吡格列酮对脂多糖诱导的星形胶质细胞炎性细胞因子释放的影响

目的研究吡格列酮对脂多糖(LPS)诱导的星形胶质细胞炎症介质释放的抑制作用及其信号传导通路。方法神经胶质酸性蛋白(glial fibrillary acid protein,GFAP)免疫荧光染色法鉴定星形胶质细胞纯度。ELISA方法检测IL-1β、IL-6和TNF-α蛋白表达量的变化。Griess法测定培养细胞上清液中一氧化氮(NO)含量。结果星形胶质细胞经GFAP免疫荧光鉴定,其阳性率可达95%以上。LPS组能明显增加星形胶质细胞分泌IL-1β、IL-6、TNF-α及NO。吡格列酮能明显抑制LPS引起的这些作用,并呈一定浓度依赖性。过氧化物酶体增殖物激活受体γ(PPARγ)的特异性阻断剂GW9662能明显对抗吡格列酮对LPS引起的IL-1β、IL-6、TNF-α及NO增加的抑制作用。与LPS组相比,JNK特异性阻断剂SP600125(5μmol·L-1)亦能有效对抗LPS诱导星形胶质细胞IL-1β、IL-6、TNF-α及NO分泌的增加;特异性iNOS抑制剂SMT可明显抑制LPS引起的NO分泌增加。结论吡格列酮能明显改善LPS诱导的大鼠皮层星形胶质细胞的损伤,这种作用可能与激活PPARγ、抑制JNK信号传导通路有关。     

吡格列酮对脂多糖刺激的星形胶质细胞白介素-1β的抑制作用及机制

目的研究吡格列酮(Pio)对脂多糖(LPS)诱导的星形胶质细胞白介素-1β(IL-1β)抑制作用及JNK信号传导通路对其的影响。方法 ELISA法测定培养液中IL-1β的含量;免疫荧光染色法观察星形胶质细胞IL-1β的蛋白表达;Western blot检测星形胶质细胞磷酸化JNK1和磷酸化c-Jun蛋白表达水平的改变。结果星形胶质细胞在LPS(10 mg.L-1)刺激下IL-1β的含量、蛋白表达以及磷酸化JNK1、磷酸化c-Jun蛋白水平与正常对照组比较均增高。特异性JNK特异性阻断剂SP600125(10.0μmol.L-1)可明显抑制LPS引起的IL-1β产生增加;Pio(0.1、1.0、10.0μmol.L-1)则可降低IL-1β产生,抑制IL-1β的蛋白表达及下调p-JNK1、p-c-Jun蛋白水平。结论 Pio能明显抑制LPS诱导的大鼠皮层星形胶质细胞IL-1β表达增加,这种作用可能与其下调JNK信号转导通路有关。     

PPARγ参与吡格列酮的镇痛作用

目的:在动物疼痛模型上,观察过氧化物酶体增殖剂激活受体γ(peroxisome proliferator-activa-ted receptor gamma,PPARγ)激动剂吡格列酮(pioglitazone,Piog)的镇痛作用及其与PPARγ的关系。方法:采用腹腔注射(0.78,1.25和2 mg.kg-1,ip)和脑室注射(0.02和0.04 mg.kg-1,icv)给予Piog,应用小鼠扭体反应测定痛阈;预先注射PPARγ的特异性抑制剂GW9662(0.5和1 mg.kg-1,ip或5和10μg.kg-1,icv)研究Piog的镇痛作用与PPARγ的关系。结果:Piog(0.78,1.25和2 mg.kg-1,ip)在小鼠扭体实验中呈现出剂量依赖性镇痛作用。脑室注射Piog(0.02和0.04 mg.kg-1,icv,外周剂量的1/50)亦出现镇痛作用。PPARγ的特异性抑制剂GW9662(1 mg.kg-1,ip或5,10μg.kg-1,icv)均能取消Piog的镇痛作用。结论:Pi-og具有镇痛作用,中枢神经系统可能参与Piog的镇痛作用。PPARγ尤其是中枢的PPARγ可能与Piog的镇痛作用...     

