【摘要】：背景和目的蛛網(wǎng)膜下腔出血(Subarachnoid Hemorrhage,SAH)主要發(fā)生于相對(duì)年輕的人群,其導(dǎo)致的高死殘率對(duì)社會(huì)和家庭造成了巨大的損失。目前認(rèn)為,SAH的病理生理機(jī)制主要涉及腦神經(jīng)血管網(wǎng)絡(luò),該網(wǎng)絡(luò)包含腦內(nèi)大血管下游所有的小血管以及與這些血管相關(guān)的所有細(xì)胞。血腦屏障(Blood-brain barrier,BBB)是神經(jīng)血管網(wǎng)絡(luò)中最為重要的結(jié)構(gòu)之一,它的損傷與SAH后發(fā)生的血管性腦水腫有著極為緊密的聯(lián)系。因此,保護(hù)BBB免受損傷將有助于SAH病人的康復(fù)。青蒿琥酯,作為半合成水溶性的青蒿素衍生物,已經(jīng)成為腦型瘧疾和其他各種重型瘧疾的標(biāo)準(zhǔn)治療藥物。青蒿琥酯的抗瘧作用高效、安全且耐受良好。而且,大量的研究也指出,其具有廣泛的藥理學(xué)活性,例如抗寄生蟲(chóng)、抗腫瘤、抗炎和抗微生物等。我們知道,神經(jīng)系統(tǒng)疾病的發(fā)生涉及多種病因和復(fù)雜的病理生理機(jī)制。近來(lái)的研究也顯示單一作用機(jī)制和具有嚴(yán)重副作用的藥物不可能用于治療神經(jīng)系統(tǒng)疾病。因此,具有多種作用效應(yīng)的青蒿琥酯可能在預(yù)防和治療神經(jīng)系統(tǒng)疾病方面具有重要的應(yīng)用潛力。更為重要的是,青蒿琥酯能特異性地在腦組織中保持高濃度。新近研究發(fā)現(xiàn),青蒿琥酯能夠緩解小鼠實(shí)驗(yàn)性腦型瘧疾導(dǎo)致的BBB損傷,而且這種緩解與瘧原蟲(chóng)的殺滅無(wú)關(guān)。另外,FTY720(S1P1的激動(dòng)劑)聯(lián)合青蒿琥酯治療小鼠腦型瘧疾可以明顯減輕BBB的損傷并提高其存活率。因此,我們有理由相信青蒿琥酯對(duì)SAH具有治療作用。1-磷酸鞘氨醇受體-1(Sphingosine-1-phosphate receptor-1,S1P1)主要表達(dá)于血管內(nèi)皮細(xì)胞上。S1P1特異性地與Gi/o家族結(jié)合,在維持血流依賴性血管網(wǎng)絡(luò)方面具有重要的作用。在小鼠體內(nèi)全部或僅內(nèi)皮細(xì)胞上敲除S1P1基因都會(huì)對(duì)血管叢產(chǎn)生極為嚴(yán)重的后果。以往的研究指出,激活S1P1可保護(hù)多種卒中模型導(dǎo)致的腦損傷,如:增加S1P的表達(dá)可以提高S1P1的活性,進(jìn)而阻止SAH后小鼠早期腦損傷的發(fā)展。但是,對(duì)S1P1在保護(hù)受損腦組織中涉及的下游信號(hào)通路并沒(méi)有完全弄清。研究顯示,S1P1既可通過(guò)激活PI3K/Akt信號(hào)通路抑制凋亡、阻止Fox O3a活化并最終促進(jìn)PC12細(xì)胞的存活;也可使心肌細(xì)胞在缺氧條件下存活;還可促進(jìn)脂肪干細(xì)胞分化成為表達(dá)內(nèi)皮型NO合酶的內(nèi)皮樣細(xì)胞等。因此,pi3k是s1p1分子一個(gè)極為重要的下游效應(yīng)器。而且,taddei等人發(fā)現(xiàn)激活pi3k/akt分子可以滅活gsk-3β并阻止β-catenin的核轉(zhuǎn)位,這樣有利于解除其對(duì)claudin-5表達(dá)的抑制并最終增加claudin-5的表達(dá)。類似研究也指出,小鼠腦出血后激活pi3k/akt信號(hào)通路可以減少gsk-3β的激活并穩(wěn)定β-catenin,最終增加緊密連接蛋白claudin-3和claudin-5的表達(dá)。眾所周知,緊密連接蛋白claudin-3和claudin-5對(duì)維護(hù)bbb的完整性極為重要。高效地促進(jìn)claudin-3和claudin-5的表達(dá),可以有效地緩解各種中樞神經(jīng)系統(tǒng)疾病導(dǎo)致的bbb損傷。基于上述研究成果,我們推測(cè)sah后給予青蒿琥酯可以激活s1p1進(jìn)而保護(hù)bbb的完整性。我們利用腦血管內(nèi)穿法來(lái)構(gòu)建sah大鼠模型,進(jìn)而研究sah后青蒿琥酯對(duì)bbb的保護(hù)效應(yīng)和潛在機(jī)制。材料與方法整個(gè)課題研究包括在體和離體實(shí)驗(yàn)兩部分。腦血管內(nèi)穿法被用于構(gòu)建大鼠sah模型。1、18分sah分級(jí)評(píng)分法被用于評(píng)價(jià)大鼠sah后24和72小時(shí)的出血量,以此來(lái)判斷模型構(gòu)建成功與否。2、改良garcia神經(jīng)功能評(píng)分被用于檢測(cè)大鼠sah后24和72小時(shí)的神經(jīng)系統(tǒng)功能。3、腦水腫程度則通過(guò)檢測(cè)大鼠sah后24和72小時(shí)的腦水含量來(lái)進(jìn)行評(píng)價(jià)。4、血腦屏障完整性則通過(guò)檢測(cè)大鼠sah后24小時(shí)腦組織的伊文斯藍(lán)滲出量、伊文斯藍(lán)的自發(fā)熒光以及透射電鏡來(lái)進(jìn)行評(píng)估。5、大鼠sah后24小時(shí)s1p1表達(dá)量則通過(guò)免疫組化染色來(lái)進(jìn)行檢測(cè)。6、westernblot被用于檢測(cè)大鼠sah后24或72小時(shí),s1p1、sphk1、sphk2、p-akt/akt、p-gsk3β/gsk3β、p-β-catenin/β-catenin、claudin-3和claudin-5蛋白的表達(dá)情況。此外,離體實(shí)驗(yàn)中,s1p1的表達(dá)量也使用westernblot來(lái)檢測(cè)。7、cck-8被用于檢測(cè)大鼠腦血管內(nèi)皮細(xì)胞在給予青蒿琥酯24小時(shí)后的活性。8、在體實(shí)驗(yàn)中,sirna的抑制效果則使用rt-pcr來(lái)進(jìn)行評(píng)估。9、自發(fā)性高血壓大鼠血壓的測(cè)定,則使用mrbp血壓測(cè)量?jī)x在2%高鹽溶液給予后,每周檢測(cè)一次。