Activation of Alpha-7 Nicotinic Acetylcholine Receptor Reduces Brain Edema in Mice with Ischemic Stroke and Bone Fracture

Stroke is an important risk factor for bone fracture. We showed previously that bone fracture at the acute stage of ischemic stroke worsens, and activation of α-7 nicotinic acetylcholine receptor (α-7 nAChR) improves, stroke recovery by attenuating inflammation. We hypothesized that activation of α-7 nAChR also improves the blood-brain barrier (BBB) integrity. Permanent distal middle cerebral artery occlusion (pMCAO) was performed on 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 (MLA, α-7 nAChR antagonist), or saline 1 and 2 days after pMCAO. Brain water content, the expression of Monoamine Oxidase B (MAO-B), and tight junction protein (claudin-5) were assessed. We found that tibia fracture increased water content in the ischemic stroke brain (p = 0.006) and MAO-B-positive astrocytes (p < 0.001). PHA treatment reduced water content and MAO-B-positive astrocytes and increased claudin-5 expression in stroke and stroke + tibia fracture mice (p < 0.05), while MLA had the opposite effect. Our findings suggest that in addition to inhibiting inflammation, activation of α-7 nAChR also reduces brain edema, possibly through diminished astrocyte oxidative stress and improved BBB integrity. Thus, the α-7 nAchR-specific agonist could be developed into a new therapy for improving recovery of patients with stroke or stroke + bone fracture.