吡格列酮在大鼠放射性肺纤维化中保护作用的研究

目的探讨吡格列酮在放射性肺纤维化中的保护作用,以及对AT1R(血管紧张素Ⅱ1型受体表达的影响。方法 SD大鼠60只,共分为5组。空白组:不接受任何干预;照射+安慰剂组:接受12 Gy照射+安慰剂干预;单独给药组:接受吡格列酮10 mg/(kg·d)干预;照射+吡格列酮a组:接受12 Gy照射+吡格列酮10 mg/(kg·d)干预;照射+吡格列酮b组:接受12 Gy照射+吡格列酮20 mg/(kg·d)干预。采用HE及M asson染色观察大鼠肺组织纤维化情况;采用免疫组化观察AT1R在肺组织中的分布情况;采用蛋白免疫印迹杂交及RT-PCR检测AT1R蛋白及mRNA的表达情况。结果 HE及M asson染色显示,受照射大鼠肺组织细胞出现变性、坏死,肺组织出现明显纤维化;大鼠给予吡格列酮干预后,受照射大鼠的肺组织损伤减轻,肺组织纤维化减轻;免疫组化提示,照射后大鼠肺组织及上皮细胞中AT1R表达较空白组及单独给药组明显,照射+吡格列酮组的AT1R表达较照射+安慰剂组少;Western blot及RT-PCR提示,接受吡格列酮干预的受照射大鼠,AT1R蛋白及mRNA表达水平被明显抑制。结论吡格列酮在放射性肺纤维化中具有保护作用,其可能通过下调AT1的表达来实现对放射性肺损伤的保护作用。     

吡格列酮对淀粉样β蛋白片段1-42引起的大鼠海马神经细胞凋亡相关蛋白表达的影响

目的研究吡格列酮(Pio)对淀粉样β蛋白片段1-42(Aβ1-42)所致大鼠海马神经细胞凋亡的抑制作用及作用机制。方法大鼠随机分为5组,即正常对照组,Aβ1-42损伤组,Aβ1-42+Pio20,40及80mg·kg-1组。于d1和2,Pio处理组大鼠灌胃给予Pio,正常对照组和Aβ1-42损伤组灌胃给予0.2%二甲亚砜。d2给药处理后,Aβ1-42损伤组及Pio处理组大鼠左侧脑室内单次注射Aβ1-425μL(2.0mmol·L-1)制备大鼠痴呆模型,正常对照组注射等量的生理盐水。再连续给药6d后,取海马CA1区,用Western蛋白印迹法检测半胱氨酸天冬氨酸蛋白酶(caspase)3,caspase7,caspase9及μ-钙蛋白酶和多聚ADP-核糖聚合酶(PARP)蛋白表达水平的变化。结果脑室内注射Aβ1-42可使大鼠海马CA1区活化的caspase3,caspase7,caspase9蛋白及μ-钙蛋白酶表达水平明显增高,分子质量116kuPARP表达明显减少,而分子质量89ku劈切PARP表达明显增加。Pio40及80mg·kg-1可明显抑制Aβ1-42所致海马CA1区活化的caspase9和μ-钙蛋白酶表达增加,也可明显抑制Aβ1-42所致的PARP表达的改变。但Pio20mg·kg-1对Aβ1-42所致海马caspase9,μ-钙蛋白酶和PARP表达无明显作用。Pio20,40及80mg·kg-1均可抑制Aβ1-42所致海马CA1区活化的caspase3和caspase7表达增加。结论Pio对Aβ1-42引起的海马神经细胞凋亡具有明显的抑制作用。     

PPARγ激动剂吡格列酮抑制胶质瘤细胞生长、凋亡的实验研究

目的探讨过氧化物酶体增长因子活化受体了激动剂（PPARγ）吡格列酮抑制胶质瘤细胞生长的机制。方法应用细胞增殖力测定、AO／EB荧光染色、流式细胞仪检测吡格列酮抑制胶质瘤细胞生长的情况。结果吡格列酮对胶质瘤细胞株U-251的生长有抑制作用,并呈时间与剂量依赖关系（P〈0．05）;可诱导胶质瘤细胞的凋亡,呈时间依赖关系（P〈0．05）,并出现细胞凋亡征象。结论PPARγ激动剂吡格列酮对胶质瘤细胞U-251具有生长抑制作用。其可诱导胶质瘤细胞凋亡可能是细胞生长抑制的机制之一。     

