Promoting glymphatic flow: A non-invasive strategy using 40 Hz light flickering.

The glymphatic system is critical for brain homeostasis by eliminating metabolic waste, whose disturbance contributes to the accumulation of pathogenic proteins in neurodegenerative diseases. Promoting glymphatic clearance is a potential and attractive strategy for several brain disorders, including neurodegenerative diseases. Previous studies have uncovered that 40 Hz flickering augmented glymphatic flow and facilitated sleep (Zhou et al. in Cell Res 34:214-231, 2024) since sleep drives waste clearance via glymphatic flow (Xie et al. in Science 342:373-377, 2013). However, it remains unclear whether 40 Hz light flickering directly increased glymphatic flow or indirectly by promoting sleep. A recent article published in Cell Discovery by Chen et al. (Sun et al. in Cell Discov 10:81, 2024) revealed that 40 Hz light flickering facilitated glymphatic flow, by promoting the polarization of astrocytic aquaporin-4 (AQP4) and vasomotion through upregulated adenosine-A2A receptor (A2AR) signaling, independent of sleep. These findings suggest that 40 Hz light flickering may be used as a non-invasive approach to control the function of the glymphatic-lymphatic system, to help remove metabolic waste in the brain, thereby presenting a potential strategy for neurodegenerative disease treatment.

BBPT attenuated 6-OHDA-induced toxicity by modulating oxidative stress, apoptotic, and inflammatory proteins in primary neurons and rat models of Parkinson's disease.

Parkinson's disease (PD) results from the degeneration of dopaminergic neurons in substantia nigra pars compacta (SNpc). Adenosine A2AR acting through the striato-pallidal pathway has emerged as a non-dopaminergic target in the therapy of PD. In the present work, the anti-parkinsonian potential of (4E)-4-(4-bromobenzylideneamino)-3-phenyl-2,3-dihydro-2-thioxo- thiazole-5-carbonitrile (BBPT) was explored. BBPT exhibited significant antioxidant activity in situ. In the MTT assay, the BBPT treatment showed insignificant toxicity to the primary midbrain neuronal (PMDN) cells. 6-OHDA induced PMDN cells, 3 h post-treated with BBPT showed 80-85 % survival of the cells and restoration of dopamine and TNF-α levels. The acute and sub-acute toxicity test for BBPT was performed with Sprague Dawley (SD) rats. In toxicity assay, any significant physical, hematological, or biochemical changes in the rats were not observed. To evaluate the effect of BBPT in vivo, a 6-OHDA-induced unilaterally lesioned SD rat model of PD was established. We observed that the BBPT treatment improved the behavioral symptoms in 6-OHDA-induced unilaterally lesioned rats. The proteins of 6-OHDA-induced BBPT-treated rats were isolated from the brain tissue to assess the antioxidant effect (GSH, catalase, SOD, lipid-peroxidation, nitrite), dopamine levels, and the restoration in the apoptosis and inflammation. Our results demonstrated that BBPT increased the anti-oxidant enzyme levels, restored the caspase-3/Bcl-2 levels to arrest apoptosis, and attenuated the TNF-α/IL-6 levels, thus restoring the neuronal damage in unilaterally lesioned 6-OHDA-induced SD rats. Precisely, the findings suggested that BBPT possessed significant anti-parkinsonian activity and has the potential to prevent dopaminergic neurodegeneration.

Effect of simultaneous application of adenosine A1 receptor agonist and A2A receptor antagonist on memory, inflammatory factors, and PSD-95 in lipopolysaccharide-induced memory impairment.

The potential role of adenosine, a natural neuroprotective agent, and its receptors in the pathogenesis of Alzheimer's disease has been proposed. The present study aims to examine the effect of administering both an A1 receptor agonist and an A2A adenosine receptor antagonist simultaneously on memory, inflammatory factors, and PSD-95 in an LPS-induced Alzheimer's disease model in rats. Fifty-six male Wistar rats were randomly divided into seven groups: Saline, LPS, Saline + Vehicle, LPS + Vehicle, LPS + SCH58261 (A2A receptor antagonist), LPS + CPA (A1 receptor agonist), LPS + SCH58261+CPA. LPS (3 mg/kg/ip) was used to cause memory impairment. Treatment was performed by intraventricular injection of CPA at a dose of 700 µg and SCH-58261 at 40 µg for ten days. Passive avoidance and Y-maze tests were performed to examine animals' memories. IL-10, TNF-α, and PSD-95 levels were measured in the brain using ELISA and western blot, respectively. Compared to the groups receiving each medication separately, the simultaneous administration of CPA and SCH58261 improved memory (P<0.05). Additionally, compared to the single medication groups, there was a significant increase in IL-10, PSD-95, and a significant decrease in TNF-α in the brain tissue (P<0.05). These findings suggest that the activation of A1 receptors along with A2A receptor inhibition could be a potential therapeutic strategy for Alzheimer's disease. These findings suggest that A1 receptor activation combined with A2A receptor inhibition may be a promising therapeutic approach for Alzheimer's disease.

