Abstract
Cerebral ischemia is a multifactorial pathology characterized first by an acute injury, due to excitotoxicity, followed by a secondary brain injury that develops hours to days after ischemia. During ischemia, adenosine acts as an endogenous neuroprotectant. Few studies have investigated the role of A2B receptor in brain ischemia because of the low potency of adenosine for it and the few selective ligands developed so far. A2B receptors are scarcely but widely distributed in the brain on neurons, glial and endothelial cells and on hematopoietic cells, lymphocytes and neutrophils, where they exert mainly anti-inflammatory effects, inhibiting vascular adhesion and inflammatory cells migration. Aim of this work was to verify whether chronic administration of the A2B agonist, BAY60-6583 (0.1 mg/kg i.p., twice/day), starting 4 h after focal ischemia induced by transient (1 h) Middle Cerebral Artery occlusion (tMCAo) in the rat, was protective after the ischemic insult. BAY60-6583 improved the neurological deficit up to 7 days after tMCAo. Seven days after ischemia BAY60-6583 reduced significantly the ischemic brain damage in cortex and striatum, counteracted ischemia-induced neuronal death, reduced microglia activation and astrocytes alteration. Moreover, it decreased the expression of TNF-α and increased that of IL-10 in peripheral plasma. Two days after ischemia BAY60-6583 reduced blood cell infiltration in the ischemic cortex. The present study indicates that A2B receptors stimulation can attenuate the neuroinflammation that develops after ischemia, suggesting that A2B receptors may represent a new interesting pharmacological target to protect from degeneration after brain ischemia.
Highlights
Stroke is the second leading cause of death (Mozaffarian et al, 2015) and the third leading cause of disability (Murray et al, 2012) in Western Countries and is considered a disease of immense importance for public health, with serious economic and social consequences
Protracted neuroinflammation is recognized as the predominant mechanism of secondary brain injury progression, being characterized by damage to the endothelium and to the blood brain barrier (BBB) and infiltration of peripheral leukocytes and macrophages in brain parenchyma, that contribute to expand the ischemic damage
Treatment with BAY60-6583 significantly reduced the neurological deficit in comparison to vehicle-treated rats at 1, 5 and 7 days (*at least p < 0.02) after tMCAo
Summary
Stroke is the second leading cause of death (Mozaffarian et al, 2015) and the third leading cause of disability (Murray et al, 2012) in Western Countries and is considered a disease of immense importance for public health, with serious economic and social consequences. Only few studies have explored the role of A2B receptors in brain ischemia. It is well known that the acute pathogenic mechanisms after the ischemic insult consists of excitotoxicity and peri-infarct depolarization and that a few hours after the onset of ischemia, activation of microglia, the resident immune cells, and production or activation of inflammatory mediators take place (Dirnagl et al, 1999). Besides the approved treatment with tPA in the first hours after ischemia, an important strategy to counteract the ischemic damage is to control brain injury progression after ischemia. Studies in mice ablated of A2B receptors on bone marrow cells indicate an important contribution of vascular A2B receptors in attenuating vascular leakage during hypoxia (Eckle et al, 2008). It was found that activation of A2B receptors in a model of femoral artery injury is vasoprotective (Yang et al, 2006; Chen et al, 2011)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