10、sah后24或72小時(shí),青蒿琥酯的治療作用通過(guò)神經(jīng)功能評(píng)分、腦水含量、伊文斯藍(lán)滲出量、伊文斯藍(lán)自發(fā)熒光和透射電鏡進(jìn)行評(píng)價(jià)。11、青蒿琥酯對(duì)sah后bbb保護(hù)涉及的具體分子機(jī)制,則通過(guò)分別給予不同拮抗劑(如DMS,VPC23019和Wortmannin)和si RNA(如S1P1 si RNA和Scr siRNA)進(jìn)行確認(rèn)。12、青蒿琥酯的預(yù)防作用則通過(guò)檢測(cè)SAH后24小時(shí),大鼠的神經(jīng)功能、腦水含量、以及伊文斯藍(lán)滲出量來(lái)評(píng)價(jià)。結(jié)果1、我們發(fā)現(xiàn),相對(duì)高濃度的青蒿琥酯(100mg/kg,200mg/kg)可以有效地緩解SAH后模型大鼠的神經(jīng)功能缺損、抑制腦水腫并減輕BBB的損傷。2、青蒿琥酯在在體和離體實(shí)驗(yàn)中,均能明顯增加S1P1的表達(dá)。但對(duì)神經(jīng)鞘氨醇激酶Sph K1和Sph K2的表達(dá)則沒(méi)有影響,而且給予神經(jīng)鞘氨醇激酶抑制劑N,N-dimethylsphingosine,并不能逆轉(zhuǎn)青蒿琥酯的作用。3、200mg/kg青蒿琥酯可以提高SAH 24h后蛋白分子p-Akt、Claudin-3和Claudin-5的表達(dá),并降低p-GSK-3/GSK-3β和p-β-catenin/β-catenin的比率。青蒿琥酯的這些作用可以被VPC23019、wortmannin和S1P1 si RNA所逆轉(zhuǎn)。4、預(yù)先給予200mg/kg青蒿琥酯,并不能提高SAH后24h模型大鼠的神經(jīng)功能評(píng)分,而且腦水含量和伊文斯藍(lán)的滲出量也未明顯減少。但預(yù)防性給予青蒿琥酯,可以明顯減輕自發(fā)性高血壓大鼠(SHR)慢性高血壓導(dǎo)致的BBB損傷。結(jié)論1、青蒿琥酯可以通過(guò)維護(hù)血腦屏障完整性進(jìn)而減少腦水腫,來(lái)緩解SAH導(dǎo)致的腦損傷。因其可顯著提高S1P1表達(dá)量,而對(duì)神經(jīng)鞘氨醇激酶Sph K1和Sph K2表達(dá)的影響則不大,所以,此作用可能與提高S1P的濃度無(wú)關(guān)。2、S1P1與PI3K信號(hào)通路關(guān)系密切,S1P1激活能夠增加PI3K/Akt的活性,進(jìn)而滅活GSK-3β并穩(wěn)定β-catenin,最終提高SAH模型大鼠緊密連接蛋白Claudin-3和Claudin-5的表達(dá),保護(hù)了血腦屏障。3、高血壓可以提高正常SHR大鼠血腦屏障的通透性,預(yù)先給予青蒿琥酯能夠顯著減輕其在高血壓誘導(dǎo)下的血腦屏障損傷。
[Abstract]:BACKGROUND AND OBJECTIVE Subarachnoid hemorrhage (SAH) mainly occurs in relatively young people, resulting in high mortality and disability rate which has caused enormous losses to society and families. Blood-brain barrier (BBB) is one of the most important structures in the neural-vascular network. Its damage is closely related to vascular brain edema after SAH. Therefore, protecting BBB from injury will help the rehabilitation of SAH patients. Sexual artemisinin derivatives have become standard treatments for cerebral malaria and other serious forms of malaria. Artesunate is highly effective, safe and well tolerated. Moreover, numerous studies have shown that it has a wide range of pharmacological activities, such as antiparasite, antitumor, anti-inflammatory and antimicrobial activities. Recent studies have also shown that drugs with single mechanism of action and serious side effects are unlikely to be used to treat nervous system diseases. Therefore, artesunate with multiple effects may have important potential applications in the prevention and treatment of nervous system diseases. More importantly, artesunate can specifically maintain high concentrations in brain tissue. Recent studies have shown that artesunate can alleviate BBB damage caused by experimental cerebral malaria in mice, and this remission has nothing to do with the eradication of malaria parasites. In addition, FTY720 (S1P1 agonist) combined with artesunate in the treatment of cerebral malaria in mice