Sedum kamtschaticum Exerts Hypnotic Effects via the Adenosine A2A Receptor in Mice.

Insomnia is a common sleep disorder with significant societal and economic impacts. Current pharmacotherapies for insomnia are often accompanied by side effects, necessitating the development of new therapeutic drugs. In this study, the hypnotic effects and mechanisms of Sedum kamtschaticum 30% ethanol extract (ESK) and one of its active compounds, myricitrin, were investigated using pentobarbital-induced sleep experiments, immunohistochemistry (IHC), receptor binding assays, and enzyme-linked immunosorbent assay (ELISA). The pentobarbital-induced sleep experiments revealed that ESK and myricitrin reduced sleep latency and prolonged total sleep time in a dose-dependent manner. Based on c-Fos immunostaining, ESK, and myricitrin enhanced the GABAergic neural activity in sleep-promoting ventrolateral preoptic nucleus (VLPO) GABAergic. By measuring the level of GABA released from VLPO GABAergic neurons, ESK and myricitrin were found to increase GABA release in the hypothalamus. These effects were significantly inhibited by SCH. Moreover, ESK exhibited a concentration-dependent binding affinity for the adenosine A2A receptors (A2AR). In conclusion, ESK and myricitrin have hypnotic effects, and their underlying mechanisms may be related to the activation of A2AR.

Novel Quinazoline Derivatives as Highly Effective A2A Adenosine Receptor Antagonists.

The adenosine A2A receptor (A2AR) has been identified as a therapeutic target for treating neurodegenerative diseases and cancer. In recent years, we have highlighted the 2-aminoquinazoline heterocycle as an promising scaffold for designing new A2AR antagonists, exemplified by 6-bromo-4-(furan-2-yl)quinazolin-2-amine 1 (Ki (hA2AR) = 20 nM). Here, we report the synthesis of new 2-aminoquinazoline derivatives with substitutions at the C6- and C7-positions, and the introduction of aminoalkyl chains containing tertiary amines at the C2-position to enhance antagonist activity and solubility properties. Compound 5m showed a high affinity for hA2AR with a Ki value of 5 nM and demonstrated antagonist activity with an IC50 of 6 µM in a cyclic AMP assay. Introducing aminopentylpiperidine and 4-[(piperidin-1-yl)methyl]aniline substituents maintained the binding affinities (9x, Ki = 21 nM; 10d, Ki = 15 nM) and functional antagonist activities (9x, IC50 = 9 µM; 10d, IC50 = 5 µM) of the synthesized compounds while improving solubility. This study provides insights into the future development of A2AR antagonists for therapeutic applications.

Current Understanding of the Role of Adenosine Receptors in Cancer.

Cancer, a complex array of diseases, involves the unbridled proliferation and dissemination of aberrant cells in the body, forming tumors that can infiltrate neighboring tissues and metastasize to distant sites. With over 200 types, each cancer has unique attributes, risks, and treatment avenues. Therapeutic options encompass surgery, chemotherapy, radiation therapy, hormone therapy, immunotherapy, targeted therapy, or a blend of these methods. Yet, these treatments face challenges like late-stage diagnoses, tumor diversity, severe side effects, drug resistance, targeted drug delivery hurdles, and cost barriers. Despite these hurdles, advancements in cancer research, encompassing biology, genetics, and treatment, have enhanced early detection methods, treatment options, and survival rates. Adenosine receptors (ARs), including A1, A2A, A2B, and A3 subtypes, exhibit diverse roles in cancer progression, sometimes promoting or inhibiting tumor growth depending on the receptor subtype, cancer type, and tumor microenvironment. Research on AR ligands has revealed promising anticancer effects in lab studies and animal models, hinting at their potential as cancer therapeutics. Understanding the intricate signaling pathways and interactions of adenosine receptors in cancer is pivotal for crafting targeted therapies that optimize benefits while mitigating drawbacks. This review delves into each adenosine receptor subtype's distinct roles and signaling pathways in cancer, shedding light on their potential as targets for improving cancer treatment outcomes.

A randomized phase 1 study of safety, tolerability, and pharmacokinetics of MK-1088, a novel dual adenosine receptor antagonist, in healthy adult participants.

