磷酸二酯酶5抑制劑的神經保護作用研究進展

徐 凡，雷 鳴，龍 隆，龔其海，高健美

(遵義醫學院1.藥學院、2.基礎藥理省部共建教育部重點實驗室，貴州 遵義 563000)

磷酸二酯酶5抑制劑的神經保護作用研究進展

徐 凡1，雷 鳴1，龍 隆1，龔其海2，高健美1

(遵義醫學院1.藥學院、2.基礎藥理省部共建教育部重點實驗室，貴州 遵義 563000)

近年來，磷酸二酯酶5(phosphodiesterase 5，PDE5)在神經系統疾病發生及發展過程中的作用備受關注，其抑制劑可發揮神經保護作用，機制與抑制PDE5后產生的抗中風、抗氧化、抗神經炎癥及改善認知障礙等作用有關。該文結合國內外研究報道，系統地綜述了PDE5抑制劑的神經保護作用及其相關作用機制。

磷酸二酯酶5抑制劑；神經保護；抗中風；抗神經炎癥；抗氧化；改善認知障礙；研究進展

大腦在缺血、缺氧條件下會發生一系列的瀑布級聯反應，從而導致神經系統疾病的發生發展，神經保護則是對級聯反應的各個環節加以影響和調控，保護及修復受損的神經組織，并使之恢復或部分恢復原有功能[1]。目前，神經保護藥物主要包括氧自由基清除劑依達拉奉、鈣通道拮抗劑尼莫地平、谷氨酸受體拮抗劑等。近年來[2-3]，研究者在動物及人類的腦中均發現有磷酸二酯酶5(phosphodiesterase 5，PDE5)的存在，并且發現傳統的PDE5抑制劑，如西地那非和他達那非以及新報道的PDE5抑制劑優克那非和淫羊藿苷(icariin，ICA)都可透過血腦屏障，在中風、阿爾茨海默病(Alzheimer’s disease，AD)等神經系統疾病中發揮保護作用，其機制與抑制PDE5后產生的抗中風、抗氧化、抗神經炎癥及改善認知障礙等作用有關[4-5]。本文結合國內外研究結果及所在團隊的研究工作，系統綜述了PDE5抑制劑的神經保護作用，旨在為更好地開發利用PDE5抑制劑防治中樞神經系統疾病提供依據。

1 PDE5抑制劑對腦中風后神經血管修復的作用

中風的治療主要通過促進血管重構以恢復大腦的供血和阻斷神經細胞死亡的級聯反應來實現[6]。Zhang等[7]將內皮細胞與PDE5抑制劑西地那非共培養后發現，西地那非可誘導內皮細胞形成類毛細血管，表明西地那非有促進血管發生的潛能。隨后，此課題組采用大腦中動脈梗死誘導大鼠中風模型后發現，西地那非可明顯促進中風大鼠神經功能的恢復，并增加大鼠腦皮質區域血管密度，促進內皮細胞的增殖以及突觸素的免疫活性[8]。甘靖等[9]發現西地那非可改善大鼠腦缺血/再灌注后急性期神經功能，其機制可能與海馬前體神經細胞標記物微管相關蛋白陽性細胞及血管內皮生長因子的表達增加有關。同樣，他達那非也可促進大鼠腦栓塞模型的神經功能恢復[10]。Li等[11]通過衡量中風大鼠的核磁共振圖像和功能表現來評價西地那非對中風的治療效果，并應用血管內皮屏障抗原染色來進行腦血管的形態學和量化分析，發現西地那非可選擇性地增加缺血周邊區腦血流量以及血管活性。但無論是西地那非還是他達那非，均不能有效減少中風病灶的大小[9-10]。在大腦發育過程中，腦室內的神經干細胞(neuron stem cell, NSC)分化成神經細胞，而后遷移至皮層，聚集形成皮質神經元[12]。Zhang等[13]采用溴脫氧尿苷標記神經元的方法，發現用西地那非處理(中風后2 h或24 h)中風大鼠后，可大幅增加其室下區及齒狀回的新生神經元，且某些神經元可表現出成熟神經元的特征。免疫熒光染色法表明，西地那非能夠增加中年中風小鼠NSC標記物巢蛋白、成熟神經元及少突膠質細胞的表達[14]。體外實驗數據表明，西地那非可直接作用于NSC，通過促進干細胞增殖與分化來增強神經發生作用[15]。研究表明，PDE5抑制劑西地那非與他達那非均能在中風后提高腦環磷鳥嘌呤核苷(cyclic guanosinc monophosphate, cGMP)的濃度，從而作用于血管內皮細胞、NSC和少突細胞，進而促進中風誘導的血管發生、神經發生及突觸再生過程[4]。