吡格列酮对HepG2细胞增殖和凋亡的影响及机制研究

目的观察吡格列酮对体外培养的HepG2细胞增殖和凋亡的影响,并探讨其是否通过PPARγ依赖途径发挥上述药理作用。方法将不同浓度的吡格列酮作用于体外培养HepG2细胞,以MTT比色法检测HepG2细胞增殖情况,以3H-TdR参入实验检测细胞DNA合成速率,采用RT-PCR和Western blot检测PPARγmRNA和蛋白的表达,以流式细胞术检测细胞凋亡和细胞周期;同时观察PPARγ特异性拮抗剂GW9662和(或)瞬时转染pSG5-PPARγ真核表达质粒对吡格列酮细胞增殖作用的影响;并将PPARγ小干扰RNA(pGCsi-PPARγ)表达质粒稳定转染HepG2细胞,观察PPARγ沉默后吡格列酮对HepG2细胞增殖作用的影响。结果吡格列酮作用于HepG2细胞后,导致HepG2细胞的增殖受到抑制、DNA合成速率减慢,并诱导细胞凋亡,呈一定的剂量依赖关系;在此过程中,G0/G1期细胞比例明显增加,S期细胞比例明显减少,但PPARγmRNA和蛋白的表达没有变化;GW9662部分拮抗吡格列酮的增殖抑制作用,但转染pSG5-PPARγ真核表达质粒可以逆转GW9662的作用;吡格列酮在高浓度(20μmol.L-1)时对pGCsi-PPARγ表达质粒稳定转染的HepG2细胞仍表现出增殖抑制作用。结论吡格列酮能够抑制HepG2细胞的增殖并诱导凋亡,具有潜在的抗瘤作用,这种作用与其诱导细胞G0/G1期的停滞有关,PPARγ依赖和非依赖途径参与上述过程。     

地塞米松与吡格列酮对哮喘T_H1/T_H2细胞因子作用机制的比较

目的初步探讨地塞米松(DXM)和过氧化物酶增殖活化受体γ(PPARγ)激动剂吡格列酮对哮喘模型TH1/TH2细胞因子表达的影响及其机制,并比较二者的异同。方法24只Balb/c小鼠随机分为正常对照组、哮喘组、地塞米松组和吡格列酮组,每组各6只。采用W estern b lot方法检测各组小鼠肺组织T-bet和GATA3的表达,同时运用流式细胞仪检测小鼠脾细胞胞内白介素4(IL-4)和干扰素γ(IFNγ)的表达。结果哮喘模型鼠脾细胞内IL-4/IFNγ比值与正常组相比明显升高(P<0.01),经DXM治疗后,IL-4/IFNγ比值明显降低,肺组织GATA 3和T-bet的表达均减低(P<0.01),但GATA 3比T-bet减低更明显;而经吡格列酮治疗后,不仅IL-4/IFNγ比值明显降低(P<0.01),同时肺组织T-bet的表达也明显增高(P<0.01),但GATA3无变化(P>0.05)。结论地塞米松与吡格列酮对哮喘TH1/TH2细胞因子的调节及机制有所不同,地塞米松同时抑制GATA3和T-bet的表达,从而扭转了IL-4和IFNγ的比值;而吡格列酮可能通过参与调控TH1细胞转化过程中重要转录因子T-bet的表达,改变IL-4/IFNγ比值,从而改善相应的炎性症状。     

吡格列酮与罗格列酮的药理作用机制有哪些异同？

答吡格列酮和罗格列酮均为噻唑烷二酮类降糖药物,其作用机理均通过激活过氧化物酶体增殖物活化受体-γ（PPAR—γ）,从而增加肝脏以外的组织,如脂肪和肌肉细胞的胰岛素敏感性来降低血糖。由于吡格列酮和罗格列酮的分子结构不同,吡格列酮高选择性地作用于PPAR-γ,因此它们在心血管的安全性方面可能存在差异。     

甘草黄酮抑制脂多糖诱导的小胶质细胞诱导型一氧化氮合酶表达

目的探究甘草黄酮(Gla)对脂多糖(LPS)诱导的BV-2小胶质细胞一氧化碳(NO)生成和诱导型一氧化氮合酶(i NOS)表达影响。方法将BV-2细胞分为对照组、LPS组和Gla处理组,并进行相应处理。采用NO试剂盒检测NO释放量;转录聚合酶链反应(RT-PCR)法检测i NOS m RNA表达量;免疫荧光染色显示i NOS蛋白在BV-2细胞表达情况。结果 LPS刺激可显著增加BV-2小胶质细胞NO释放量和i NOS mRNA生成量(P<0.01),造成大量i-NOS阳性细胞出现,细胞体积增大,突起变粗短。Gla处理则可显著降低BV-2细胞NO释放量和i NOS mRNA生成量(P<0.01),同时i NOS阳性细胞数明显减少,细胞体积缩小,突起变细长。结论 Gla可调节BV-2细胞i-NOS表达,抑制LPS诱导的小胶质细胞神经炎症。     