This phase 1 first-in-human study evaluated the safety, tolerability, and pharmacokinetics of MK-1088, a novel, small-molecule dual inhibitor of adenosine A2A and A2B receptors. Healthy adult participants were enrolled in two panels (n = 8 each) and randomly assigned to receive MK-1088 (n = 6) or placebo (n = 2) orally in each of five treatment periods. Participants in panel A received single ascending doses of MK-1088 at 1, 10, 50, and 150 mg or placebo in a fasted or fed (50 mg only) state. Participants in panel B received MK-1088 at 3, 25, 100, and 224 mg or placebo in a fasted state. Primary objectives were to evaluate safety, tolerability, and plasma pharmacokinetics following a single dose of MK-1088. The secondary objective was to evaluate the effects of a high-fat meal on pharmacokinetics. All participants (n = 16) completed the study (median age: 33 years [range: 20-43]; all were male). Treatment-related adverse events (AEs) occurred in 1 of 6 (17%), 4 of 6 (67%), 4 of 6 (67%), and 2 of 6 (33%) participants after receiving MK-1088 at 3, 25, 100, and 224 mg, respectively. No serious AEs or deaths due to any cause occurred. MK-1088 was rapidly absorbed after a single dose; half-life was ~ 11 h in the 100-224 mg dose range. The target concentration at 12 h (> 0.3 µM) was exceeded at the 50-mg dose level. MK-1088 plasma pharmacokinetics increased dose proportionately. A high-fat meal did not significantly affect pharmacokinetics at the 50-mg dose. MK-1088 was well tolerated and demonstrated dose-proportional pharmacokinetic properties that were not affected by a high-fat meal.

Exploring novel A2AAR antagonists: Design, synthesis, and evaluation of 2,6,9-trisubstituted purine derivatives as promising antifibrotic agents.

A series of 2,6,9-trisubstituted purine derivatives were designed and synthesized with diverse chemical moieties. Through a comprehensive biological evaluation, we identified 4-(6-(methylamino)-2-(phenylethynyl)-9H-purin-9-yl)phenol (6a) as a promising A2AAR antagonist with potent antifibrotic properties. Compound 6a demonstrated significant efficacy in inhibiting CRE promoter activity and in reducing the expression of fibrogenic marker proteins and downstream effectors of A2AAR activation, surpassing the A2AAR antagonist ZM241385 and initial screening hits, 9-benzyl-N-methyl-2-(phenylethynyl)-9H-purin-6-amine (5a) and 9-((benzyloxy)methyl)-N-methyl-2-(phenylethynyl)-9H-purin-6-amine (5j). Further validation revealed that compound 6a effectively inhibited fibrogenic marker proteins induced by A2AAR overexpression or TGF-ß1 treatment in hepatic stellate cells, alongside reducing PKA and CREB phosphorylation. These findings suggest that compound 6a exerts its antifibrotic action by modulating the cAMP/PKA/CREB pathway through A2AAR inhibition. Overall, our study provides valuable insights for the development of novel therapeutics that target hepatic fibrosis through A2AAR antagonism.

Heukharang (Lactuca sativa L.) extracts enhanced the sleep behavior of mice: potential involvement of adenosine A1 and A2A receptors.

A significant proportion of the world's population suffers from insomnia, a disorder characterized by complications in initiating and maintaining sleep. Many medications used to treat insomnia target the γ-aminobutyric acid (GABA) neurotransmitter system. However, these substances, such as benzodiazepines, induce significant adverse consequences, including dependence and memory impairment, after prolonged use. Thus, current studies are aimed at developing therapeutic hypnotics derived from natural sources that may cause less severe side effects. Heukharang is a variety of lettuce from Korea that was discovered to contain sleep-promoting compounds. Therefore, we investigated the potential effects of sub-chronic administration of Heukharang extract (FSD-LS) on sleep behavior (pentobarbital-induced sleeping test), brain wave activity and sleep architecture (electroencephalography), and physiological behavior (open-field test and rota-rod) in mice, along with radioligand binding assays (GABAA, adenosine A1 and A2A receptors). We found that FSD-LS prolonged the total sleep duration and reduced the onset time of sleep, and enhanced delta wave power and non-rapid eye movement (NREM) sleep duration, all indicating persistent sleep-enhancing effects. FSD-LS lacked adverse effects on the spontaneous locomotor activity and motor coordination of mice, unlike diazepam. Pharmacological blocking using caffeine and bicuculline supported the possible involvement of adenosine receptors in the sleep-promoting effects of FSD-LS, with partial contribution from GABA receptor activity. Overall, our study recommends FSD-LS as a potential source for the development of sleep-aiding therapeutics.

