ar-r-17779 and Reperfusion-Injury

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.

Topics: alpha7 Nicotinic Acetylcholine Receptor; Animals; Brain; Bridged-Ring Compounds; Disease Models, Animal; Infarction, Middle Cerebral Artery; Ischemic Stroke; Male; Mice, Inbred C57BL; Microglia; Nicotinic Agonists; Reperfusion Injury; Signal Transduction; Spiro Compounds

Pre-injury vagal nerve stimulation protects against gut and lung injury after experimental hemorrhagic shock (HS). This likely occurs via the cholinergic anti-inflammatory pathway and the α7 nicotinic acetylcholine receptor (α7nAChR). We hypothesized that, in an in vitro model, either nicotine or a selective α7nAChR agonist (AR-R17779) would modulate intestinal and pulmonary effects of gut ischemia-reperfusion after hypoxic insult.. Confluent HT29 intestinal epithelial cells were co-cultured with Escherichia coli. Cell cultures were subjected to 21% (control) or 5% O2 (hypoxia) for 90 minutes followed by reoxygenation (H/R). HT29 cells were treated with nicotine or AR-R17779 before or immediately after hypoxic insult. From the HT29 cell culture supernatants, tumor necrosis factor-α and interleukin-6 levels were quantitated. Confluent pulmonary microvascular epithelial cells (HMVEC) were co-cultured with HT29 supernatants and permeability and intercellular adhesion molecule-1 expression were determined.. In post H/R insult treatments with the receptor agonist, cytokine levels in HT29 cells were reduced to control levels. In HMVEC experiments, a protective effect was seen with treatment post H/R injury. Disruption of HT29 actin microfilaments was demonstrated after H/R insult and was abrogated by both agonists.. Post-insult pharmacologic stimulation seems to mimic the protective effects of pre-HS vagal nerve stimulation seen in animal studies.

Topics: Bridged-Ring Compounds; Cell Hypoxia; HT29 Cells; Humans; Interleukin-6; Intestinal Mucosa; Intestines; Lung Injury; Nicotine; Reperfusion Injury; Spiro Compounds; Tumor Necrosis Factor-alpha; Vagus Nerve