Figure 1 - uploaded by Alessandro Castorina
Content may be subject to copyright.
Chemical structure of caffeine and adenosine. Depicted are the chemical structures of the widely used drug "caffeine" and the endogenously produced nucleoside "adenosine" for comparison. Structural similarities are highlighted in red. 

Chemical structure of caffeine and adenosine. Depicted are the chemical structures of the widely used drug "caffeine" and the endogenously produced nucleoside "adenosine" for comparison. Structural similarities are highlighted in red. 

Context in source publication

Context 1
... to current knowledge, the mechanisms of action of the methylxanthine caffeine (1,3,7-trimeth- ylxanthine) to trigger ameliorative effects in the brain seem to be related to the structural similarities between the compound itself and an endogenously produced molecule known as adenosine (Figure 1). Adenosine is a purine nucleoside composed of a molecule of adenine at- tached to a ribose sugar molecule (ribofuranose) moiety via a β-N 9 -glycosidic bond. ...

Citations

... Istradefylline has not been tested in humans with AD/dementia; however, this may represent a worthwhile exploratory investigation given this compound is clinically available in some countries. Interestingly, A 2A R agonism may be useful very early in the disease process, where its anti-inflammatory effects may dampen disease progression [241]. A 2A R induction of BDNF signalling could also contribute to greater neuronal survival and maintenance of synaptic plasticity; however, these considerations remain largely unexplored. ...
... K, Masters CL (1991) Amyloid precursor protein (APP) and beta A4 amyloid in the etiology of Alzheimer's disease: precursor-product relationships in the derangement of neuronal function. Brain Pathol 1(4):[241][242][243][244][245][246][247][248][249][250][251]. https:// doi. ...
Article
Full-text available
Alzheimer’s disease (AD) is the most common dementia in the elderly and its increasing prevalence presents treatment challenges. Despite a better understanding of the disease, the current mainstay of treatment cannot modify pathogenesis or effectively address the associated cognitive and memory deficits. Emerging evidence suggests adenosine G protein-coupled receptors (GPCRs) are promising therapeutic targets for Alzheimer’s disease. The adenosine A 1 and A 2A receptors are expressed in the human brain and have a proposed involvement in the pathogenesis of dementia. Targeting these receptors preclinically can mitigate pathogenic β-amyloid and tau neurotoxicity whilst improving cognition and memory. In this review, we provide an accessible summary of the literature on Alzheimer’s disease and the therapeutic potential of A 1 and A 2A receptors. Although there are no available medicines targeting these receptors approved for treating dementia, we provide insights into some novel strategies, including allosterism and the targeting of oligomers, which may increase drug discovery success and enhance the therapeutic response.
... Accumulating evidence reveals that ATP and adenosine in the CNS play important roles in the pathogenesis of AD [5,6,7,8,9]. There is now a widespread consensus that the pathogenesis of AD is accompanied by the enhancement of adenosine receptor-mediated excitatory damage leading to impairing learning and memory [5,10]. ...
Article
Full-text available
Background Alzheimer's disease (AD) is a chronic, progressive neurodegenerative disease. Recent studies have reported the close association between cognitive function in AD and purinergic receptors in the central nervous system. In the current study, we investigated the effect of CD73 inhibitor α, β-methylene ADP (APCP) on cognitive impairment of AD in mice, and to explore the potential underlying mechanisms. Results We found that acute administration of Aβ1–42 (i.c.v.) resulted in a significant increase in adenosine release by using microdialysis study. Chronic administration of APCP (10, 30 mg/kg) for 20 d obviously mitigated the spatial working memory impairment of Aβ1–42-treated mice in both Morris water maze (MWM) test and Y-maze test. In addition, the extracellular adenosine production in the hippocampus was inhibited by APCP in Aβ-treated mice. Further analyses indicated expression of acetyltransferase (ChAT) in hippocampus of mice of was significantly reduced, while acetylcholinesterase (AChE) expression increased, which compared to model group. We observed that APCP did not significantly alter the NLRP3 inflammasome activity in hippocampus, indicating that anti-central inflammation seems not to be involved in APCP effect. Conclusions In conclusion, we report for the first time that inhibition of CD73 by APCP was able to protect against memory loss induced by Aβ1–42 in mice, which may be due to the decrease of CD73-driven adenosine production in hippocampus. Enhancement of central cholinergic function of the central nervous system may also be involved in the effects of APCP. How to cite: Song W, Tang Y, Wei L, et al. Protective effect of CD73 inhibitor α, β-methylene ADP against amyloid-β-Induced cognitive impairment by inhibiting adenosine production in hippocampus. Electron J Biotechnol 2020;48. https://doi.org/10.1016/j.ejbt.2020.09.002
... 160 In contrast, A 2A R activation has shown antiinflammatory effects at the early onset of AD, also preventing Ab neurotoxicity. 161 Because neuronal and synaptic losses are the main features of AD pathogenesis, stem cell therapy has been evaluated as a new strategy to induce neuroregeneration and increase neuronal survival. 162 For instance, exogenous transplant of embryonic NSCs into a transgenic mouse model of AD has rescued memory deficits but showed no signs of Ab clearance. ...
... Furthermore, these mice culture neurons showed the reduced production of Aβ 1-40 and Aβ 1-42 peptides [52]. A 2A Rs antagonists and/or caffeine prophylactic and long-term neuroprotective process are suggested to be based on inhibition of reactive oxygen species activity, tau pathology, and Aβ production by neuronal cells [53]. ...
Chapter
Full-text available