can be demonstrated. Therefore, we have reason to believe that artesunate has therapeutic effect on SAH. Sphingosine-1-phosphate receptor-1 (S1P1) is mainly expressed in vascular endothelial cells. S1P1 is specifically bound to the Gi/o family and plays an important role in maintaining blood flow-dependent vascular network. Knocking out the S1P1 gene on all or only endothelial cells in mice can have extremely serious consequences for the vascular plexus. Previous studies have shown that activating S1P1 protects against brain damage caused by various stroke models, such as increasing the expression of S1P can increase the activity of S1P1, thereby preventing the development of early brain damage in mice after SAH. The downstream signaling pathways involved in the protection of damaged brain tissues by S1P1 have not been fully understood. Studies have shown that S1P1 can inhibit apoptosis, prevent Fox O3a activation and ultimately promote the survival of PC12 cells by activating PI3K/Akt signaling pathway; it can also promote the survival of cardiomyocytes under hypoxia conditions; and it can also promote the differentiation of adipose-derived stem cells into expressed cells. Therefore, PI3K is a very important downstream effector of s1p1. Moreover, Taddei et al. found that activation of PI3K / Akt can inactivate GSK-3 beta and prevent the nuclear translocation of beta-catenin, which is beneficial to relieve its inhibition of claudin-5 expression and eventually increase claudin-5 expression. Activation of pi3k/akt signaling pathway after intracerebral hemorrhage in mice reduces GSK-3 beta activation and stabilizes beta-catenin, and ultimately increases the expression of tight junction proteins Claudin-3 and claudin-5. It is well known that tight junction proteins Claudin-3 and claudin-5 are very important for maintaining the integrity of bbb. Based on the above results, we hypothesized that artesunate could activate S1P1 and protect the integrity of BBB after sah. We constructed SAH rat model by cerebrovascular endopuncture, and then studied the protective effect and potential mechanism of artesunate on BBB after sah. Methods The whole subject was divided into two parts: in vitro and in vivo. Cerebrovascular endoscopy was used to construct rat SAH model. 1,18 points SAH grading method was used to evaluate the amount of bleeding 24 and 72 hours after SAH in order to judge whether the model was successfully constructed. 2. Modified Garcia neurological function score was used to detect 24 and 72 hours after SAH in rats. Neurological function was assessed at 24 and 72 hours after sah. Blood-brain barrier integrity was assessed at 24 hours after SAH by Evans blue exudation, Evans blue autofluorescence and transmission electron microscopy. 