A3 adenosine receptor agonist IB-MECA reverses chronic cerebral ischemia-induced inhibitory avoidance memory deficit

Cheng, Pengfei; Zhang, Junxiang; Chu, Zhensheng; Liu, Wenting; Lin, Hui; Wu, Yu; Zhu, Jiaying

doi:10.1016/j.ejphar.2022.174874

Cited by 5 publications

(3 citation statements)

References 53 publications

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“…The BCAS+MRS1523+H‐89 group was intraperitoneally injected with MRS1523 (1 mg/kg) and H‐89 (MedChemExpress, HY‐15979, 2 mg/kg). The doses of ADORA3 antagonist and H‐89 used in mice were referenced from previous literature 22,23 . All procedures were approved by the Medical Ethics Committee of Nanjing Drum Tower Hospital (2023AE01011).…”

Section: Methodsmentioning

confidence: 99%

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Inhibition of ADORA3 promotes microglial phagocytosis and alleviates chronic ischemic white matter injury

Xu,

Tang,

Zhou

et al. 2024

CNS Neurosci Ther

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BackgroundAdenosine A3 receptor (ADORA3) belongs to the adenosine receptor families and the role of ADORA3 in vascular dementia (VaD) is largely unexplored. The present study sought to determine the therapeutic role of ADORA3 antagonist in a mouse model of VaD.MethodsThe GSE122063 dataset was selected to screen the differential expression genes and pathways between VaD patients and controls. A mouse model of bilateral carotid artery stenosis (BCAS) was established. The cognitive functions were examined by the novel object recognition test, Y maze test, and fear of conditioning test. The white matter injury (WMI) was examined by 9.4 T MRI, western blot, and immunofluorescence staining. The mechanisms of ADORA3‐regulated phagocytosis by microglia were examined using qPCR, western blot, dual immunofluorescence staining, and flow cytometry.ResultsThe expression of ADORA3 was elevated in brain tissues of VaD patients and ADORA3 was indicated as a key gene for VaD in the GSE122063. In BCAS mice, the expression of ADORA3 was predominantly elevated in microglia in the corpus callosum. ADORA3 antagonist promotes microglial phagocytosis to myelin debris by facilitating cAMP/PKA/p‐CREB pathway and thereby ameliorates WMI and cognitive impairment in BCAS mice. The therapeutic effect of ADORA3 antagonist was partially reversed by the inhibition of the cAMP/PKA pathway.ConclusionsADORA3 antagonist alleviates chronic ischemic WMI by modulating myelin clearance of microglia, which may be a potential therapeutic target for the treatment of VaD.

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Section: Methodsmentioning

confidence: 99%

“…The doses of ADORA3 antagonist and H‐89 used in mice were referenced from previous literature. 22 , 23 All procedures were approved by the Medical Ethics Committee of Nanjing Drum Tower Hospital (2023AE01011).…”

Section: Methodsmentioning

confidence: 99%

Inhibition of ADORA3 promotes microglial phagocytosis and alleviates chronic ischemic white matter injury

Xu,

Tang,

Zhou

et al. 2024

CNS Neurosci Ther

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“…In a rat model of focal ischemia induced by transient middle cerebral artery occlusion, the A 2B AR agonist, BAY60-6583, improved neurological deficits, significantly reduced brain damage in the cortex and striatum, reduced the activation of microglia and alterations in astrocytes, decreased the expression of TNF-α, increased the expression of IL-10, and reduced the infiltration of blood cells in the ischemic cortex [ 69 ]. Regarding A 3 AR, its stimulation with the selective agonist, IB-MECA, improved memory deficits caused by chronic cerebral ischemia in mice, reduced ERK phosphorylation and GFAP expression, and upregulated MAP-2 and IFN-β [ 70 ]. In a study using nonhuman primates with transient middle cerebral artery occlusion, the dual A 1 /A 3 agonist, AST-004, exhibited a reduction in ischemic damage, thereby demonstrating the potential to simultaneously target the two neuroprotective AR subtypes [ 71 ].…”

Section: Ars In Cns Diseasesmentioning

confidence: 99%

Pharmacology of Adenosine Receptors: Recent Advancements

Vincenzi,

Pasquini,

Contri

et al. 2023

Biomolecules

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Adenosine receptors (ARs) are widely acknowledged pharmacological targets yet are still underutilized in clinical practice. Their ubiquitous distribution in almost all cells and tissues of the body makes them, on the one hand, excellent candidates for numerous diseases, and on the other hand, intrinsically challenging to exploit selectively and in a site-specific manner. This review endeavors to comprehensively depict the substantial advancements witnessed in recent years concerning the development of drugs that modulate ARs. Through preclinical and clinical research, it has become evident that the modulation of ARs holds promise for the treatment of numerous diseases, including central nervous system disorders, cardiovascular and metabolic conditions, inflammatory and autoimmune diseases, and cancer. The latest studies discussed herein shed light on novel mechanisms through which ARs exert control over pathophysiological states. They also introduce new ligands and innovative strategies for receptor activation, presenting compelling evidence of efficacy along with the implicated signaling pathways. Collectively, these emerging insights underscore a promising trajectory toward harnessing the therapeutic potential of these multifaceted targets.

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