Endogenous Activation of Adenosine A₁ Receptors Accelerates Ischemic Suppression of Spontaneous Electrocortical Activity

Abstract

Cerebral ischemia induces a rapid suppression of spontaneous brain rhythms prior to major alterations in ionic homeostasis. It was found in vitro during ischemia that the rapidly formed adenosine, resulting from the intracellular breakdown of ATP, may inhibit synaptic transmission via the A(1) receptor subtype. The link between endogenous A(1) receptor activation during ischemia and the suppression of spontaneous electrocortical activity has not yet been established in the intact brain. The aim of this study was to investigate in vivo the effects of A(1) receptor antagonism by 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) on the time to electrocortical suppression during global cerebral ischemia. Adult male Wistar rats under chloral hydrate anesthesia were subjected to 1-min transient "four-vessel occlusion" ischemic episodes, separated by 20-min reperfusion. The rats were injected intraperitoneally with either 1.25 mg/kg DPCPX dissolved in 2 ml/kg dimethyl sulfoxide (DMSO) or the same volume of DMSO alone, 15 min before the third ischemic episode. Time to electrocortical suppression was estimated based on the decay of the root mean square of two-channel electrocorticographic recordings. During the first two ischemic episodes, electrocortical suppression appeared after approximately 12 s in both groups. After DMSO administration, ischemic suppression remained unchanged. After DPCPX administration, the time to electrocortical suppression was increased by approximately 10 s, and bursts of activity were recorded during the entire ischemia. These effects disappeared within 15 h after DPCPX administration. Our data provide evidence that during cerebral ischemia endogenous activation of A(1) receptors accelerates the electrical "shut-down" of the whole brain.

The Purine Salvage Pathway and the Restoration of Cerebral ATP: Implications for Brain Slice Physiology and Brain Injury

“…We were initially drawn to the issue of ATP levels in brain slices through observations that the release of adenosine provoked by hypoxia or OGD, which is largely responsible for the inhibition of excitatory synaptic transmission during and after metabolic stress in vitro [51][52][53][54][55] and in vivo [56][57][58], was reduced the second time the insult was delivered ( Fig. 2).…”

Therapeutic Effect of Caffeine Treatment Immediately Following Neonatal Hypoxic-Ischemic Injury on Spatial Memory in Male Rats

“…Additionally, adenosine accumulation following hypoxia is thought to be responsible for electrical suppression in the brain. For example, the release of adenosine was directly related to the depression of excitatory synaptic transmissions in hippocampal slices of P10–24 rats [39,40] and increased adenosine levels following hypoxia as measured in vivo in adult animals led to suppressed electrically evoked synaptic transmission [41]. Again these latter deleterious effects are thought to be mediated via activation of A1Rs.…”

Metabolic Challenge to Glia Activates an Adenosine-Mediated Safety Mechanism that Promotes Neuronal Survival by Delaying the Onset of Spreading Depression Waves

“…Therefore, not surprisingly, blockage of the adenosine A 1 receptor during an ischemic episode restores synaptic transmission, precipitates the occurrence of anoxic depolarization, and increases the infarct size (Fowler, 1989;Rudolphi et al, 1992). Adenosine-mediated neuroprotection also occurs in experimental models in which cellular respiration has been pharmacologically depressed (chemical anoxia; Ilie et al, 2006).…”