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Background: Methotrexate (MTX) is a common chemotherapeutic drug that inhibits DNA synthesis and induces apoptosis. Treatment with MTX increased CD73 expression, which leads to higher levels of extracellular adenosine. Adenosine levels are also high in the tumor microenvironment through Cancer cells metabolism. That promotes the survival of cancer cells and contributes to tumor immune evasion through the Adenosine 2a Receptor. A2A receptor antagonists are an emerging class of agents that treat cancers by enhancing immunotherapy, both as monotherapy and in combination with other therapeutic agents. Caffeine is an adenosine receptor antagonist. Herein, we demonstrate the ability of a novel well prepared and characterized nano formula CAF-FA-CS-NPs (D4) for A2aR blockade when combination with MTX to improve its antitumor efficacy by enhancing the immune system and eliminating immune suppression., Methods: CAF-FA-CS-NPs (D4) were prepared and characterized for particle size, loading efficiency, and release profile. Molecular docking was used to validate the binding affinity of caffeine and folic acid to A2A receptor. The effects of the nano formula were evaluated on human liver cancer cells (HepG2), breast cancer cells (MCF-7), and MDA-MB-231, as well as normal human cells (WI-38). Different combination ratios of MTX and D4 were studied to identify the optimal combination for further genetic studies., Results: Molecular docking results validated that caffeine and folic acid have binding affinity to A2A receptor. The CS-NPs were successfully prepared using ionic gelation method, with caffeine and folic acid being loaded and conjugated to the nanoparticles through electrostatic interactions. The CAF loading capacity in D4 was 77.9 ± 4.37% with an encapsulation efficiency of 98.5 ± 0.37. The particle size was optimized through ratio variations. The resulting nanoparticles were fully characterized. The results showed that (D4) had antioxidant activity and cytotoxicity against different cancer cells. The combination of D4 with MTX (IC50 D4 + 0.5 IC50 MTX) resulted in the downregulation of Bcl-2, FOXP3, CD39, and CD73 gene expression levels and upregulation of Bax and A2AR gene expression levels in HepG2 cells., Conclusions: This study suggests that CAF-FA-CS-NPs (D4) in combination with MTX may be a promising candidate for cancer immunotherapy, by inhibiting A2aR signaling and leading to improved immune activation and anti-tumor activity of MTX., (© 2023. The Author(s).)

Controversial studies indicate the adenosine compound (a neuromodulator with neuroprotective activity) intervention on cognitive performance. On the other hand, Japanese sake yeast has been enriched with oral adenosine analogs as a novel natural agent. As the first report, we aimed to evaluate the effects of Japanese sake yeast supplement in a mouse model of chronic restraint stress-induced cognitive dysfunction. Mice were subjected to a one-week stress protocol and concomitantly treated orally with sake yeast at the dose level of 100, 200 and 300 mg/kg once daily for a week. The spatial and conditioned fear memory functions were evaluated with the Morris Water Maze (MWM) and the Passive Avoidance Learning (PAL) test, respectively. In all dosing regimens, improvements in spatial cognition were observed significantly in the MWM. 200 and 300 mg/kg of sake yeast significantly improved short- and long-term fear memory functions in the PAL test. Memory-enhancing effect of sake yeast was potentiated by the injection of ZM241385 (15 mg/kg), a selective adenosine A 2A receptor (A 2A R) antagonist, but completely disappeared by the injection of 8-cyclopentyltheophylline (CPT-8, 10 mg/kg), a selective adenosine A 1 receptor (A 1 R) antagonist. The findings of the present study demonstrate the efficacy of sake yeast in acting as a cognitive performance-enhancing agent. Eventually, sake yeast and its ingredient S-adenosyl methionine (SAM) may be useful in improving memory in patients suffering from many dementia forms including Alzheimer's disease (AD)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Adenosine 2A (A 2A ) receptors co-localize with dopamine D 2  receptors in striatopallidal medium spiny neurons of the indirect pathway. A 2A  receptor activation in the striatum or pallidum decreases D 2  signaling. In contrast, A 2A  receptor antagonism may help potentiate it. Furthermore, previous PET studies have shown increased A 2A  receptor availability in striatum of late-stage PD patients with dyskinesia. However, human in vivo evidence for striatal A 2A  receptor availability in early-stage PD is limited. This study aimed to investigate possible differences in A 2A  receptor availability in the striatum and pallidum of early- and moderate-stage PD patients without dyskinesias., Methods: Brain MRI and PET with [ 11 C]TMSX radioligand, targeting A 2A  receptors, was performed in 9 patients with early- and 9 with moderate-stage PD without dyskinesia and in 6 healthy controls. Distribution volume ratios (DVR) were calculated to assess specific [ 11 C]TMSX binding in caudate, putamen and pallidum., Results: A 2A  receptor availability (DVR) was decreased in the bilateral caudate of early-stage PD patients when compared with healthy controls (P = 0.02). Conversely, DVR was increased bilaterally in the pallidum of moderate-stage PD patients compared to healthy controls (P = 0.03). Increased mean striatal DVR correlated with higher motor symptom severity ([Formula: see text] = 0.47, P = 0.02)., Conclusion: Our results imply regional and disease stage-dependent changes in A 2A  receptor signaling in PD pathophysiology and in response to dopaminergic medication., (© 2022. The Author(s).)

