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

ABSTRACT: 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.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-1?, 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.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-1?, and interleukin-6. These effects of LXA4 were abolished by FPR2 siRNA.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.

SUBMITTER: Guo Z

PROVIDER: S-EPMC4729632 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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

Guo Zongduo Z Hu Qin Q Xu Liang L Guo Zhen-Ni ZN Ou Yibo Y He Yue Y Yin Cheng C Sun Xiaochuan X Tang Jiping J Zhang John H JH

Stroke 20160105 2

<h4>Background and purpose</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 26732571

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Project description:BackgroundSpinal cord injury (SCI) is a severe neurological disorder with many disabling consequences, including persistent neuropathic pain, which develops in about 40 % of SCI patients and is induced and sustained by excessive and uncontrolled spinal neuroinflammation. Here, we have evaluated the effects of lipoxin A4 (LXA4), a member of a unique class of endogenous lipid mediators with both anti-inflammatory and analgesic properties, on spinal neuroinflammation and chronic pain in an experimental model of SCI.MethodsSpinal hemisection at T10 was carried out in adult male CD1 mice and Wistar rats. To test if LXA4 can reduce neuroinflammation and neuropathic pain, each animal received two intrathecal injections of LXA4 (300 pmol) or vehicle at 4 and 24 h after SCI. Sensitivity to mechanical stimulation of the hind paws was evaluated using von Frey monofilaments, and neuroinflammation was tested by measuring the mRNA and/or protein expression levels of glial markers and cytokines in the spinal cord samples after SCI. Also, microglia cultures prepared from murine cortical tissue were used to assess the direct effects of LXA4 on microglial activation and release of pro-inflammatory TNF-α.ResultsLXA4 treatment caused significant reductions in the intensity of mechanical pain hypersensitivity and spinal expression levels of microglial markers and pro-inflammatory cytokines induced by SCI, when compared to rodents receiving control vehicle injections. Notably, the increased expressions of the microglial marker IBA-1 and of the pro-inflammatory cytokine TNF-α were the most affected by the LXA4 treatment. Furthermore, cortical microglial cultures expressed ALX/FPR2 receptors for LXA4 and displayed potentially anti-inflammatory responses upon challenge with LXA4.ConclusionsCollectively, our results suggest that LXA4 can effectively modulate microglial activation and TNF-α release through ALX/FPR2 receptors, ultimately reducing neuropathic pain in rodents after spinal cord hemisection. The dual anti-inflammatory and analgesic properties of LXA4, allied to its endogenous nature and safety profile, may render this lipid mediator as new therapeutic approach for treating various neuroinflammatory disorders and chronic pain with only limited side effects.

Dataset Information

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

Publications

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

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