Ferulic acid inhibits nitric oxide-induced apoptosis by enhancing GABA81 receptor expression in transient focal cerebral ischemia in rats

Aim:

Ferulic acid (4-hydroxy-3-methoxycinnamic acid, FA) provides neuroprotection against apoptosis in a transient middle cerebral artery occlusion (MCAo) model. This study was to further investigate the anti-apoptotic effect of FA during reperfusion after cerebral ischemia.

Methods:

Rats were subjected to 90 min of cerebral ischemia followed by 3 or 24 h of reperfusion after which they were sacrificed.

Results:

Intravenous FA (100 mg/kg) administered immediately after middle cerebral artery occlusion (MCAo) or 2 h after reperfusion effectively abrogated the elevation of postsynaptic density-95 (PSD-95), neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase (iNOS), nitrotyrosine, and cleaved caspase-3 levels as well as apoptosis in the ischemic cortex at 24 h of reperfusion. FA further inhibited Bax translocation, cytochrome c release, and p38 mitogen-activated protein (MAP) kinase phosphorylation. Moreover, FA enhanced the expression of gamma-aminobutyric acid type B receptor subunit 1 (GABA_B1) in the ischemic cortex at 3 and 24 h of reperfusion. In addition, nitrotyrosine-positive cells colocalized with cleaved caspase-3-positive cells, and phospho-p38 MAP kinase-positive cells colocalized with nitrotyrosine- and Bax-positive cells, indicating a positive relationship among the expression of nitrotyrosine, phospho-p38 MAP kinase, Bax, and cleaved caspase-3. The mutually exclusive expression of GABA_B1 and nitrotyrosine revealed that there is a negative correlation between GABA_B1 and nitrotyrosine expression profiles. Additionally, pretreatment with saclofen, a GABA_B receptor antagonist, abolished the neuroprotection of FA against nitric oxide (NO)-induced apoptosis.

Conclusion:

FA significantly enhances GABA_B1 receptor expression at early reperfusion and thereby provides neuroprotection against p38 MAP kinase-mediated NO-induced apoptosis at 24 h of reperfusion.     

CCl_4诱导的大鼠肝纤维化模型肝纤维化逆转与MAPK信号通路的研究

目的通过检测CCl4诱导肝纤维化大鼠逆转恢复各时期MAPK信号通路蛋白动态变化,研究其在肝纤维化恢复期可能的调控作用。方法采用CCl4皮下注射SD大鼠12周,复制肝纤维化模型,分别于注射12周,停药后2、4、6、8周取材。通过检测各组ALT、AST、Hyp、LN、PⅢNP的含量变化和肝脏病理组织切片Masson染色,加以验证。采用West-ern blot法检测各组肝组织中MAPK通路蛋白表达。结果 ALT、AST、Hyp、LN、PⅢNP等反映肝损伤和纤维化进程的指标在第12周最高,即模型组最高,并且随着肝纤维化逆转而含量逐渐降低,Masson染色结果与之一致,表明大鼠肝纤维化模型期与各恢复期模型建立完成。p-ERK1/2在模型组表达明显降低,与正常组相比差异有显著性(P<0.01),恢复4周表达明显升高,与模型组相比差异有显著性(P<0.01),以后逐渐降低。p-JNK1/2在模型组表达明显降低(P<0.01),恢复期逐渐升高(P<0.05)。p-p38在模型组表达明显升高(P<0.01),恢复期逐渐降低(P<0.05)。p-ERK/ERK与Hyp相关系数r=-0.46,P=0.003;p-JNK/JNK与Hyp相关系数r=-0.53,P=0.0004;p-p38/p38与Hyp相关系数r=0.81,P=0.0001。结论 MAPK信号通路中的ERK、JNK和p38信号通路在肝纤维化逆转中发挥重要作用。     