2 PDE5抑制劑的抗神經炎癥作用

體內、體外實驗均證實PDE5抑制劑具有抗神經炎癥的作用[16-17]。眾所周知，小膠質細胞被認為是中樞神經系統炎癥發生的主要介導者之一[18]。Moretti等[19]采用大腦中動脈阻塞誘導新生小鼠中風模型后發現，西地那非可明顯緩解由小膠質細胞介導的神經炎癥反應。亦有研究證實，西地那非能夠治療由脂多糖誘導星形膠質細胞產生的炎性反應，其機制與降低鈣離子反應強度有關。Hernandez-Rabaza等[20]通過制備門腔靜脈分流大鼠模型模擬神經炎癥，結果發現西地那非能夠降低大鼠海馬中白細胞介素1β、腫瘤壞死因子等炎癥細胞因子來發揮抗炎作用。Raposo等[21]進一步證實了西地那非可緩解由雙環己酮草酰二腙誘導的誘導型一氧化氮合酶(induced NO synthase，iNOS)基因敲除小鼠的神經炎癥反應，其機制可能與增加腦中cGMP濃度有關。有趣的是，iNOS基因敲除小鼠較野生型小鼠更易被誘導發生炎癥反應，這可能與iNOS/NO/cGMP信號通路參與了神經炎癥的發生關系密切[19,21]。

3 PDE5抑制劑的抗氧化作用

氧化應激條件下可產生過多活性氧(reactive oxygen species, ROS)產物，從而導致線粒體的功能和結構遭到破壞，最終導致神經細胞死亡[22]。活化的小膠質細胞通過分泌ROS，促使神經退行性病變的發生及發展[23]。然而，Park等[24]認為，活化的小膠質細胞并非ROS產生的主要來源，而大多由NADPH氧化酶產生。有報道稱，PDE5抑制劑西地那非通過抑制NADPH氧化酶的表達，從而明顯減少了肺動脈上皮中的負氧離子[25-26]。同時，西地那非可下調gp91phox和細胞內ROS水平，gp91phox是NADPH氧化酶的一個具有催化作用的關鍵亞基[17]。最近，Sung等[27]用晚期糖基化終末產物誘導HT-22海馬神經細胞發生氧化應激反應，使其喪失線粒體功能，給予西地那非后可保護其線粒體功能，此外，還能減少因氧化應激引起的細胞凋亡。進一步研究發現，無活性的cGMP類似物Rp-8-Br-cGMP及cGMP抑制劑都可削弱西地那非的保護作用。此外，NO/cGMP軸本身也可通過增高cGMP濃度來抑制NADPH氧化酶的表達[28]。綜上，可以推測PDE5抑制劑抗氧化的機制可能與增高cGMP水平，從而抑制NADPH氧化酶的表達有關。