5. S1P1 expression at 24 hours after SAH in rats Western blot was used to detect the expression of s1p1, sphk1, sphk2, p-Akt / akt, p-gsk3 beta, p-beta-catenin / beta-catenin, Claudin-3 and claudin-5 proteins 24 or 72 hours after SAH in rats. In addition, in vitro, the expression of S1P1 was also detected by Western blot, and CCK-8 was also detected by Western blot. In vivo, siRNA inhibitory effect was evaluated by rt-pcr. In spontaneously hypertensive rats, blood pressure was measured by mrbp blood pressure meter after 2% high salt solution was given, once a week, once a week, 24 or 72 hours after sah, artesunate treatment. The therapeutic effect was evaluated by neurological function score, brain water content, Evans blue exudation, Evans blue autofluorescence and transmission electron microscopy. 11. Specific molecular mechanisms involved in the protection of BBB after SAH by artesunate were confirmed by different antagonists (such as DMS, VPC23019 and Wortmannin) and siRNA (such as S1P1 siRNA and SCr siRNA). Results 1. Relatively high concentration of artesunate (100mg/kg, 200mg/kg) could effectively alleviate the neurological impairment, inhibit brain edema and reduce the damage of BBB. 2. Artesunate significantly increased the expression of S1P1 in vivo and in vitro, but had no effect on the expression of Sph K1 and Sph K 2, and the effect of Artesunate could not be reversed by N, N-dimethylsphingosine, an inhibitor of sphingosine kinase. The expression of daughter p-Akt, Claudin-3 and Claudin-5 and the ratio of p-GSK-3/GSK-3 beta and p-beta-catenin/beta-catenin were decreased. These effects of artesunate could be reversed by VPC23019, wortmannin and S1P1si RNA. Pre-administration of 200 mg/kg artesunate did not increase the neurological function score of SAH-induced 24 h rats, and the brain water content and Evans content were also decreased. However, preventive administration of artesunate can significantly alleviate BBB injury induced by chronic hypertension in spontaneously hypertensive rats (SHR). Conclusion 1. Artesunate can alleviate brain injury induced by SAH by maintaining the integrity of blood-brain barrier and thereby reducing brain edema. S1P1 is closely related to PI3K signaling pathway. Activation of S1P1 can increase PI3K/Akt activity, inactivate GSK-3 beta and stabilize beta-catenin, and ultimately increase the tight junction proteins Claudin-3 and Claudin-5 in SAH model rats. Artesunate can significantly reduce the blood-brain barrier damage induced by hypertension.
【學(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R743.35

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9 梁愛(ài)華;薛寶云;李春英;王金華;王嵐;;青蒿琥酯對(duì)內(nèi)毒素誘導(dǎo)的一氧化氮合成的抑制作用[A];2002中藥研究論文集[C];2002年

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