Suppression of CXCL2 Upregulation Underlies the Therapeutic Effect of the Retinoid Am80 on Intracerebral Hemorrhage in Mice
Suppression of CXCL2 Upregulation Underlies the Therapeutic Effect of the Retinoid Am80 on Intracerebral Hemorrhage in Mice
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DOI：
10.1002/jnr.23379
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发表时间：
2014-08-01
影响因子：
4.2
通讯作者：
Katsuki, Hiroshi
中科院分区：
文献类型：
--
作者：
Matsushita, Hideaki;Hijioka, Masanori;Katsuki, Hiroshi
我们先前证明，合成的维甲酸受体激动剂Am80可以减轻脑出血(ICH)引起的神经病理改变和神经功能障碍。由于炎症事件是AM80影响的脑出血病理的显著特征之一，本研究探讨了促炎细胞因子/趋化因子在AM80对脑出血的影响中的潜在参与。小鼠纹状体注射胶原酶诱导的ICH可显著上调IL-1β、肿瘤坏死因子-α、IL-6、CXCL1、CXCL2和CCL3的mRNAs表达。我们发现，地塞米松(DEX)和AM80对这些细胞因子/趋化因子表达的增加有不同的调节作用；仅地塞米松(DEX)可减弱肿瘤坏死因子-α的表达，而CXCL2的表达仅可被AM80减弱。地塞米松和Am80均能抑制IL-1β和IL-6的表达。神经学评估显示，AM80，而不是DEX，显著缓解了脑出血后小鼠的运动功能障碍。根据这些结果，我们怀疑CXCL2可能在决定运动功能障碍的程度中起关键作用。事实上，基于磁共振成像的单个小鼠脑出血分类显示，血肿侵入内囊导致严重的神经功能障碍，与没有内囊侵犯的脑出血相比，CXCL2的表达水平更高。此外，CXCR1/2拮抗剂瑞帕利欣可改善脑出血后的神经功能障碍。总之，抑制CXCL2的表达可能有助于AM80作为脑出血的治疗药物，而阻断CXCL2信号可能为脑出血的治疗提供一个有希望的靶点。(C)2014年威利期刊公司。
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)-1 beta, tumor necrosis factor (TNF)-alpha, IL-6, CXCL1, CXCL2, and CCL3. We found that dexamethasone (DEX) and Am80 differently modulated the increase in expression of these cytokines/chemokines; TNF-alpha expression was attenuated only by DEX, whereas CXCL2 expression was attenuated only by Am80. Expression of IL-1 beta 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. (C) 2014 Wiley Periodicals, Inc.