Adenosine A2A receptor as a potential regulator of Mycobacterium leprae survival mechanisms: new insights into leprosy neural damage.

Background: Leprosy is a chronic infectious disease caused by Mycobacterium leprae, which can lead to a disabling neurodegenerative condition. M. leprae preferentially infects skin macrophages and Schwann cells-glial cells of the peripheral nervous system. The infection modifies the host cell lipid metabolism, subverting it in favor of the formation of cholesterol-rich lipid droplets (LD) that are essential for bacterial survival. Although researchers have made progress in understanding leprosy pathogenesis, many aspects of the molecular and cellular mechanisms of host-pathogen interaction still require clarification. The purinergic system utilizes extracellular ATP and adenosine as critical signaling molecules and plays several roles in pathophysiological processes. Furthermore, nucleoside surface receptors such as the adenosine receptor A2AR involved in neuroimmune response, lipid metabolism, and neuron-glia interaction are targets for the treatment of different diseases. Despite the importance of this system, nothing has been described about its role in leprosy, particularly adenosinergic signaling (AdoS) during M. leprae-Schwann cell interaction. Methods: M. leprae was purified from the hind footpad of athymic nu/nu mice. ST88-14 human cells were infected with M. leprae in the presence or absence of specific agonists or antagonists of AdoS. Enzymatic activity assays, fluorescence microscopy, Western blotting, and RT-qPCR analysis were performed. M. leprae viability was investigated by RT-qPCR, and cytokines were evaluated by enzyme-linked immunosorbent assay. Results: We demonstrated that M. leprae-infected Schwann cells upregulated CD73 and ADA and downregulated A2AR expression and the phosphorylation of the transcription factor CREB (p-CREB). On the other hand, activation of A2AR with its selective agonist, CGS21680, resulted in: 1) reduced lipid droplets accumulation and pro-lipogenic gene expression; 2) reduced production of IL-6 and IL-8; 3) reduced intracellular M. leprae viability; 4) increased levels of p-CREB. Conclusion: These findings suggest the involvement of the AdoS in leprosy neuropathogenesis and support the idea that M. leprae, by downmodulating the expression and activity of A2AR in Schwann cells, decreases A2AR downstream signaling, contributing to the maintenance of LD accumulation and intracellular viability of the bacillus.

Improving compliance around protected areas through fair administration of rules.

Protected area management often depends heavily on law enforcement to secure compliance with rules. However, this can contribute to conflict between protected area authorities and local people, negatively affecting both human well-being and conservation outcomes. Compliance is affected by many factors, including whether those who enforce rules are perceived to do so fairly, as well as the perceived rule-related behavior of others. We used factorial survey experiments to explore how fair respondents living around protected areas in Indonesia and Tanzania perceive sanctions distributed by law enforcers to be. We presented scenarios to respondents to assess how crime type, offender characteristics, and corruption influenced their judgments regarding the fairness of administered sanctions. We also assessed how descriptive norms and corruption influenced individuals' willingness to obey protected area rules. Data were collected from 229 people in Indonesia and 217 in Tanzania. Results showed that in both locations, lawful sanctions, such as arrests or warnings, were perceived as fairer, and sanctions that involved corruption were perceived as least fair. Attitudes toward protected area rules, corruption, and descriptive norms all influenced people's willingness to comply, whereas multidimensional poverty did not. Our results highlight the need for conservation policy and practice to move beyond narratives that focus on the need for more law enforcement. To improve protected area compliance and secure better outcomes for people and nature, conservation must focus on ensuring the fair administration of rules and enhancing the legitimacy of rules themselves.