In Parkinson's disease, the focus has long been on motor symptoms and therapy with dopaminergic substances. In recent years, the importance of non-motor symptoms has been increasingly recognized, as they occur early in the course of the disease and restrict considerably the quality of life. However, this also made the need for treatment of non-dopaminergic deficits obvious. Adenosine A 2A receptor antagonists were identified as an additional therapy, since the adenosine A 2A receptors are non-dopaminergic and selectively localized in the basal ganglia. This means that the striato-thalamo-cortical loops can be modulated. An adenosine A 2A receptor antagonist was already approved in Japan in 2013 and in the USA in 2019 as an add-on to L-DOPA. Approval for this drug in Europe is expected in the near future. In this overview, we present the theoretical basis and current data on its efficacy and therapeutic use., Competing Interests: W. Jost ist oder war als Berater und Referent für folgende Firmen tätig: Abbvie, Bial, Desitin, Kyowa Kirin, Stada, UCB, Zambon L. Tönges erhielt Honorare als wissenschaftlicher Berater, für Vortrags- und Schulungstätigkeiten oder Autorenschaften von Abbvie, Bayer, Boehringer, Bial, Desitin, GE, Kyowa Kirin, Stadapharm, UCB Pharma und Zambon., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Purpose: To evaluate AZD4635, an adenosine A2A receptor antagonist, as monotherapy or in combination with durvalumab in patients with advanced solid tumors., Patients and Methods: In phase Ia (dose escalation), patients had relapsed/refractory solid tumors; in phase Ib (dose expansion), patients had checkpoint inhibitor-naïve metastatic castration-resistant prostate cancer (mCRPC) or colorectal carcinoma, non-small cell lung cancer with prior anti-PD-1/PD-L1 exposure, or other solid tumors (checkpoint-naïve or prior anti-PD-1/PD-L1 exposure). Patients received AZD4635 monotherapy (75-200 mg once daily or 125 mg twice daily) or in combination with durvalumab (AZD4635 75 or 100 mg once daily). The primary objective was safety; secondary objectives included antitumor activity and pharmacokinetics; exploratory objectives included evaluation of an adenosine gene signature in patients with mCRPC., Results: As of September 8, 2020, 250 patients were treated (AZD4635, n = 161; AZD4635+durvalumab, n = 89). In phase Ia, DLTs were observed with monotherapy (125 mg twice daily; n = 2) and with combination treatment (75 mg; n = 1) in patients receiving nanosuspension. The most common treatment-related adverse events included nausea, fatigue, vomiting, decreased appetite, dizziness, and diarrhea. The RP2D of the AZD4635 capsule formulation was 75 mg once daily, as monotherapy or in combination with durvalumab. The pharmacokinetic profile was dose-proportional, and exposure was adequate to cover target with 100 mg nanosuspension or 75 mg capsule once daily. In patients with mCRPC receiving monotherapy or combination treatment, tumor responses (2/39 and 6/37, respectively) and prostate-specific antigen responses (3/60 and 10/45, respectively) were observed. High versus low blood-based adenosine signature was associated with median progression-free survival of 21 weeks versus 8.7 weeks., Conclusions: AZD4635 monotherapy or combination therapy was well tolerated. Objective responses support additional phase II combination studies in patients with mCRPC., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background: Multiple sclerosis (MS) is one of the most common autoimmune disorders characterized by the infiltration of immune cells into the brain and demyelination. The unwanted immunosuppressive side effect of therapeutically successful natalizumab led us to focus on the choroid plexus (CP), a key site for the first wave of immune cell infiltration in experimental autoimmune encephalomyelitis (EAE), for the control of immune cells trafficking. Adenosine A 2A receptor (A 2A R) is emerging as a potential pharmacological target to control EAE pathogenesis. However, the cellular basis for the A 2A R-mediated protection remains undetermined., Methods: In the EAE model, we assessed A 2A R expression and leukocyte trafficking determinants in the CP by immunohistochemistry and qPCR analyses. We determined the effect of the A 2A R antagonist KW6002 treatment at days 8-12 or 8-14 post-immunization on T cell infiltration across the CP and EAE pathology. We determined the critical role of the CP-A 2A R on T cell infiltration and EAE pathology by focal knock-down of CP-A 2A R via intracerebroventricular injection of CRE-TAT recombinase into the A 2A R flox/flox mice. In the cultured CP epithelium, we also evaluated the effect of overexpression of A 2A Rs or the A 2A R agonist CGS21680 treatment on the CP permeability and lymphocytes migration., Results: We found the specific upregulation of A 2A R in the CP associated with enhanced CP gateway activity peaked at day 12 post-immunization in EAE mice. Furthermore, the KW6002 treatment at days 8-12 or 8-14 post-immunization reduced T cell trafficking across the CP and attenuated EAE pathology. Importantly, focal CP-A 2A R knock-down attenuated the pathogenic infiltration of Th17 + cells across the CP via inhibiting the CCR6-CCL20 axis through NFκB/STAT3 pathway and protected against EAE pathology. Lastly, activation of A 2A R in the cultured epithelium by A 2A R overexpression or CGS21680 treatment increased the permeability of the CP epithelium and facilitated lymphocytes migration., Conclusion: These findings define the CP niche as one of the primary sites of A 2A R action, whereby A 2A R antagonists confer protection against EAE pathology. Thus, pharmacological targeting of the CP-A 2A R represents a novel therapeutic strategy for MS by controlling immune cell trafficking across CP., (© 2022. The Author(s).)

