Alpha‐7 nicotinic acetylcholine receptor agonist treatment reduces neuroinflammation, oxidative stress, and brain injury in mice with ischemic stroke and bone fracture. (4th August 2014) - Han, Zhenying
Abstract Bone fracture at the acute stage of stroke exacerbates stroke injury by increasing neuroinflammation. We hypothesize that activation of α‐7 nicotinic acetylcholine receptor (α‐7 nAchR) attenuates neuroinflammation and oxidative stress, and reduces brain injury in mice with bone fracture and stroke. Permanent middle cerebral artery occlusion (pMCAO) was performed in C57BL/6J mice followed by tibia fracture 1 day later. Mice were treated with 0.8 mg/kg PHA 568487 (PHA, α‐7 nAchR‐specific agonist), 6 mg/kg methyllycaconitine (α‐7 nAchR antagonist), or saline 1 and 2 days after pMCAO. Behavior was tested 3 days after pMCAO. Neuronal injury, CD68+, M1 (pro‐inflammatory) and M2 (anti‐inflammatory) microglia/macrophages, phosphorylated p65 component of nuclear factor kappa b in microglia/macrophages, oxidative and anti‐oxidant gene expression were quantified. Compared to saline‐treated mice, PHA‐treated mice performed better in behavioral tests, had fewer apoptotic neurons (NeuN+TUNEL+), fewer CD68+ and M1 macrophages, and more M2 macrophages. PHA increased anti‐oxidant gene expression and decreased oxidative stress and phosphorylation of nuclear factor kappa b p65. Methyllycaconitine had the opposite effects. Our data indicate that α‐7 nAchR agonist treatment reduces neuroinflammation and oxidative stress, which are associated with reduced brain injury in mice with ischemic stroke plus tibia fracture. Bone fracture at the acute stage of stroke exacerbates neuroinflammation, oxidative stress, and brain injury, and our study has shown that the α‐7 nAchR agonist, PHA (PHA 568487), attenuates neuroinflammation, oxidative stress, and brain injury in mice with stroke and bone fracture. Hence, PHA could provide an opportunity to develop a new strategy to reduce brain injury in patients suffering from stroke and bone fracture.