Mejoras en el cumplimiento alrededor de las áreas protegidas mediante la administración imparcial de reglas Resumen El manejo de áreas protegidas casi siempre depende de la aplicación de la ley para asegurar el cumplimiento de las reglas. Sin embargo, esto puede contribuir al conflicto entro las autoridades de las áreas protegidas y los locales, lo que afecta negativamente al bienestar humano y a los resultados de conservación. El cumplimiento se ve afectado por muchos factores, incluido si se percibe que quienes aplican las reglas lo hacen de manera imparcial, así como el comportamiento relacionado a las reglas de las demás. Aplicamos experimentos de censo factorial para explorar cómo los respondientes imparciales que viven en torno a las áreas protegidas en Indonesia y Tanzania perciben las sanciones distribuidas por los agentes de la ley. Les presentamos escenarios para analizar cómo el tipo de crimen, características del ofensor y la corrupción influyen sobre sus juicios con respecto a la imparcialidad de las sanciones administradas. También analizamos cómo las normas descriptivas y la corrupción influyen sobre la voluntad individual de obedecer las reglas del área protegida. Recolectamos los datos de 299 personas en Indonesia y 217 en Tanzania. Los resultados mostraron que, en ambas localidades, las sanciones legales, como arrestos o advertencias, eran percibidas como más justas, y las sanciones que involucraban corrupción eran percibidas como las menos justas. Todas las actitudes hacia las reglas de las áreas protegidas, la corrupción y las normas descriptivas influyeron sobre la voluntad de las personas para obedecer, mientras que la pobreza multidimensional no influyó. Nuestros resultados enfatizan la necesidad de que las políticas y prácticas de conservación vayan más allá de las narrativas que se enfocan en la necesidad de una mayor aplicación de la ley. Para incrementar el cumplimiento en las áreas protegidas y asegurar mejores resultados para las personas y la naturaleza, la conservación debe enfocarse en garantizar la administración imparcial de las reglas e incrementar su legitimidad.

Neuronal A2A receptor exacerbates synapse loss and memory deficits in APP/PS1 mice.

Early pathological upregulation of adenosine A2A receptors (A2ARs), one of the caffeine targets, by neurons is thought to be involved in the development of synaptic and memory deficits in Alzheimer's disease (AD) but mechanisms remain ill-defined. To tackle this question, we promoted a neuronal upregulation of A2AR in the hippocampus of APP/PS1 mice developing AD-like amyloidogenesis. Our findings revealed that the early upregulation of A2AR in the presence of an ongoing amyloid pathology exacerbates memory impairments of APP/PS1 mice. These behavioural changes were not linked to major change in the development of amyloid pathology but rather associated with increased phosphorylated tau at neuritic plaques. Moreover, proteomic and transcriptomic analyses coupled with quantitative immunofluorescence studies indicated that neuronal upregulation of the receptor promoted both neuronal and non-neuronal autonomous alterations, i.e. enhanced neuroinflammatory response but also loss of excitatory synapses and impaired neuronal mitochondrial function, presumably accounting for the detrimental effect on memory. Overall, our results provide compelling evidence that neuronal A2AR dysfunction, as seen in the brain of patients, contributes to amyloid-related pathogenesis and underscores the potential of A2AR as a relevant therapeutic target for mitigating cognitive impairments in this neurodegenerative disorder.

Neuroprotective compounds alter the expression of genes coding for proteins related to mitochondrial function in activated microglia.

A hallmark of neuroinflammatory disorders is mitochondrial dysfunction. Nevertheless, the transcriptional changes underlying this alteration are not well-defined. Microglia activation, a decrease in mitochondrion biogenesis and a subsequent alteration of the redox are common factors in diseases coursing with neuroinflammation. In the last two decades, components of the adenosinergic system have been proposed as potential therapeutic targets to combat neuroinflammation. In this research, we analyzed by RNAseq the gene expression in activated microglia treated with an adenosine A2A receptor antagonist, SCH 582561, and/or an A3 receptor agonist, 2-Cl-IB-MECA, since these receptors are deeply related to neurodegeneration and inflammation. The analysis was focused on genes related to inflammation and REDOX homeostasis. It was detected that in the three conditions (microglia treated with 2-Cl-IB-MECA, SCH 582561, and their combination) more than 40 % of the detected genes codified by the mitochondrial genome were differentially expressed (FDR < 0.05) (14/34, 16/34, and 13/34) respectively, being almost all of them (>85 %) upregulated in the microglia treated with adenosinergic compounds. Also, we analyzed the differential expression of genes related to mitochondrial function and oxidative stress codified by the nuclear genome. Additionally, we evaluated the oxygen consumption rate (OCR) of mitochondria in microglia treated with LPS and IFN-γ, both alone and in combination with adenosinergic compounds. The data showed an improvement in mitochondrial function with the antagonist of the adenosine A2A receptor, compared to the effects of pro-inflammatory stimulus, confirming a functional effect consistent with the RNAseq data.

The adenosine A2A receptor in human sperm: its role in sperm motility and association with in vitro fertilization outcomes.