Ischemic preconditioning (IP) of the liver by a brief interruption of the blood flow protects the damage induced by a subsequent ischemia/reperfusion (I/R) preventing parenchymal and nonparenchymal liver cell damage. The discovery of IP has shown the existence of intrinsic systems of cytoprotection whose activation can stave off the progression of irreversible tissue damage. Deciphering the molecular mediators that underlie the cytoprotective effects of preconditioning can pave the way to important therapeutic possibilities. Pharmacological activation of critical mediators of IP would be expected to emulate or even to intensify its salubrious effects. In vitro and in vivo studies have demonstrated the role of the adenosine A2a receptor (A2aR) as a trigger of liver IP. This review will provide insight into the phenotypic changes that underline the resistance to death of liver cells preconditioned by pharmacological activation of A2aR and their implications to develop innovative strategies against liver IR damage.

Curcumin, obtained from Curcuma longa, has been in use for manifold human disorders. The present study explores the effect of curcumin against pentylenetetrazol (PTZ) seizure threshold in mice. The possible involvement of adenosine receptor(s) mechanism was also investigated. Minimal dose of PTZ (i.v., mg/kg) needed to induce different phases of convulsions were recorded as an index of seizure threshold. Curcumin (20-120 mg/kg, p.o.) produced an increase in seizure threshold for convulsions induced by PTZ i.v. infusion. The anticonvulsant effect of curcumin (80 mg/kg) was prevented by 8-phenyltheophylline (0.5 mg/kg, i.p., non-selective adenosine receptor antagonist) and 8-cyclopentyl-1,3-dipropylxanthine (5 mg/kg, i.p., adenosine A1 receptor antagonist) but not by 8-(3-cholorostryl)caffeine (4 mg/kg, i.p., adenosine A2A receptor antagonist). Further, 5'-N-ethylcarboxamidoadenosine (0.005 mg/kg, i.p., non-selective A1 /A2 receptor agonist), or N(6) -cyclohexyladenosine (0.2 mg/kg, i.p., adenosine A1 receptor agonist), was able to potentiate the anticonvulsant action of curcumin. In contrast, 5'-(N-cyclopropyl) carboxamidoadenosine (0.1 mg/kg, i.p., adenosine A2A receptor agonist) failed to potentiate the effect of curcumin. This study demonstrated the anticonvulsant effect of curcumin against PTZ i.v. seizure threshold via a direct or indirect activation of adenosine A1 but not A2A receptors in mice. Thus, curcumin may prove to be an effective adjunct in treatment of convulsions., (Copyright © 2013 John Wiley & Sons, Ltd.)

Hypoxia-driven increase of extracellular adenosine in local tissue microenvironments of inflamed and cancerous tissues plays a critical role in the regulation of tissue destruction by activated immune cells. Accumulated data suggest that injection or consumption of A2A adenosine receptor (A2AR) antagonists may represent a drug treatment that diminishes adenosine-mediated immunosuppression. Since this, in turn, enhances the immune response, inhibition of adenosine-A2AR signaling may be a promising approach to enhance anti-tumor or anti-pathogen immune response. Patients with disorders characterized by excessive inflammation may be at risk to A2AR antagonists (e.g. caffeine) because of the effect to increase inflammatory damage secondary to enhanced immunity. On the other hand, enhancement of hypoxia-adenosinergic immunomodulatory pathways may be beneficial to prevent inflammatory tissue destruction.

In this study, we examined the combination effects of L-DOPA and adenosine receptor antagonists on rotational behaviors in a hemi-Parkinsonian mouse model induced by unilateral 6-hydroxydopamine (6-OHDA) injection. The adenosine A(2A) antagonist SCH-58261, but not the A(1)-receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine or A(2B)-receptor antagonist alloxazine, synergistically potentiated the L-DOPA-induced rotational behaviors in the 6-OHDA-lesioned mice. In addtion, the 6-OHDA-induced lesions of the dopaminergic system did not affect the in vivo binding of an adenosine A(2A)-receptor tracer [(11)C]SCH-442416 in the striatatum. These findings suggest that adenosine A(2A) antagonists are extremely useful for pharmacotherapy of L-DOPA in Parkinson's disease patients.

Surgery of the thoracic aorta continues to have a significant risk of neurologic complication. Several strategies to minimize this risk are emerging. Pharmacologic protection from these complications continues to be researched, but at this point few medications are being used clinically. This article reviews the pathophysiology of ischemic spinal cord injury and summarizes the investigational pharmacology that may prevent these serious complications.