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

Background: Chronic cerebral ischemia (CCI) is a major cause of subcortical ischemic vascular dementia. Here, we examined the neuroprotective action of the A3 adenosine receptor agonist N-6-(3-iodobenzyl)-adenosine-5 '-N-methylcarboxamide (IB-MECA) on white matter lesions following CCI. Methods: A CCI mouse model was established using unilateral common carotid artery occlusion. IB-MECA and 3propyl-6-ethyl-5-[(ethylthio)carbonyl]-2 phenyl-4-propyl-3-pyridine carboxylate (MRS1523), an antagonist of the A3 adenosine receptor, were administered by intraperitoneal injection. The inhibitory avoidance test was used to examine changes in memory performance. Microtubule-associated protein 2 (MAP-2) and neurofilament were assessed by immunohistochemistry, while expressions of phosphorylated extracellular signal-regulated kinase (ERK), ERK, interferon-beta (IFN-beta), and glial fibrillary acidic protein (GFAP) were assessed by western blot assay. Results: The memory retention score was reduced in vehicle-treated mice compared with IB-MECA-treated (p < 0.05) mice. Compared to sham-operated mice, p-ERK, GFAP and IFN-beta were increased, while MAP-2 and neurofilament were reduced in vehicle-treated mice (p < 0.01 for each). IB-MECA reduced ERK phosphorylation (p < 0.01) and GFAP expression (p < 0.05), but upregulated MAP-2 and IFN-beta (p < 0.01 for both), compared with vehicle. MRS1523 suppressed the effects of IB-MECA on the memory deficit, ERK phosphorylation, and on MAP 2, neurofilament, GFAP and IFN-beta levels. Conclusion: Our results suggest that A3 adenosine receptor stimulation ameliorates CCI-induced memory deficits, modulates thde ERK signaling pathway, preserves MAP-2 and neurofilament expression, regulates GFAP expression, and upregulates the anti-inflammatory cytokine IFN-beta. Thus, the A3 adenosine receptor may be a therapeutic target for treatment of cognitive disorders and cerebral inflammatory diseases.

Automated summary

The study found that the A3 adenosine receptor agonist can improve memory deficits caused by chronic cerebral ischemia, and regulate brain inflammation by modulating the ERK signaling pathway and protecting protein expression.