Background: The involvement of ATP and cAMP in sperm function has been extensively documented, but the understanding of the role of adenosine and adenosine receptors remains incomplete. This study aimed to examine the presence of adenosine A2A receptor (A2AR) and study the functional role of A2AR in human sperm. Methods: The presence and localization of A2AR in human sperm were examined by western blotting and immunofluorescence assays. The functional role of A2AR in sperm was assessed by incubating human sperm with an A2AR agonist (regadenoson) and an A2AR antagonist (SCH58261). The sperm level of A2AR was examined by western blotting in normozoospermic and asthenozoospermic men to evaluate the association of A2AR with sperm motility and in vitro fertilization (IVF) outcomes. Results: A2AR with a molecular weight of 43 kDa was detected in the tail of human sperm. SCH58261 decreased the motility, penetration ability, intracellular Ca2+ concentration, and CatSper current of human sperm. Although regadenoson did not affect these sperm parameters, it alleviated the adverse effects of SCH58261 on these parameters. In addition, the mean level of A2AR in sperm from asthenozoospermic men was lower than that in sperm from normozoospermic men. The sperm level of A2AR was positively correlated with progressive motility. Furthermore, the fertilization rate during IVF was lower in men with decreased sperm level of A2AR than in men with normal sperm level of A2AR. Conclusions: These results indicate that A2AR is important for human sperm motility and is associated with IVF outcome.

An agonist of the adenosine A2A receptor, CGS21680, promotes corneal epithelial wound healing via the YAP signalling pathway.

BACKGROUND AND PURPOSE: The adenosine A2A receptor (A2AR) is involved in various physiological and pathological processes in the eye; however, the role of the A2AR signalling in corneal epithelial wound healing is not known. Here, the expression, therapeutic effects and signalling mechanism of A2AR in corneal epithelial wound healing were investigated using the A2AR agonist CGS21680. EXPERIMENTAL APPROACH: A2AR localization and expression during wound healing in the murine cornea were determined by immunofluorescence staining, quantitative reverse transcription polymerase chain reaction (RT-qPCR) and western blotting. The effect of CGS21680 on corneal epithelial wound healing in the lesioned corneal and cultured human corneal epithelial cells (hCECs) by modulating cellular proliferation and migration was critically evaluated. The role of Hippo-YAP signalling in mediating the CGS21680 effect on wound healing by pharmacological inhibition of YAP signalling was explored. KEY RESULTS: A2AR expression was up-regulated after corneal epithelial injury. Topical administration of CGS21680 dose-dependently promoted corneal epithelial wound healing in the injured corneal epithelium by promoting cellular proliferation. Furthermore, CGS21680 accelerated the cellular proliferation and migration of hCECs in vitro. A2AR activation promoted early up-regulation and later down-regulation of YAP signalling molecules, and pharmacological inhibition of YAP signalling reverted CGS21680-mediated wound healing effect in vivo and in vitro. CONCLUSION AND IMPLICATIONS: A2AR activation promotes wound healing by enhancing cellular proliferation and migration through the YAP signalling pathway. A2ARs play an important role in the maintenance of corneal epithelium integrity and may represent a novel therapeutic target for facilitating corneal epithelial wound healing.

A2AR antagonists triggered the AMPK/m-TOR autophagic pathway to reverse the calcium-dependent cell damage in 6-OHDA induced model of PD.

Calcium dyshomeostasis, oxidative stress, autophagy and apoptosis are the pathogenesis of selective dopaminergic neuronal loss in Parkinson's disease (PD). Earlier, we reported that A2A R modulates IP3-dependent intracellular Ca2+ signalling via PKA. Moreover, A2A R antagonist has been reported to reduce oxidative stress and apoptosis in PD models, however intracellular Ca2+ ([Ca2+]i) dependent autophagy regulation in the 6-OHDA model of PD has not been explored. In the present study, we investigated the A2A R antagonists mediated neuroprotective effects in 6-OHDA-induced primary midbrain neuronal (PMN) cells and unilateral lesioned rat model of PD. 6-OHDA-induced oxidative stress (ROS and superoxide) and [Ca2+]i was measured using Fluo4AM, DCFDA and DHE dye respectively. Furthermore, autophagy was assessed by Western blot of p-m-TOR/mTOR, p-AMPK/AMPK, LC3I/II, Beclin and ß-actin. Apoptosis was measured by Annexin V-APC-PI detection and Western blot of Bcl2, Bax, caspase3 and ß-actin. Dopamine levels were measured by Dopamine ELISA kit and Western blot of tyrosine hydroxylase. Our results suggest that 6-OHDA-induced PMN cell death occurred due to the interruption of [Ca2+]i homeostasis, accompanied by activation of autophagy and apoptosis. A2A R antagonists prevented 6-OHDA-induced neuronal cell death by decreasing [Ca2+]i overload and oxidative stress. In addition, we found that A2A R antagonists upregulated mTOR phosphorylation and downregulated AMPK phosphorylation thereby reducing autophagy and apoptosis both in 6-OHDA induced PMN cells and 6-OHDA unilateral lesioned rat model. In conclusion, A2A R antagonists alleviated 6-OHDA toxicity by modulating [Ca2+]i signalling to inhibit autophagy mediated by the AMPK/mTOR pathway.

