OASFs, functional data obtained in the presence of  A2A and A3 adenosine agonists and antagonists showed that EMFs inhibit the release of (PGE2) and of the proinflammatory cytokines interleukin-6 (IL-6) and interleukin-8 (IL-8), whilst stimulate the release of interleukin-10 (IL-10), an antinflammatory cytokine. Further, results show that these effects appear to be mediated by the EMF-induced upregulation of A2A and A3 ARs. No effects of EMFs or ARs have been observed on matrix degrading enzymes production. Conclusions: EMFs display anti-inflammatory effects in human OASFs and these EMF-induced .ffects are in part mediated by the adenosine pathway, specifically by the A2A and A3 ARs activation. Taken together, these results suggest that SFs could represent potential therapeutic targets cells for EMF treatment and open new clinical perspectives to the control of inflammation associated to joint diseases. 1. Martel-Pelletier J et al. Eklem Hastalik Cerrahisi. 2010; 21(1):2-14. 2. De Mattei M et al. Osteoarthritis Cartilage. 2009; 17(2):252-262

A2A Adenosine Receptor: A Possible Therapeutic Target for Alzheimer’s Disease by Regulating NLRP3 Inflammasome Activity?

The A2A adenosine receptor, a member of the P1 purinergic receptor family, plays a crucial role in the pathophysiology of different neurodegenerative illnesses, including Alzheimer’s disease (AD). It regulates both neurons and glial cells, thus modulating synaptic transmission and neuroinflammation. AD is a complex, progressive neurological condition that is the leading cause of dementia in the world’s old population (>65 years of age). Amyloid peptide-β extracellular accumulation and neurofibrillary tangles constitute the principal etiologic tracts, resulting in apoptosis, brain shrinkage, and neuroinflammation. Interestingly, a growing body of evidence suggests a role of NLRP3 inflammasome as a target to treat neurodegenerative diseases. It represents a tripartite multiprotein complex including NLRP3, ASC, and procaspase-1. Its activation requires two steps that lead with IL-1β and IL-18 release through caspase-1 activation. NLRP3 inhibition provides neuroprotection, and in recent years adenosine, through the A2A receptor, has been reported to modulate NLRP3 functions to reduce organ damage. In this review, we describe the role of NLRP3 in AD pathogenesis, both alone and in connection to A2A receptor regulation, in order to highlight a novel approach to address treatment of AD

Expression and functional characterization of adenosine receptors in bovine synovial fibroblasts

none7noneDe Mattei M.; Masieri F.F.; Pellati A.; Ongaro A.; Varani K.; Borea P.A.; Caruso A.DE MATTEI, Monica; Masieri, Federica Francesca; Pellati, Agnese; Ongaro, Alessia; Varani, Katia; Borea, Pier Andrea; Caruso, Angel

Functional tissue engineering in articular cartilage repair: is there a role for electromagnetic biophysical stimulation?

Hyaline cartilage lesions represent an important global health problem. Several approaches have been developed in the last decades to resolve this disability cause, including tissue engineering, but to date, there is not a definitive procedure that is able to promote a repair tissue with the same mechanical and functional characteristics of native cartilage, and to obtain its integration in the subchondral bone. The need of resolutive technologies to obtain a "more effective" tissue substitutes has led Butler to propose the "Functional Tissue Engineering" (FTE) paradigm, whose principles are outlined in a so-called FTE road map. It consists of a two-phase strategy: in vitro tissue engineering and clinically surgery evaluation. The first phase, based on construct development, should take into account not only the chondrocyte biology, as their sensitivity to biochemical and physical stimuli, the risk of dedifferentiation in culture, and the ability to produce extracellular matrix, but also the features of suitable scaffolds. The in vivo phase analyzes the inflammatory microenvironment where the construct will be placed, because the cytokines released by synoviocytes and chondrocytes could affect the construct integrity, and, in particular, cause matrix degradation. The use of pulsed electromagnetic fields (PEMFs) represents an innovative therapeutic approach, because it is demonstrated that this physical stimulus increases the anabolic activity of chondrocytes and cartilage explants with consequent increase of matrix synthesis, but, at the same time, PEMFs limit the catabolic effects of inflammatory cytokines, reducing the construct degradation inside the surgical microenvironment. PEMFs mediate an up-regulation of A2A adenosine receptors and a potentiation of their anti-inflammatory effects

Pharmacology of Adenosine Receptors: Recent Advancements

Adenosine receptors (ARs) are widely acknowledged pharmacological targets yet are still underutilized in clinical practice. Their ubiquitous distribution in almost all cells and tissues of the body makes them, on the one hand, excellent candidates for numerous diseases, and on the other hand, intrinsically challenging to exploit selectively and in a site-specific manner. This review endeavors to comprehensively depict the substantial advancements witnessed in recent years concerning the development of drugs that modulate ARs. Through preclinical and clinical research, it has become evident that the modulation of ARs holds promise for the treatment of numerous diseases, including central nervous system disorders, cardiovascular and metabolic conditions, inflammatory and autoimmune diseases, and cancer. The latest studies discussed herein shed light on novel mechanisms through which ARs exert control over pathophysiological states. They also introduce new ligands and innovative strategies for receptor activation, presenting compelling evidence of efficacy along with the implicated signaling pathways. Collectively, these emerging insights underscore a promising trajectory toward harnessing the therapeutic potential of these multifaceted targets

Caffeine for Prevention of Alzheimer's Disease: Is the A2A Adenosine Receptor Its Target?

Alzheimer's disease (AD) is the most prevalent kind of dementia with roughly 135 million cases expected in the world by 2050. Unfortunately, current medications for the treatment of AD can only relieve symptoms but they do not act as disease-modifying agents that can stop the course of AD. Caffeine is one of the most widely used drugs in the world today, and a number of clinical studies suggest that drinking coffee may be good for health, especially in the fight against neurodegenerative conditions such as AD. Experimental works conducted "in vivo" and "in vitro" provide intriguing evidence that caffeine exerts its neuroprotective effects by antagonistically binding to A2A receptors (A2ARs), a subset of GPCRs that are triggered by the endogenous nucleoside adenosine. This review provides a summary of the scientific data supporting the critical role that A2ARs play in memory loss and cognitive decline, as well as the evidence supporting the protective benefits against neurodegeneration that may be attained by caffeine's antagonistic action on these receptors. They are a novel and fascinating target for regulating and enhancing synaptic activity, achieving symptomatic and potentially disease-modifying effects, and protecting against neurodegeneration