Abstract
Inflammation plays a central role in stroke-induced brain injury. The alpha7 nicotinic acetylcholine receptor (α7nAChR) can modulate immune responses in both the periphery and the brain. The aims of the present study were to investigate α7nAChR expression in different brain regions and evaluate the potential effect of the selective α7nAChR agonist AR-R17779 on ischemia–reperfusion brain injury in mice. Droplet digital PCR (ddPCR) was used to evaluate the absolute expression of the gene encoding α7nAChR (Chrna7) in hippocampus, striatum, thalamus and cortex in adult, naïve mice. Mice subjected to transient middle cerebral artery occlusion (tMCAO) or sham surgery were treated with α7nAChR agonist AR-R17779 (12 mg/kg) or saline once daily for 5 days. Infarct size and microglial activation 7 days after tMCAO were analyzed using immunohistochemistry. Chrna7 expression was found in all analyzed brain regions in naïve mice with the highest expression in cortex and hippocampus. At sacrifice, white blood cell count was significantly decreased in AR-R17779 treated mice compared with saline controls in the sham groups, although, no effect was seen in the tMCAO groups. Brain injury and microglial activation were evident 7 days after tMCAO. However, no difference was found between mice treated with saline or AR-R17779. In conclusion, α7nAChR expression varies in different brain regions and, despite a decrease in white blood cells in sham mice receiving AR-R17779, this compound does not affect stroke-induced brain injury.
Highlights
Stroke is the third leading cause of death [1] and the leading cause of disabilities [2] in the western world, with ischemic stroke accounting for 80% of all stroke incidents
Chrna7 expression patterns were investigated in different brain regions known to be affected by the transient middle cerebral artery occlusion model
We further characterized microglial activation in the brain by phenotype scoring in sections stained with the microglia marker ionized calcium-binding adapter molecule 1 (Iba-1). transient middle cerebral artery occlusion (tMCAO) surgery per se caused microglial activation compared with mice undergoing sham surgeries (Figure 2E–J)
Summary
Stroke is the third leading cause of death [1] and the leading cause of disabilities [2] in the western world, with ischemic stroke accounting for 80% of all stroke incidents. Despite increasing knowledge about the molecular mechanisms involved in stroke pathology, pharmacological treatment is still limited to tissue plasminogen activators (tPA) that act by breaking down clot formation [3]. Only one in seven patients show reduced disability even when tPA is administered 3.0–4.5 h after stroke onset [3]. Blood flow is disrupted and the tissue suffers from oxygen and nutrient deficit, resulting in several biochemical events eventually leading to neuronal cell death at the center of the infarct [4]. Neuronal cell death causes danger-associated molecular patterns (DAMPs) to be released, initiating an inflammatory response where both the innate and adaptive immune system
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