Abstract W P98: Activation of α7 Nicotinic Acetylcholine Receptor Reduces Pro-Inflammatory Macrophage and Improves Ischemic Stroke Recovery
Background and Purpose: Inflammation influences stroke recovery. Activation of α7 nicotinic acetylcholine receptor (α7 nAchR) attenuates inflammation. We hypothesize that α7 nAchR agonist treatment reduces pro-inflammatory macrophages (M1) and improves ischemic stroke recovery.
Methods: C57BL/6 mice underwent permanent distal middle cerebral artery occlusion (pMCAO). They were randomly assigned to 7 groups: injected intraperitoneally with 0.4 or 0.8 mg/Kg PHA568487 (PHA, α7 nAchR agonist), 4 or 6 mg/Kg methyllycaconitine (MLA, α7 nAchR antagonist), or saline immediately after pMCAO, or with 0.8 mg/Kg PHA or 6 mg/kg MLA immediately and 24 hours after pMCAO. Behavior was assessed by corner and adhesive removal tests at 3, 7, and 14 days after pMCAO (n=12). Atrophic volume (n=7) and the percentage of total (CD68+) and M1 (CD11b+/Iba1+) macrophages (n=6) among total cells in the peri-infarct region were quantified 14 days after pMCAO. The expression of M1 (CD11b and iNOS) and M2 marker (CD206) were quantified using real-time RT-PCR (n=4).
Results: Compared to the saline-treated mice, those treated with two doses of 0.8 mg/kg PHA performed better in both behavioral tests at 3 (adhesive: p=0.01, corner: p=0.02) and 7 (adhesive: p=0.005, corner: p=0.03) days, and in the adhesive removal test at 14 days (p=0.004) after pMCAO. They had smaller atrophic volume (16±7 mm3 vs 26±5 mm3, p=0.008), and fewer total (9±2.5% vs 15.8±1.7%, p<0.001) and M1 (14±2.3% vs 20.6±4.2%, p=0.005) macrophages. Mice treated with two doses of 6 mg/kg MLA performed worse in the behavioral tests at all times (p<0.05), had larger atrophic volume (48±20 mm3, p=0.03), and more total (25±4.2%, p=0.0003) and M1 macrophages (28±4.5%, p=0.01). The expression of CD11b and iNOS decreased (p<0.05) in the PHA group, and increased (p=0.01) in the MLA group. CD206 expression increased (p=0.04) in the PHA group and did not change in the MLA group. One-dose treatment had no effect.
Conclusions: Activation of α7 nAchR reduces pro-inflammatory macrophages in the peri-infarct region, which is associated with reduction of atrophic volume and improvement of behavioral recovery.
Author Disclosures: Z. Han: None. F. Shen: None. Y. He: None. V. Degos: None. M. Camus: None. M. Wankhede: None. M. Maze: None. W. Young: None. H. Su: None.
- © 2014 by American Heart Association, Inc.