Genetic Polymorphisms of P2RX7 but Not of ADORA2A Are Associated with the Severity of SARS-CoV-2 Infection.

SARS-CoV-2 infection ranges from mild to severe presentations, according to the intensity of the aberrant inflammatory response. Purinergic receptors dually control the inflammatory response: while adenosine A2A receptors (A2ARs) are anti-inflammatory, ATP P2X7 receptors (P2X7Rs) exert pro-inflammatory effects. The aim of this study was to assess if there were differences in allelic and genotypic frequencies of a loss-of-function SNP of ADORA2A (rs2298383) and a gain-of-function single nucleotide polymorphism (SNP) of P2RX7 (rs208294) in the severity of SARS-CoV-2-associated infection. Fifty-five individuals were enrolled and categorized according to the severity of the infection. Endpoint genotyping was performed in blood cells to screen for both SNPs. The TT genotype (vs. CT + CC) and the T allele (vs. C allele) of P2RX7 SNP were found to be associated with more severe forms of COVID-19, whereas the association between ADORA2A SNP and the severity of infection was not significantly different. The T allele of P2RX7 SNP was more frequent in people with more than one comorbidity and with cardiovascular conditions and was associated with colorectal cancer. Our findings suggest a more prominent role of P2X7R rather than of A2AR polymorphisms in SARS-CoV-2 infection, although larger population-based studies should be performed to validate our conclusions.

Psychology as a Science of the Soul: Evangelos Christou's The Logos of the Soul (1963).

After Evangelos Christou (1923-1956) studied philosophy at King's College, Cambridge, with Wittgenstein and others, he earned a doctorate at the Jung Institute in Zürich. He then returned home to Alexandria, near which he died in a car crash. The Logos of the Soul, published posthumously, argued for a psychology that would be neither a natural scientific psychology, devoted to causal analyses, nor a philosophical discipline that analysed mental events. Psychology would be an autonomous science of the soul, an unknown distinct from body and mind. Science deals with bodies and behaviours; philosophy with the mental concepts and acts. Psychology deals with "psychological experience". Dreams and fantasies can be sources of psychological experience, but so can perceptual acts and mental acts. Meaning occurs when something encounters an ego or self in a psychological experience. Observation in psychology is participant observation, akin to witnessing of a drama. Psychological methods, such as psychotherapy, are both means of discovery and means of becoming. Christou's work brought together Jung's analytical psychology and mid-century British philosophy in order to stake out the ground for psychology that would be an empirical analysis of psychological experience and a logical analysis of the concepts used in that psychology.

Après qu'Evangelos Christou (1923­1956) ait étudié la philosophie au King's College à Cambridge, avec Wittgenstein et d'autres, il fit un doctorat à l'Institut Jung de Zurich. Il retourna ensuite à Alexandrie, où il mourut peu de temps après dans un accident de voiture. The Logos of the Soul, publié à titre posthume, plaide pour une psychologie qui ne serait ni une psychologie scientifique naturelle, dédiée aux analyses causales, ni une discipline philosophique qui analyse les événements du mental. La psychologie serait une science autonome de l'âme, une inconnue distincte du corps et du mental. La science traite des corps et des comportements; la philosophie s'occupe des concepts et des actes. La psychologie s'intéresse à « l'expérience psychologique ¼. Les rêves et les fantasmes peuvent être des sources d'expérience psychologique, mais il en est de même pour les actes de perception et les actes du mental. Le sens apparait quand quelque chose rencontre un moi ou un soi dans une expérience psychologique. L'observation en psychologie est une observation participative, qui s'apparente à être témoin d'une pièce dramatique. Les méthodes psychologiques, telles la psychothérapie, sont à la fois des moyens d'exploration et des moyens pour devenir. L'œuvre de Christou a relié la psychologie analytique de Jung et la philosophie britannique du milieu du siècle afin de revendiquer le terrain pour une psychologie qui serait une analyse empirique de l'expérience psychologique et une analyse logique des concepts utilisés dans cette psychologie.

