Recent improvements in the development of A2B adenosine receptor agonists

Adenosine is known to exert most of its physiological functions by acting as local modulator at four receptor subtypes named A1, A2A, A2B and A3 (ARs). Principally as a result of the difficulty in identifying potent and selective agonists, the A2B AR is the least extensively characterised of the adenosine receptors family. Despite these limitations, growing understanding of the physiological meaning of this target indicates promising therapeutic perspectives for specific ligands. As A2B AR signalling seems to be associated with pre/postconditioning cardioprotective and anti-inflammatory mechanisms, selective agonists may represent a new therapeutic group for patients suffering from coronary artery disease. Herein we present an overview of the recent advancements in identifying potent and selective A2B AR agonists reported in scientific and patent literature. These compounds can be classified into adenosine-like and nonadenosine ligands. Nucleoside-based agonists are the result of modifying adenosine by substitution at the N6-, C2-positions of the purine heterocycle and/or at the 5′-position of the ribose moiety or combinations of these substitutions. Compounds 1-deoxy-1-{6-[N′-(furan-2-carbonyl)-hydrazino]-9H-purin-9-yl}-N-ethyl-β-D-ribofuranuronamide (19, hA1Ki = 1050 nM, hA2AKi = 1550 nM, hA2B EC50 = 82 nM, hA3Ki > 5 μM) and its 2-chloro analogue 23 (hA1Ki = 3500 nM, hA2AKi = 4950 nM, hA2B EC50 = 210 nM, hA3Ki > 5 μM) were confirmed to be potent and selective full agonists in a cyclic adenosine monophosphate (cAMP) functional assay in Chinese hamster ovary (CHO) cells expressing hA2B AR. Nonribose ligands are represented by conveniently substituted dicarbonitrilepyridines, among which 2-[6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]pyridin-2-ylsulfanyl]acetamide (BAY-60–6583, hA1, hA2A, hA3 EC50 > 10 μM; hA2B EC50 = 3 nM) is currently under preclinical-phase investigation for treating coronary artery disorders and atherosclerosis

Life-style and travel demand

Lifestyle, Congestion, Travel behavior, Long-range forecasting,

Prevention of neuronal apoptosis by astrocytes through thiol-mediated stress response modulation and accelerated recovery from proteotoxic stress

The development of drugs directly interfering with neurodegeneration has proven to be astonishingly difficult. Alternative therapeutic approaches could result from a better understanding of the supportive function of glial cells for stressed neurons. Therefore, here, we investigated the mechanisms involved in the endogenous neuro-defensive activity of astrocytes. A well-established model of postmitotic human dopaminergic neurons (LUHMES cells) was used in the absence ('LUHMES' mono-culture) or presence ('co-culture') of astrocytes. Inhibition of the LUHMES proteasome led to proteotoxic (protein aggregates; ATF-4 induction) and oxidative (GSH-depletion; NRF-2 induction) stress, followed by neuronal apoptosis. The presence of astrocytes attenuated the neuronal stress response, and drastically reduced neurodegeneration. A similar difference between LUHMES mono- and co-cultures was observed, when proteotoxic and oxidative stress was triggered indirectly by inhibitors of mitochondrial function (rotenone, MPP+). Human and murine astrocytes continuously released glutathione (GSH) into the medium, and transfer of glia-conditioned medium was sufficient to rescue LUHMES, unless it was depleted for GSH. Also, direct addition of GSH to LUHMES rescued the neurons from inhibition of the proteasome. Both astrocytes and GSH blunted the neuronal ATF-4 response and similarly upregulated NRF-1/NFE2L1, a transcription factor counter-regulating neuronal proteotoxic stress. Astrocyte co-culture also helped to recover the neurons' ability to degrade aggregated poly-ubiquitinated proteins. Overexpression of NRF-1 attenuated the toxicity of proteasome inhibition, while knockdown increased toxicity. Thus, astrocytic thiol supply increased neuronal resilience to various proteotoxic stressors by simultaneously attenuating cell death-related stress responses, and enhancing the recovery from proteotoxic stress through upregulation of NRF-1.publishe

Biomaterials developments for brain tissue engineering

The Central Nervous System (CNS) is a highly complex organ that works as the control centre of the body, managing vital and non-vital functions. Neuro-diseases can lead to the degeneration of neural tissue, breakage of the neuronal networks which can affect vital functions and originate cognitive deficits. The complexity of the neural networks, their components and the low regenerative capacity of the CNS are on the basis for the lack of recovery, having the need for therapies that can promote tissue repair and recovery. Most brain processes are mediated through molecules (e.g. cytokines, neurotransmitters) and cells response accordingly and to surrounding cues, either biological or physical, which offers molecule administration and/or cell transplantation a great potential for use in brain recovery. Biomaterials and in particular, of natural origin are attractive candidates owed to their intrinsic biological cues and biocompatibility and degradability. Through the use of biomaterials, it is possible to protect the cells/molecules from body clearance, enzymatic degradation while maintaining the components in a place of interest. Moreover, by means of combining several components, it is possible to obtain a more targeted and controlled delivery, to image the biomaterial implantation and its degradation over time and tackling simultaneously occurring events (cell death and inflammation) in brain diseases. In this chapter, it is reviewed some brain-affecting diseases and the current developments on tissue engineering approaches for a functional recovery of the brain from those diseases.(undefined)info:eu-repo/semantics/publishedVersio

Neurodegeneration and neuroglia:Emphasis on Astroglia in Alzheimer's disease

Neurodegenerative diseases, which affect almost exclusively humans, are chronic disorders that ultimately result in atrophy of the brain and profound cognitive deficit. Neurodegenerative process reflects a profound failure of brain homeostasis. Incidentally, neuroglial cells, being primarily the cells responsible for brain homeostasis and defense, naturally contribute to an overall homeostatic failure underlying neurodegeneration. In this chapter we shall deliver a brief on astroglial contribution to common neurodegenerative disorders and then continue with a detailed account on the pathological potential of astroglia in Alzheimer's disease. Astrocytes undergo complex alterations in Alzheimer's disease, which are represented by region-specific atrophy and asthenia at the early stages and reactivity at the late stages of the disease. These complex changes can be considered as pathologically relevant because they may define the early cognitive deficits and the later neurotoxicity in Alzheimer's disease. Targeting astroglia in neurodegeneration may result in new therapeutic strategies aimed at preventing and delaying the progression of Alzheimer's disease.</p