Adenosine Receptors as Neuroinflammation Modulators: Role of A1 Agonists and A2A Antagonists

Abstract

The pathological condition of neuroinflammation is caused by the activation of the neuroimmune cells astrocytes and microglia. The autacoid adenosine seems to be an important neuromodulator in this condition. Its main receptors involved in the neuroinflammation modulation are A1AR and A2AAR. Evidence suggests that A1AR activation produces a neuroprotective effect and A2AARs block prevents neuroinflammation. The aim of this work is to elucidate the effects of these receptors in neuroinflammation using the partial agonist 2′-dCCPA (2-chloro-N6-cyclopentyl-2′-deoxyadenosine) (C1 KiA1AR = 550 nM, KiA2AAR = 24,800 nM, and KiA3AR = 5560 nM, α = 0.70, EC50A1AR = 832 nM) and the newly synthesized in house compound 8-chloro-9-ethyl-2-phenethoxyadenine (C2 KiA2AAR = 0.75 nM; KiA1AR = 17 nM and KiA3AR = 227 nM, IC50A2AAR = 251 nM unpublished results). The experiments were performed in in vitro and in in vivo models of neuroinflammation. Results showed that C1 was able to prevent the inflammatory effect induced by cytokine cocktail (TNF-α, IL-1β, and IFN-γ) while C2 possess both anti-inflammatory and antioxidant properties, counteracting both neuroinflammation in mixed glial cells and in an animal model of neuroinflammation. In conclusion, C2 is a potential candidate for neuroinflammation therapy.

Adenosine Receptors Modulate the Exogenous Ketogenic Supplement-Evoked Alleviating Effect on Lipopolysaccharide-Generated Increase in Absence Epileptic Activity in WAG/Rij Rats

“…It has been demonstrated that adenosine is a key anti-inflammatory mediator [50]. In the central nervous system, adenosine exerts its effects on inflammatory processes mainly through A1Rs and A2ARs [51]. A1Rs and A2ARs are expressed in astrocytes, oligodendrocytes, and microglia modulating inflammatory processes [50,52].…”

Combined Therapy of A1AR Agonists and A2AAR Antagonists in Neuroinflammation

“…Briefly, media were aspired and cells fixed with Fixative Solution for 15 min (high-purity 4% formaldehyde in PBS (Phosphate Buffered Saline), pH = 7.3). After that, they were washed 3 times with PBS and permeabilized with a Permeabilization Solution (0.5% Triton X-100) for 15 min [ 58 ]. They were washed again with PBS and incubated for 1 h with Blocking Buffer (3% BSA (Bovine Serum Albumin), fraction V delipidated in PBS).…”

Adenosine and Inflammation: Here, There and Everywhere

“…Following neuronal stress and damage, extracellular brain adenosine concentration is dramatically increased resulting in the promotion or attenuation of neuroinflammation. Many of the immunomodulatory effects of adenosine in the CNS are mediated by A 1 and A 2A AR subtypes [ 159 , 160 ], although recent evidence also points to the involvement of A 2B and A 3 ARs [ 161 , 162 ]. The expression of all four ARs has been detected in astrocytes, oligodendrocytes, and microglia [ 163 ].…”