吡格列酮对淀粉样β蛋白片段1-42引起的大鼠海马c-Jun氨基端激酶信号传导通路改变的作用

目的探讨吡格列酮(Pio)对淀粉样β蛋白片段1-42(Aβ1-42)所致大鼠海马神经细胞损伤保护作用的信号传导机制。方法 SD大鼠左侧脑单次icv给予5μlAβ1-422.0mmol.L-1制备大鼠痴呆模型。65只大鼠随机分为正常对照组、Aβ1-42模型组及Pio20,40和80mg.kg-1组;Pio组大鼠在icv单次给予Aβ1-42前24h先ig给予Pio20,40及80mg.kg-1,每天一次,连续给药7d。Western印迹法检测海马CA1区磷酸化丝裂原激活蛋白激酶激酶4(MKK4)、磷酸化c-Jun氨基端激酶1(JNK1)和磷酸化c-Jun的蛋白表达水平;应用激光共聚焦显微镜观察磷酸化JNK在小胶质细胞表达部位。结果与正常对照组比较,Aβ1-42模型组大鼠icv给予Aβ1-42后,可引起海马CA1区磷酸化的MKK4,JNK1和c-Jun的表达明显增加(P<0.01);与Aβ1-42模型组比较,Pio20,40和80mg.kg-1可剂量依赖性地对抗Aβ1-42引起的磷酸化MKK4,JNK1和c-Jun表达的增加(P<0.01),Pio40mg.kg-1使磷酸化MKK4蛋白与总量MKK4蛋白之比从Aβ1-42模型组的1.02±0.35降低到0.44±0.06,磷酸化JNK1从0.94±0.17降低到0.55±0.05,磷酸化c-Jun从4.64±0.41降低到2.48±0.12(P<0.01)。荧光免疫组织化学双染,激光共聚焦显微镜观察结果显示,磷酸化的JNK主要在小胶质细胞表达。结论 Pio通过抑制小胶质细胞内JNK激酶信号传导通路的活化,对抗Aβ1-42引起的海马神经细胞损伤。     

Role of nitric oxide produced by constitutive and inducible nitric oxide synthases in the mouse gastric fundus

In the present study, the role of nitric oxide (NO) produced by constitutive and inducible nitric oxide synthases (cNOS and iNOS, resepctively) on the contraction and relaxation of fundus in normal and lipopolysaccharide (LPS)-treated mice was examined. A whole fundic ring isolated from mice pretreated with reserpine was mounted in an organ bath containing Krebs' solution with 0.001 mmol/L atropine. Rings were contracted initially by 5-hydroxytryptamine (5-HT; 0.03 mmol/L) before relaxation was induced using ATP (0.03 mmol/L), ADP (0.03 mmol/L), pentoxifylline (0.002 mmol/L), electrical field stimulation (EFS; 50 V, 1 msec, 50 Hz, 3 min) and L-arginine (0.05 mmol/L). All drugs and EFS induced significant relaxation of isolated rings. The relaxations induced were significantly inhibited by N(G)-nitro-L-arginine methyl ester (L-NAME; 1.0 mmol/L). However, the iNOS inhibitors L-N(6)-(1-iminoethyl) lysine hydrochloride (L-NIL; 1.0 mmol/L) and amino guanidine (AMG; 1.0 mmol/L) had no significant effect on tissue relaxation. Then, the relaxant effects of 0.03 mmol/L ATP were tested on precontracted isolated fundic rings taken from 10 mg/kg LPS-treated animals. The non-selective NOS inhibitor L-NAME (10 mg/kg), the iNOS inhibitors L-NIL (3 mg/kg) and AMG (20 mg/kg) and betamethasone (0.1 mg/kg) were used to examine the role of NO produced by iNOS in the relaxation responses. It was found that the level of contraction induced by 0.03 mmol/L 5-HT in rings isolated from LPS-treated animals was significantly (P < 0.5) less than that in rings from untreated mice. However, precontracted tissues from LPS-treated mice were significantly relaxed by ATP and the relaxation response to ATP was significantly inhibited by L-NIL, ANG and betamethasone, but not by L-NAME. We suggest that, in LPS-treated mice, the production of NO from iNOS produces a reduction in the contractile response, as well as a decrease in NO formation by cNOS, resulting in changes to smooth muscle cell function.     

