Sumiyoshi Manabu, Satomi Junichiro, Kitazato Keiko T, Yagi Kenji, Shimada Kenji, Kurashiki Yoshitaka, Korai Masaaki, Miyamoto Takeshi, Suzue Ryoko, Kuwayama Kazuyuki, Nagahiro Shinji
Department of Neurosurgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Department of Neurosurgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
J Stroke Cerebrovasc Dis. 2015 Jun;24(6):1187-95. doi: 10.1016/j.jstrokecerebrovasdis.2015.01.009. Epub 2015 Apr 25.
High mobility group box 1 (HMGB1) elevation after cerebral ischemia activates inflammatory pathways via receptors such as the receptor for advanced glycation end products (RAGE) and toll-like receptors (TLRs) and leads to brain damage. Eicosapentaenoic acid (EPA), a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, attenuates postischemic inflammation and brain damage in male animals. However, postischemic HMGB1 signaling and the effects of EPA on ovariectomized (OVX(+)) rats remain unclear. We hypothesized that EPA attenuates brain damage in OVX(+) rats via the inhibition of HMGB1 signaling in a PPARγ-dependent manner. Seven-week-old female Sprague-Dawley rats were divided into 3 groups; nonovariectomized (OVX(-)) rats and EPA-treated and EPA-untreated OVX(+) rats before cerebral ischemia induction. Another set of EPA-treated OVX(+) rats was injected with the PPARγ inhibitor GW9662. OVX(+) decreased the messenger RNA level of PPARγ and increased that of HMGB1, RAGE, TLR9, and tumor necrosis factor alpha (TNFα) in parallel with ischemic brain damage. EPA restored the PPARγ expression, downregulated the HMGB1 signal-related molecules, and attenuated the ischemic brain damage. Neither OVX(+) nor EPA affected the expression of TLR2 or TLR4. Interestingly, GW9662 partially abrogated the EPA-induced neuroprotection and the downregulation of RAGE and TLR9. In contrast, GW9662 did not affect HMGB1 or TNFα. These results suggest that EPA exerts PPARγ-dependent and PPARγ-independent effects on postischemic HMGB1/TLR9 pathway. The cortical infarct volume exacerbated by OVX(+) is associated with the upregulation of the HMGB1/TLR9 pathway. Suppression of this pathway may help to limit ischemic brain damage in postmenopausal women.
脑缺血后高迁移率族蛋白B1（HMGB1）水平升高会通过晚期糖基化终末产物受体（RAGE）和Toll样受体（TLR）等受体激活炎症通路，进而导致脑损伤。二十碳五烯酸（EPA）是一种过氧化物酶体增殖物激活受体γ（PPARγ）激动剂，可减轻雄性动物缺血后的炎症反应和脑损伤。然而，缺血后HMGB1信号传导以及EPA对去卵巢（OVX(+)）大鼠的影响仍不清楚。我们推测，EPA通过以PPARγ依赖的方式抑制HMGB1信号传导来减轻OVX(+)大鼠的脑损伤。将7周龄雌性Sprague-Dawley大鼠分为3组；未去卵巢（OVX(-)）大鼠以及在脑缺血诱导前接受EPA治疗和未接受EPA治疗的OVX(+)大鼠。另一组接受EPA治疗的OVX(+)大鼠注射了PPARγ抑制剂GW9662。OVX(+)会降低PPARγ的信使RNA水平，并与缺血性脑损伤同时增加HMGB1、RAGE、TLR9和肿瘤坏死因子α（TNFα）的信使RNA水平。EPA恢复了PPARγ的表达，下调了HMGB1信号相关分子，并减轻了缺血性脑损伤。OVX(+)和EPA均未影响TLR2或TLR4的表达。有趣的是，GW9662部分消除了EPA诱导的神经保护作用以及RAGE和TLR9的下调。相比之下，GW9662不影响HMGB1或TNFα。这些结果表明，EPA对缺血后HMGB1/TLR9通路发挥PPARγ依赖和PPARγ非依赖的作用。OVX(+)加剧的皮质梗死体积与HMGB1/TLR9通路的上调有关。抑制该通路可能有助于限制绝经后女性的缺血性脑损伤。
