Abstract
Ischemia is a multifactorial pathology characterized by different events evolving in time. Immediately after the ischemic insult, primary brain damage is due to the massive increase of extracellular glutamate. Adenosine in the brain increases dramatically during ischemia in concentrations able to stimulate all its receptors, A1, A2A, A2B, and A3. Although adenosine exerts clear neuroprotective effects through A1 receptors during ischemia, the use of selective A1 receptor agonists is hampered by their undesirable peripheral side effects. So far, no evidence is available on the involvement of adenosine A2B receptors in cerebral ischemia. This study explored the role of adenosine A2B receptors on synaptic and cellular responses during oxygen and glucose deprivation (OGD) in the CA1 region of rat hippocampus in vitro. We conducted extracellular recordings of CA1 field excitatory post-synaptic potentials (fEPSPs); the extent of damage on neurons and glia was assessed by immunohistochemistry. Seven min OGD induced anoxic depolarization (AD) in all hippocampal slices tested and completely abolished fEPSPs that did not recover after return to normoxic condition. Seven minutes OGD was applied in the presence of the selective adenosine A2B receptor antagonists MRS1754 (500 nM) or PSB603 (50 nM), separately administered 15 min before, during and 5 min after OGD. Both antagonists were able to prevent or delay the appearance of AD and to modify synaptic responses after OGD, allowing significant recovery of neurotransmission. Adenosine A2B receptor antagonism also counteracted the reduction of neuronal density in CA1 stratum pyramidale, decreased apoptosis at least up to 3 h after the end of OGD, and maintained activated mTOR levels similar to those of controls, thus sparing neurons from the degenerative effects caused by the simil-ischemic conditions. Astrocytes significantly proliferated in CA1 stratum radiatum already 3 h after the end of OGD, possibly due to increased glutamate release. A2Breceptor antagonism significantly prevented astrocyte modifications. Both A2B receptor antagonists did not protect CA1 neurons from the neurodegeneration induced by glutamate application, indicating that the antagonistic effect is upstream of glutamate release. The selective antagonists of the adenosine A2B receptor subtype may thus represent a new class of neuroprotective drugs in ischemia.
Highlights
Cerebral ischemic stroke represents a life threatening neurological disorder that leads to mortality and long-term disability in surviving patients
We studied the effects of two selective adenosine A2B receptor antagonists, MRS1754 and PSB603, on anoxic depolarization (AD) development in the CA1 region of acute rat hippocampal slices under severe oxygen and glucose deprivation (OGD) episodes by extracellular recording of field excitatory post-synaptic potentials (fEPSPs) on 133 hippocampal slices taken from 42 rats
The putative protective role of adenosine A2B receptors in cerebral ischemia was studied in the CA1 region of hippocampal slices under oxygen-glucose deprivation, an experimental condition that mimics, albeit with the limits of in vitro methodology, the most common causes of cerebral ischemia, such as vessel occlusion
Summary
Cerebral ischemic stroke represents a life threatening neurological disorder that leads to mortality and long-term disability in surviving patients. Ischemic stroke remains one of the main causes of death and disability in the western countries with only very limited therapeutic options (Dirnagl, 2012). Acute brain injury after stroke is caused primarily by the lack of oxygen and glucose. In such conditions, mammalian neurons rapidly depolarize, and excessive release of glutamate occurs, causing excitotoxic cell death, largely due to over-activation of glutamatergic N-methyl-D-aspartate (NMDA) receptors. NMDA receptors are highly permeable to Ca2+ and are responsible for intracellular Ca2+ increase that reaches neurotoxic levels which, by activating cell lipases, endonucleases, proteases, and phosphatases, bring to acute excitotoxic cell death (Choi, 1992). One of the early events occurring by an ischemic episode in vivo and during oxygen and glucose deprivation (OGD) in vitro, is the release of substantial amounts of adenosine (Latini et al, 1998; Melani et al, 1999; Frenguelli et al, 2007)
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