Continuous adenosine A2A receptor antagonism after focal cerebral ischemia in spontaneously hypertensive rats

Abstract

Antagonism of the adenosine A2A receptor (A2AR) has been shown to elicit substantial neuroprotective properties when given immediately after cerebral ischemia. We asked whether the continuous application of a selective A2AR antagonist within a clinically relevant time window will be a feasible and effective approach to treat focal cerebral ischemia. To answer this question, we subjected 20 male spontaneously hypertensive rats to permanent middle cerebral artery occlusion and randomized them equally to a verum and a control group. Two hours after stroke onset, the animals received a subcutaneous implantation of an osmotic minipump filled with 5 mg kg(-1) day(-1) 8-(3-chlorostyryl) caffeine (CSC) or vehicle solution. The serum level of CSC was measured twice a day for three consecutive days. The infarct volume was determined at days 1 and 3 using magnetic resonance imaging. We found the serum level of CSC showing a bell-shaped curve with its maximum at 36 h. The infarct volume was not affected by continuous CSC treatment. These results suggest that delayed and continuous CSC application was not sufficient to treat acute ischemic stroke, potentially due to unfavorable hepatic elimination and metabolization of the pharmaceutical.

AdenosineA2AReceptors Modulate Acute Injury and Neuroinflammation in Brain Ischemia

“…Altogether, evidence suggests that A 2A receptor antagonists provide protection centrally by reducing excitotoxicity, while A 2A receptor agonists provide protection by acting on blood cells controlling massive infiltration and neuroinflammation in the hours after brain ischemia. In agreement the lack of detecting a protection by A 2A receptor antagonism at later time after stroke [ 53 , our unpublished observation] might be attributable to the fact that protection is overwhelmed by subsequent damage brought about by blood cell infiltration that starts 6 hours after ischemia and peaks at 2 days thereafter [ 46 , 165 , 169 ].…”

“…Most recently, the question has been raised if A 2A receptor continuous blockade over an extended time-window after ischemia is protective. CSC continuously administered over 72 hours, using subcutaneously implanted osmotic minipumps, after permanent MCAo in spontaneously hypertensive rats, did not decrease brain infarct volume determined by magnetic resonance imaging 3 days after induction of ischemia [ 53 ]. Authors attributed the lack of protection to high hepatic metabolism and elimination of CSC [ 53 ].…”

“…CSC continuously administered over 72 hours, using subcutaneously implanted osmotic minipumps, after permanent MCAo in spontaneously hypertensive rats, did not decrease brain infarct volume determined by magnetic resonance imaging 3 days after induction of ischemia [ 53 ]. Authors attributed the lack of protection to high hepatic metabolism and elimination of CSC [ 53 ]. Consistently, Melani and coworkers (unpublished observation) found a lack of protection on infarct volume by SCH58261 administered subchronically (three times in the first day) or chronically (twice/day for 7 days) 7 days after 1 hour transient MCAo.…”

In VivoPET Imaging of Adenosine 2A Receptors in Neuroinflammatory and Neurodegenerative Disease

“…A recent study suggests that, although A 2A receptor antagonists initially protect against transient ischemic injury, the protective effect is lost 7 days after ischemia despite chronic treatment with the antagonist (twice a day) [ 125 ]. Similarly, chronic 8-(3-chlorostyryl) caffeine treatment (s.c.) did not show any effect on infarct volume at 72 hours after permanent occlusion of the middle cerebral artery (MCAo) [ 126 ] and genetic deletion even worsened ischemic injury in young mice when assessed at 5 days after permanent occlusion of the common carotid artery [ 127 ]. Interestingly, A 2A receptor agonist CGS21680 (i.p.)…”

The perspective of caffeine and caffeine derived compounds in therapy

“…From the mentioned receptors, the isotype A 2A is dominantly located in central nervous system, especially in the extrastriatal forebrain, where it acts on behavior and mental excitation in a link to dopamine, glutamate and brain derived neurotrophic factor signaling (41)(42)(43)(44). In recent time, neuroprotective effects of antagonist on A 2A receptors after cerebral ischemia were discovered (45).Cerebral ischemia is considered as a consequence and maybe the primary reason for some neuropathologies with unknown etiology, antagonism on the receptors by caffeine or any other compound would have signifi cant pharmacological sense.Beside the aforementioned effects, adenosine is responsible for bronchospasm,whichis regulated through A 2B receptors (46). In the bronchus, caffeine can suppress bronchospasm and even signifi cantly ameliorate bronchoconstriction just by antagonizing of the A 2B (47,48).…”