The effect of puerarin on serum nitric oxide concentration and myocardial eNOS expression in rats with myocardial infarction

Puerarin (1) is a major effective ingredient extracted from the traditional Chinese medicine Ge-gen (Radix Puerariae, RP). Recently, puerarin has been used to treat patients with coronary artery diseases (CAD). However, the mechanisms of puerarin on CAD are still not very clear. In this study, we investigated the role of puerarin on serum nitric oxide (NO) concentration, myocardial endothelial nitric oxide synthase (eNOS) gene expression, the protein expression of eNOS and inducible nitric oxide synthase (iNOS), as well as the level of protein kinase B (Akt/PKB) phosphorylation in rats with myocardial infarction. We found that puerarin (120 mg/kg/day, i.p.) could increase serum nitrite concentration in rat with myocardial ischemia (MI). It also induced the gene expression or activation of eNOS, protein expression of eNOS, and the Akt/PKB phosphorylation. From these results, we suggested that puerarin could increase serum nitric oxide level of rat with myocardial infarction, which should be one of the mechanisms of the therapeutic effect of puerarin on CAD. The increased expression of eNOS and the Akt/PKB pathway may be the underlying mechanism by which puerarin stimulates NO production.     

The effect of puerarin on serum nitric oxide concentration and myocardial eNOS expression in rats with myocardial infarction

Puerarin (1) is a major effective ingredient extracted from the traditional Chinese medicine Ge-gen (Radix Puerariae, RP). Recently, puerarin has been used to treat patients with coronary artery diseases (CAD). However, the mechanisms of puerarin on CAD are still not very clear. In this study, we investigated the role of puerarin on serum nitric oxide (NO) concentration, myocardial endothelial nitric oxide synthase (eNOS) gene expression, the protein expression of eNOS and inducible nitric oxide synthase (iNOS), as well as the level of protein kinase B (Akt/PKB) phosphorylation in rats with myocardial infarction. We found that puerarin (120 mg/kg/day, i.p.) could increase serum nitrite concentration in rat with myocardial ischemia (MI). It also induced the gene expression or activation of eNOS, protein expression of eNOS, and the Akt/PKB phosphorylation. From these results, we suggested that puerarin could increase serum nitric oxide level of rat with myocardial infarction, which should be one of the mechanisms of the therapeutic effect of puerarin on CAD. The increased expression of eNOS and the Akt/PKB pathway may be the underlying mechanism by which puerarin stimulates NO production.     

Inhibitory effect of fucoidan on nitric oxide production in lipopolysaccharide‐activated primary microglia

1. Microglial activation plays an important role in the pathogenesis of neurodegenerative diseases by producing various pro‐inflammatory cytokines. Microglia‐derived nitric oxide (NO) is critical for the lipopolysaccharide (LPS)‐induced selective loss of dopaminergic neurons. 2. Fucoidan is a sulphated polysaccharide extracted from brown seaweeds. It has a variety of biological actions, including anticoagulant, antiviral and anti‐inflammatory effects. The aim of the present study was to investigate the effects of fucoidan on LPS‐induced cellular activation in microglia and to evaluate the inhibitory mechanisms involved. 3. To investigate the effects of fucoidan on LPS‐induced cellular activation in microglia, primary microglial cells were preincubated with fucoidan (31.25, 62.5 and 125 μg/mL) for 10 min, followed by stimulation with LPS (0.01 μg/mL). Then, cell shape and NO production were determined 24 h after LPS stimulation, whereas inducible nitric oxide synthase (iNOS) mRNA and protein expression were determined at 6 and 18 h after LPS stimulation, respectively. To evaluate the inhibitory mechanisms involved, mitogen‐activated protein kinase (MAPK) activation was also evaluated. 4. Lipopolysaccharide transformed cells into an amoeboid shape, whereas 62.5 μg/mL fucoidan inhibited this activation. Moreover, 125 μg/mL fucoidan significantly inhibited microglial NO production to 75% of that in LPS‐treated group and also significantly diminished the expression of iNOS mRNA and protein by nearly 50%. Fucoidan (125 μg/mL) also suppressed phosphorylation of p38 and extracellular signal‐regulated kinase (ERK) by approximately 50%, but not that of c‐Jun N‐terminal kinase. 5. The results provide the first evidence that fucoidan has a potent inhibitory effect against LPS‐induced NO production by microglia. The results also suggest that this inhibitory action of fucoidan involves suppression of p38 and ERK phosphorylation.