Adenosine A1 Receptor Agonist 2-chloro-N6-cyclopentyladenosine and Hippocampal Excitability During Brain Development in Rats

Abstract

Objective: The adenosinergic system may influence excitability in the brain. Endogenous and exogenous adenosine has anticonvulsant activity presumably by activating A1 receptors. Adenosine A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA) may thus bolster anticonvulsant effects, but its action and the number of A1 receptors at different developmental stages are not known. Methods: Hippocampal epileptic afterdischarges (ADs) were elicited in 12-, 15-, 18-, 25-, 45-, and 60-day-old rats. Stimulation and recording electrodes were implanted into the dorsal hippocampus. The A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA, 0.5 or 1 mg/kg) was administered intraperitoneally 10 min before the first stimulation. Control animals were injected with saline. All rats were stimulated with a 2-s series of 1-ms biphasic pulses delivered at 60 Hz with increasing stepwise intensity (0.05–0.6 mA). Each age and dose group contained 9–14 animals. The AD thresholds and durations were evaluated, and the A1 receptors were detected in the hippocampus in 7-, 10-, 12-, 15-, 18-, 21-, 25-, 32-, and 52-day-old rats. Results: Both CCPA doses significantly increased hippocampal AD thresholds in 12-, 15-, 18-, and 60-day-old rats compared to controls. In contrast, the higher dose significantly decreased AD threshold in the 25-day-old rats. The AD durations were significantly shortened in all age groups except for 25-day-old rats where they were significantly prolonged. A1 receptor expression in the hippocampus was highest in 10-day-old rats and subsequently decreased. Significance: The adenosine A1 receptor agonist CCPA exhibited anticonvulsant activity at all developmental stages studied here except for 25-day-old rats. Age-related differences might be due to the development of presynaptic A1 receptors in the hippocampus.

Neonatal Seizures and Purinergic Signalling

“…Interestingly, in this model, both agonistic and antagonistic action of A2 A receptors had an anticonvulsive effect in P12 rats, yet blocking A2 A receptors in P25 produces a proconvulsive effect [ 284 ]. These results were replicated, even when a different area of the brain (hippocampus) was stimulated to induce seizures [ 285 ], with the A1 receptor agonist 2-chloro- N 6-cyclopentyladenosine having an anticonvulsive effect at all ages except P25. These studies highlight the developmental regulation of P1 receptors and the possible age-dependent modulation of seizure phenotypes.…”

Caffeine and Clinical Outcomes in Premature Neonates

“…An understanding of the maturation and density of adenosine receptors through development is crucial to the understanding of the long-term effects of caffeine in premature infants. Postnatal changes in expression of adenosine receptors have been described in the rodent brain [100,101] A 1 receptor expression increases markedly with progressive maturation [43], with increasing density and functional maturity from postnatal days 10–15 days up to days 25–40 [102,103]. Levels on P25 and older rats are significantly lower than levels in P10–P12 brains [103].…”

“…Postnatal changes in expression of adenosine receptors have been described in the rodent brain [100,101] A 1 receptor expression increases markedly with progressive maturation [43], with increasing density and functional maturity from postnatal days 10–15 days up to days 25–40 [102,103]. Levels on P25 and older rats are significantly lower than levels in P10–P12 brains [103]. A 1 receptors are widely distributed at birth (around 10% of adult levels), increasing gradually until adulthood, and peaking during the second week of postnatal life [43,102,103].…”

“…Levels on P25 and older rats are significantly lower than levels in P10–P12 brains [103]. A 1 receptors are widely distributed at birth (around 10% of adult levels), increasing gradually until adulthood, and peaking during the second week of postnatal life [43,102,103]. Moreover, the affinity and binding capacity of A 1 receptor decrease in the hippocampus upon aging [104].…”

“…Moreover, the affinity and binding capacity of A 1 receptor decrease in the hippocampus upon aging [104]. A 1 receptors are widely present in different tissues including brain endothelial cells with consequences, on cell growth and angiogenesis during postnatal development [103]. ATP-derived adenosine preferentially activates pro-convulsive A 2 receptors than inhibitory A 1 receptors [105].…”