Adenosine A2A Receptor Antagonists in Neurodegenerative Diseases: Huge Potential and Huge Challenges

Franco, Rafael; Navarro, Gemma

doi:10.3389/fpsyt.2018.00068

Cited by 54 publications

(35 citation statements)

References 60 publications

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“…On the one hand, it is very intriguing why so many compounds effective in AD mouse models but not in the therapy of human patients (Franco & Cedazo‐Minguez, ). On the other hand, clinical trials for neuroprotection or for assessing efficacy in neurodegenerative diseases often lack suitable biomarkers to measure potential effects (Franco & Navarro, ). The number of clinical trials registered in http://ClinicalTrials.gov retrieved combining words: resveratrol and Alzheimer's disease is, as of December 2017, seven.…”

Section: Safety and Efficacy Based On Clinical Trial Resultsmentioning

confidence: 99%

Resveratrol and Related Stilbenoids, Nutraceutical/Dietary Complements with Health‐Promoting Actions: Industrial Production, Safety, and the Search for Mode of Action

Navarro

Pinilla

Ortiz

et al. 2018

Comp Rev Food Sci Food Safe

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This paper reviews the potential of stilbenoids as nutraceuticals. Stilbenoid compounds in wine are considered key factors in health-promoting benefits. Resveratrol and resveratrol-related compounds are found in a large diversity of vegetal products. The stilbene composition varies from wine to wine and from one season to another. Therefore, the article also reviews how food science and technology and wine industry may help in providing wines and/or food supplements with efficacious concentrations of stilbenes. The review also presents results from clinical trials and those derived from genomic/transcriptomic studies. The most studied stilbenoid, resveratrol, is a very safe compound. On the other hand, the potential benefits of stilbene intake are multiple and are apparently due to downregulation more than upregulation of gene expression. The field may take advantage from identifying the mechanism of action(s) and from providing useful data to show evidence for specific health benefits in a given tissue or for combating a given disease.

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Section: Safety and Efficacy Based On Clinical Trial Resultsmentioning

confidence: 99%

Resveratrol and Related Stilbenoids, Nutraceutical/Dietary Complements with Health‐Promoting Actions: Industrial Production, Safety, and the Search for Mode of Action

Navarro

Pinilla

Ortiz

et al. 2018

Comp Rev Food Sci Food Safe

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“…Similarly, it is assumed that the neuroprotective potential attributed to this class of compounds is mediated by A 2A R in neurons (Ferreira et al, ; Kaster et al, ; Meng et al, ). Preventing neuronal death is a difficult issue to be addressed in humans (Franco & Navarro, ) and in fact, istradefylline was approved to address symptoms but not to modify the course of PD (Kondo et al, ; Mizuno & Kondo, ; Navarro et al, ; Saki et al, ). Glial, and particularly, microglial GPCRs may be instrumental to afford neuroprotection in neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

“…Recent results suggest an important potential of microglial adenosine receptors in neuroprotection because expression of CD73, the ectoenzyme that produces extracellular adenosine, attenuates inflammation by promoting M2 polarization (Xu et al, ). Among the four subtypes of adenosine receptors, the A 2A is the most promising in neuroprotection (see (Franco & Navarro, ) for review). Moreover, A 2A receptor (A 2A R) antagonists are very safe (Hauser et al, ; Kondo et al, ) and one of them, istradefylline, has been approved in Japan as adjunctive treatment in Parkinson's disease (Jenner, ; Jenner et al, ; Kondo et al, ; Mizuno & Kondo, ; Saki, Yamada, Koshimura, Sasaki, & Kanda, ).…”

Section: Introductionmentioning

confidence: 99%

Potentiation of cannabinoid signaling in microglia by adenosine A_2A receptor antagonists

Franco

Reyes‐Resina

Aguinaga

et al. 2019

Glia

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Neuroprotective M2‐skewed microglia appear as promising to alter the course of neurodegenerative diseases and G protein‐coupled receptors (GPCRs) are potential targets to achieve such microglial polarization. A common feature of adenosine A2A (A2AR) and cannabinoid CB2 (CB2R) GPCRs in microglia is that their expression is upregulated in Alzheimer's disease (AD). On the one hand, CB2R seems a target for neuroprotection, delaying neurodegenerative processes like those associated to AD or Parkinson's diseases. A2AR antagonists reduce amyloid burden and improve cognitive performance and memory in AD animal models. We here show a close interrelationship between these two receptors in microglia; they are able to physically interact and affect the signaling of each other, likely due to conformational changes within the A2A‐CB2 receptor heteromer (A2A‐CB2Het). Particularly relevant is the upregulation of A2A‐CB2Het expression in samples from the APPSw,Ind AD transgenic mice model. The most relevant finding, confirmed in both heterologous cells and in primary cultures of microglia, was that blockade of A2A receptors results in increased CB2R‐mediated signaling. This heteromer‐specific feature suggests that A2AR antagonists would potentiate, via microglia, the neuroprotective action of endocannabinoids with implications for AD therapy.

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“…In the case of Parkinson's disease, microglia has been suggested to be the most likely cell type to be targeted by A 2A Rs antagonists [40]. In vitro and in vivo studies showed that local neuroinflammation make glial cells (especially microglial cells) particularly sensitive to A 2A R modulation [41].…”

Section: Adenosine a 2a Receptor Antagonist As A Neuroprotectivementioning

confidence: 99%

The Role and Development of the Antagonist of Adenosine A_2Ain Parkinson’s Disease

Aryati¹,

Salamah²,

Syahdi³

et al. 2019

Neuroprotection

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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 acetylcholine 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.

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Adenosine A2A Receptor Antagonists in Neurodegenerative Diseases: Huge Potential and Huge Challenges

Cited by 54 publications

References 60 publications

Resveratrol and Related Stilbenoids, Nutraceutical/Dietary Complements with Health‐Promoting Actions: Industrial Production, Safety, and the Search for Mode of Action

Resveratrol and Related Stilbenoids, Nutraceutical/Dietary Complements with Health‐Promoting Actions: Industrial Production, Safety, and the Search for Mode of Action

Potentiation of cannabinoid signaling in microglia by adenosine A_2A receptor antagonists

The Role and Development of the Antagonist of Adenosine A_2Ain Parkinson’s Disease

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Adenosine A2A Receptor Antagonists in Neurodegenerative Diseases: Huge Potential and Huge Challenges

Cited by 54 publications

References 60 publications

Resveratrol and Related Stilbenoids, Nutraceutical/Dietary Complements with Health‐Promoting Actions: Industrial Production, Safety, and the Search for Mode of Action

Resveratrol and Related Stilbenoids, Nutraceutical/Dietary Complements with Health‐Promoting Actions: Industrial Production, Safety, and the Search for Mode of Action

Potentiation of cannabinoid signaling in microglia by adenosine A2A receptor antagonists

The Role and Development of the Antagonist of Adenosine A2Ain Parkinson’s Disease

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Product

Resources

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Potentiation of cannabinoid signaling in microglia by adenosine A_2A receptor antagonists

The Role and Development of the Antagonist of Adenosine A_2Ain Parkinson’s Disease