Suppression of CXCL2 upregulation underlies the therapeutic effect of the retinoid Am80 on intracerebral hemorrhage in mice.

Abstract

We previously demonstrated that a synthetic retinoic acid receptor agonist, Am80, attenuated intracerebral hemorrhage (ICH)-induced neuropathological changes and neurological dysfunction. Because inflammatory events are among the prominent features of ICH pathology that are affected by Am80, this study investigated the potential involvement of proinflammatory cytokines/chemokines in the effect of Am80 on ICH. ICH induced by collagenase injection into mouse striatum caused prominent upregulation of mRNAs for interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-6, CXCL1, CXCL2, and CCL3. We found that dexamethasone (DEX) and Am80 differently modulated the increase in expression of these cytokines/chemokines; TNF-α expression was attenuated only by DEX, whereas CXCL2 expression was attenuated only by Am80. Expression of IL-1β and IL-6 was inhibited both by DEX and Am80. Neurological assessments revealed that Am80, but not DEX, significantly alleviated motor dysfunction of mice after ICH. From these results, we suspected that CXCL2 might be critically involved in determining the extent of motor dysfunction. Indeed, magnetic resonance imaging-based classification of ICH in individual mice revealed that invasion of hematoma into the internal capsule, which has been shown to cause severe neurological disabilities, was associated with higher levels of CXCL2 expression than ICH without internal capsule invasion. Moreover, a CXCR1/2 antagonist reparixin ameliorated neurological deficits after ICH. Overall, suppression of CXCL2 expression may contribute to the beneficial effect of Am80 as a therapeutic agent for ICH, and interruption of CXCL2 signaling may provide a promising target for ICH therapy.

• Authors: Hideaki Matsushita, Masanori Hijioka, Hayato Ishibashi, Junpei Anan, Yuki Kurauchi, Akinori Hisatsune, Takahiro Seki, Koichi Shudo, Hiroshi Katsuki
• Journal: Journal of neuroscience research (J Neurosci Res) Vol. 92 Issue 8 Pg. 1024-34 (Aug 2014) ISSN: 1097-4547 [Electronic] United States
• PMID: 24659080 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 Wiley Periodicals, Inc.

Chemical References

• Benzoates
• Chemokine CXCL2
• Cytokines
• Neuroprotective Agents
• Sulfonamides
• Tetrahydronaphthalenes
• tamibarotene
• reparixin

Topics

• Animals
• Benzoates (pharmacology, therapeutic use)
• Cerebral Hemorrhage (drug therapy, metabolism, pathology)
• Chemokine CXCL2 (genetics, metabolism)
• Cytokines (genetics, metabolism)
• Disease Models, Animal
• Male
• Mice
• Mice, Inbred C57BL
• Neuroprotective Agents (pharmacology, therapeutic use)
• Sulfonamides (pharmacology, therapeutic use)
• Tetrahydronaphthalenes (pharmacology, therapeutic use)
• Up-Regulation (drug effects)