Lipoxin A4 Reduces Inflammation Through Formyl Peptide Receptor 2/p38 MAPK Signaling Pathway in Subarachnoid Hemorrhage Rats

Zongduo Guo, MD, PhD*;Qin Hu, MD, PhD*;Liang Xu, MD;Zhen-Ni Guo, MD;Yibo Ou, MD, PhD;Yue He, MD, PhD;Cheng Yin, MD, PhD;Xiaochuan Sun, MD, PhD;Jiping Tang, MD;John H. Zhang, MD, PhD

Background and Purpose—Lipoxin A4 (LXA4) has been reported to reduce inflammation in several neurological injury models. We studied the effects of LXA4 on neuroinflammation after subarachnoid hemorrhage (SAH) in a rat model.

Methods—Two hundred and thirty-eight Sprague–Dawley male rats, weight 280–320 g, were used. Exogenous LXA4 (0.3 and 1.0 nmol) were injected intracerebroventricularly at 1.5 hours after SAH. Neurological scores, brain water content, and blood–brain barrier were evaluated at 24 hours after SAH; Morris water maze and T-maze tests were examined at 21 days after SAH. The expression of endogenous LXA4 and its receptor formyl peptide receptor 2 (FPR2), as well as p38, interleukin-1β, and interleukin-6 were studied either by ELISA or by Western blots. Neutrophil infiltration was observed by myeloperoxidase staining. FPR2 siRNA was used to knock down LXA4 receptor.

Results—The expression of endogenous LXA4 decreased, and the expression of FPR2 increased after SAH. Exogenous LXA4 decreased brain water content, reduced Evans blue extravasation, and improved neurological functions and improved the learning and memory ability after SAH. LXA4 reduced neutrophil infiltration and phosphorylation of p38, interleukin-1β, and interleukin-6. These effects of LXA4 were abolished by FPR2 siRNA.

Conclusions—Exogenous LXA4 inhibited inflammation by activating FPR2 and inhibiting p38 after SAH. LXA4 may serve as an alternative treatment to relieve early brain injury after SAH.

Stroke.2016;47:490-497