Abstract
Adenosine is an important neuromodulator in the central nervous system, and tissue adenosine levels increase during ischemic events, attenuating excitotoxic neuronal injury. Recently, our lab developed an electrochemical fast-scan cyclic voltammetry (FSCV) method that identified rapid, spontaneous changes in adenosine concentrations that last only about 3 seconds. Here, we investigated the effects of cerebral ischemia and reperfusion on the concentration and frequency of transient adenosine release in the caudate-putamen. In anesthetized rats, data were collected for four hours: two hours of normoxia, 30 min of cerebral ischemia induced by bilateral common carotid artery occlusion, and 90 min of reperfusion. Transient adenosine release was increased during the cerebral ischemia period and remained elevated during reperfusion. The total number of adenosine transients increased by 52% during cerebral ischemia and reperfusion compared to normoxia. The concentration of adenosine per event did not increase but the cumulative adenosine concentration during cerebral ischemia and reperfusion increased by 53% because of the higher frequency of events. Further, we evaluated the role of A2A antagonist, SCH442416, a putative neuroprotective agent to affect adenosine transients. SCH442416 significantly decreased the transient frequency during cerebral ischemia-reperfusion by 27% and the cumulative concentration by 31%. Our results demonstrate that this mode of rapid adenosine release increases during early cerebral ischemia-reperfusion injury. Rapid adenosine release could provide fast, local neuromodulation and neuroprotection during cerebral ischemia.
Highlights
Ischemic stroke is one of the leading causes of death in major industrialized countries, with a mortality rate of 30%, and results in long term disabilities in survivors [1]
This study demonstrates that the frequency of spontaneous, transient adenosine release events significantly increases during cerebral ischemia compared to normoxia and continues to be elevated through 90 min of reperfusion
Adenosine dramatically increases during ischemia [17], but here we demonstrate a new mechanism of increasing adenosine signaling during cerebral ischemia: increased frequency of transient adenosine events
Summary
Ischemic stroke is one of the leading causes of death in major industrialized countries, with a mortality rate of 30%, and results in long term disabilities in survivors [1]. Adenosine is an important inhibitory neuromodulator that increases during stroke and acts as a neuroprotective agent [2,3,4,5,6]. As a breakdown product of ATP, adenosine builds up in the extracellular space during stressful events, [7,8] and reduces excitotoxic glutamate signaling [9]. Rapid, real-time measurements of adenosine have not been studied during cerebral ischemia and reperfusion
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