Adenosine is a neuromodulator that regulates the body's response to dopamine and another neurotransmitter in the brain that is responsible for motoric, emotion, learning, and memory function. Adenosine is a G-protein-coupled receptor and has four subtypes, which are A 1, A 2A , A 2B , and A 3. Adenosine A 2A is located in the striatum of the brain. Antagonist interferes with GABA releasing, modulates acetyl-choline and releases dopamine, and also facilitates dopamine receptor's signaling. Therefore, it can reduce motoric symptoms in Parkinson's disease. Adenosine A 2A antagonist is also believed to have neuroprotective effects. Several compounds have been reported and have undergone clinical test as selective adenosine A 2A antagonists , including istradefylline, preladenant, tozadenant, vipadenant, ST-1535, and SYN-115. Nonselective adenosine A 2A antagonists from natural compounds are caffeine and theophylline.
... Hence, there is a need for further improvement in the development of AD specific drugs. Data is also available on late clinical development, methods, biomarkers and regulatory issues at the multi functional point of view [74][75][76][77][78][79][80][81] with the comparison to other neuro-degenerative disorders such as PD for the purpose of neuro-protective effects [82][83][84]. It should be noted that predominant drug targets are in the cholinergic system and the amyloid cascade although a large range of small molecules and biological products have been investigated in clinical trials. ...
Article
Full-text available
Alzheimer's disease (AD) represents an enormous global health burden in terms of human suffering and economic cost. AD management requires a shift from the prevailing paradigm targeting pathogenesis to design and develop effective drugs with adequate success in clinical trials. Therefore, it is of interest to report a review on amyloid beta (Aβ) effects and other multi-targets including cholinesterase, NFTs, tau protein and TNF associated with brain cell death to be neuro-protective from AD. It should be noted that these molecules have been generated either by target-based or phenotypic methods. Hence, the use of recent advancements in nanomedicine and other natural compounds screening tools as a feasible alternative for circumventing specific liabilities is realized. We review recent developments in the design and identification of neuro-degenerative compounds against AD generated using current advancements in computational multi-target modeling algorithms reflected by theragnosis (combination of diagnostic tests and therapy) concern.
Article
Full-text available
The physiological effects of endogenous adenosine on various organ systems are very complex and numerous which are elicited upon activation of any of the four G-protein-coupled receptors (GPCRs) denoted as A1, A2A, A2B and A3 adenosine receptors (ARs). Several fused heterocyclic and non-xanthine derivatives are reported as possible target for these receptors due to physiological problems and lack of selectivity of xanthine derivatives. In the present review, we have discussed the development of various new chemical entities as target for these receptors. In addition, compounds acting on adenosine receptors can be utilized in treating diseases like inflammation, neuroinflammation, autoimmune and related diseases
Article
Background: The consumption of caffeine has well known effects on the behavior and sleep of healthy adults. Behavioral symptoms and sleeping difficulties are common in patients with dementia which may be affected by caffeine consumption. This systematic review examines the association between caffeine intake and neuropsychiatric symptoms in patients with dementia. Methods: In January 2019 an extensive search was conducted in Medline (PubMed), Embase, Emcare, Cochrane, PsychInfo, Web of Science and gray literature. Studies were included when they: i) investigated patients diagnosed with dementia, ii) reported neuropsychiatric symptoms, iii) used caffeine or coffee consumption as an intervention, and iv) reported associations between caffeine or coffee consumption and neuropsychiatric symptoms. Studies were excluded when they also included participants without a diagnosis of dementia, or presented a review or expert opinion. Two reviewers independently rated the studies and reached consensus on the appraisal. Results: Of the seven studies eligible for this review, four reported on sleeping difficulties and five on behavioral symptoms. There was no consistent effect of caffeine administration on neuropsychiatric symptoms: e.g., both high caffeine consumption and eliminating caffeine were associated with less apathy, the total Neuropsychiatric Inventory (Nursing Home) decreased after both coffee therapy and after eliminating caffeine, and both caffeine consumption and eliminating caffeine improved sleep. Conclusion: These findings suggest that caffeine can either induce or reduce neuropsychiatric symptoms in individual patients with dementia. Therefore, in these patients, caffeine consumption requires a prudent individualized approach and further research on the effects of caffeine on individual neuropsychiatric symptoms is required.
Article
As the European population gets older, the incidence of neurological disorders increases with significant impact on social costs. Despite differences in disease etiology, several brain disorders in the elderly (e.g., Alzheimer's disease, vascular dementia, normal pressure hydrocephalus) share dementia as a common clinical feature. The current treatment for the majority of these diseases is merely symptomatic and does not modify the course of the illness. Symptoms of normal pressure hydrocephalus are the only ones that can be modified if they are recognized in time and treated appropriately. Therefore, an important clinical strategy may be disclosed by pathogenic pathways that can be modified and to find drugs that can slow down or even arrest disease progression. Possibly a way to answer this question could be by re-examining all the molecules which have so far succeeded in improving many aspects of cognitive deterioration in some neurodegenerative conditions, that were not considered because of controversial opinions. The main purpose of this summary is to further substantiate the hypothesis that the pathway of adenosine type A2A receptor could be used as a potential target to develop new/old therapeutic strategies.