Luego de estudiar filosofía en el King's College de Cambridge, con Wittgenstein y otros, Evangelos Christou (1923­1956) obtuvo un doctorado en el Instituto Jung de Zúrich. Posteriormente regresó a su casa en Alejandría, cerca de la cual murió en un accidente de auto. El Logos del alma, publicado póstumamente, abogaba por una psicología que no fuera ni una psicología científica natural, dedicada a los análisis causales, ni una disciplina filosófica que analizara los acontecimientos mentales. La psicología sería una ciencia autónoma del alma, lo desconocido distinto del cuerpo y de la mente. La ciencia se ocupa de los cuerpos y las conductas; la filosofía, de los conceptos y los actos mentales. La psicología se ocupa de la "experiencia psicológica". Los sueños y las fantasías pueden ser fuentes de experiencia psicológica, pero también los actos perceptivos y mentales. El sentido se produce cuando algo se encuentra con un ego o un self en una experiencia psicológica. La observación en psicología es una observación participante, similar a ser testigo de un drama. Los métodos psicológicos, como la psicoterapia, son a la vez medios de descubrimiento y medios de devenir. La obra de Christou reunió la psicología analítica de Jung y la filosofía británica de mediados de siglo para sentar las bases de una psicología que fuera un análisis empírico de la experiencia psicológica y un análisis lógico de los conceptos utilizados en esa psicología.

Adenosine A2A Receptor Antagonist Sch58261 Improves the Cognitive Function in Alzheimer's Disease Model Mice Through Activation of Nrf2 via an Autophagy-Dependent Pathway.

Aims: Adenosine, an important endogenous neuromodulator, contributes to a broad set of several neurodegenerative diseases. The adenosine A2A receptor (A2AR) is the most involved in neuropathological effects and plays an important role in the pathogenesis of Alzheimer's disease (AD). However, the effect of A2AR antagonist and the underlying mechanism in AD model mice remains unclear. Results: The amyloid beta (Aß)1-42-induced mice AD models were used in this study. Several behavioral experiments were performed to evaluate the improvement of AD mice treated with A2AR antagonist. For mechanism analysis, autophagy-related proteins, Kelch-like ECH-associated protein1 (Keap1)-nuclear factor erythroid-derived factor 2-related factor (Nrf2) pathway activation, and synaptic function were studied using Western blot, immunofluorescence, immunohistochemistry, transmission electron microscope, real-time quantitative PCR, and patch clamp. Pharmacological blockade of adenosine A2AR by SCH58261 (SCH) ameliorated cognitive deficits and decreased expression levels of several AD biomarkers, including Aß and hyperphosphorylation of Tau. Moreover, SCH activated the Nrf2 pathway through autophagy mediated Keap1 degradation, resulting in the improvement of neuron autophagy dysfunction, synaptic plasticity, and synaptic transmission. Innovation: Our data clarified that the SCH (an antagonist of A2AR) could increase the level of autophagy, promote the ability of antioxidative stress by the activation of Keap1-Nrf2 pathway, and improve the synaptic function in Aß1-42-induced AD mice or cell model, which provided a potential therapeutic strategy for AD. Conclusion: A2AR antagonism represents a promising strategy for the anti-AD agent development through autophagy-dependent pathway.

Adenosine A2A Receptor Blockade Provides More Effective Benefits at the Onset Rather than after Overt Neurodegeneration in a Rat Model of Parkinson's Disease.

Adenosine A2A receptor (A2AR) antagonists are the leading nondopaminergic therapy to manage Parkinson's disease (PD) since they afford both motor benefits and neuroprotection. PD begins with a synaptic dysfunction and damage in the striatum evolving to an overt neuronal damage of dopaminergic neurons in the substantia nigra. We tested if A2AR antagonists are equally effective in controlling these two degenerative processes. We used a slow intracerebroventricular infusion of the toxin MPP+ in male rats for 15 days, which caused an initial loss of synaptic markers in the striatum within 10 days, followed by a neuronal loss in the substantia nigra within 30 days. Interestingly, the initial loss of striatal nerve terminals involved a loss of both dopaminergic and glutamatergic synaptic markers, while GABAergic markers were preserved. The daily administration of the A2AR antagonist SCH58261 (0.1 mg/kg, i.p.) in the first 10 days after MPP+ infusion markedly attenuated both the initial loss of striatal synaptic markers and the subsequent loss of nigra dopaminergic neurons. Strikingly, the administration of SCH58261 (0.1 mg/kg, i.p. for 10 days) starting 20 days after MPP+ infusion was less efficacious to attenuate the loss of nigra dopaminergic neurons. This prominent A2AR-mediated control of synaptotoxicity was directly confirmed by showing that the MPTP-induced dysfunction (MTT assay) and damage (lactate dehydrogenase release assay) of striatal synaptosomes were prevented by 50 nM SCH58261. This suggests that A2AR antagonists may be more effective to counteract the onset rather than the evolution of PD pathology.