期刊
JOURNAL OF NEUROCHEMISTRY
卷 131, 期 4, 页码 498-508出版社
WILEY
DOI: 10.1111/jnc.12817
关键词
macrophage polarization; middle cerebral artery occlusion; neuroinflammation; oxidative stress
资金
- NIH [P01 NS044155, R21 NS070153, R01 NS027713, R01 GM104194]
- Fondation des Gueules Cassees, Paris, France
Bone fracture at the acute stage of stroke exacerbates stroke injury by increasing neuroinflammation. We hypothesize that activation of -7 nicotinic acetylcholine receptor (-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 1day later. Mice were treated with 0.8mg/kg PHA 568487 (PHA, -7 nAchR-specific agonist), 6mg/kg methyllycaconitine (-7 nAchR antagonist), or saline 1 and 2days after pMCAO. Behavior was tested 3days 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 -7 nAchR agonist treatment reduces neuroinflammation and oxidative stress, which are associated with reduced brain injury in mice with ischemic stroke plus tibia fracture.
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