4 PDE5抑制劑可改善認知障礙

亨廷頓病(Huntington′s disease, HD)早期可出現認知障礙。Saavedra等[29]采用酶免疫分析法檢測HD小鼠模型海馬中的cGMP，發現其濃度異常降低，但PDE5水平則無明顯變化。進一步研究證實了PDE5抑制劑西地那非可通過增加小鼠海馬cGMP，從而改善其學習記憶功能，并認為cGMP水平的調節可作為治療HD認知障礙的靶點[29]。同時，臨床研究表明腦脊液cGMP水平與AD的發展也有關，早期AD患者中cGMP的減少可加劇認知障礙及淀粉樣蛋白的沉積[30]，但缺乏臨床治療AD的相關研究。動物實驗通過Morris水迷宮及新物體識別測試來評價AD動物模型(Tg2576、TgAPP/PS1、J20小鼠)接受西地那非治療后的認知功能改變情況，發現西地那非可明顯降低Tg2576與J20小鼠的逃避潛伏期[31-32]，促進TgAPP/PS1小鼠對新穎物體的探索[16]。進一步研究表明，PDE5/cGMP信號通路可能參與改善AD小鼠認知障礙的過程，此外，西地那非還可明顯增加Tg2576與TgAPP/PS1小鼠海馬的轉錄因子環磷酸腺苷反應部分結合蛋白(cAMP-response element binding protein, CREB)及其下游腦源性神經營養因子(brain derived neurotrophic factor, BDNF)及活性調節細胞骨架聯合的蛋白(recombinant activity regulated cytoskeleton associated protein, Arc)表達[16,32]。因此，推測PDE5抑制劑可能通過增加cGMP水平從而作用于pCREB/BDNF/Arc通路，進而改善認知障礙。

5 新報道的PDE5抑制劑

西地那非類似物優克那非作為一種新報道的PDE5抑制劑，其半抑制濃度(half maximal inhibitory concentration, IC50)為2 nmol·L-1，低于西地那非(IC50=4.5 nmol·L-1)，且不良反應較少[33]。優克那非也具有抗中風、抗神經炎癥、促進神經發生及改善認知障礙等神經保護作用[34-36]。

淫羊藿苷(ICA)是從中藥淫羊藿中提取的黃酮類物質，在它被證實可抑制PDE5之前，就有研究發現其具有保護大腦缺血性損傷的功效，表明ICA具有潛在神經保護作用[37]。廖暉等[38]證明ICA能通過抑制陰莖海綿體的PDE5來激活NO/cGMP信號通路，從而治療勃起障礙。本課題組近年來致力于對淫羊藿的神經保護作用的研究，發現ICA不僅能夠降低AD小鼠海馬中PDE5的水平，增加一氧化氮合酶的表達，從而增加腦中NO和cGMP的濃度[39-40]，還可以通過改善興奮性氨基酸中毒大鼠模型認知障礙，減少神經細胞凋亡來發揮神經保護作用[41]。此外，ICA能夠通過對抗神經炎癥反應來預防腦缺血/再灌注損傷[42]。體外實驗中，我們采用氧糖剝奪/復氧細胞模型證明ICA可通過抗凋亡及調節自噬起到神經保護作用[43]。然而，ICA會在體內代謝為淫羊藿次苷Ⅱ(icariside Ⅱ, ICSⅡ)[44]，則有理由假設ICS Ⅱ也有類似神經保護效應。我們的研究證實了ICSⅡ可通過降低中風大鼠及AD大鼠海馬的PDE5蛋白產生，從而改善其神經功能及認知障礙，減少促炎性因子及神經元的死亡，進而發揮神經保護作用[45-46]。

6 展望

大量臨床前實驗證實PDE5抑制劑具有神經保護作用，效果顯著，且不良反應較少。本文結合國內外研究結果及所在團隊研究報道，系統地綜述了PDE5抑制劑抗中風、抗氧化、抗神經炎癥及改善認知障礙等神經保護作用及相關機制。這為更好地開發利用PDE5抑制劑在臨床防治中樞神經系統疾病的深入研究提供了線索，對開發新型PDE5抑制劑具有現實的指導意義。

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Recent progress in study on neuroprotection of phosphodiesterase 5 inhibitors

XU Fan1, LEI Ming1, LONG Long1, GONG Qi-hai2, GAO Jian-mei1
(1.CollogeofPharmacy, 2.DeptofPharmacologyandKeyLaboratoryofBasicPharmacologyofMinistryofEducation,ZunyiMedicalUniversity,ZunyiGuizhou563000,China)

In recent years, the role of phosphodiesterase 5(PDE5) has been highlighted in the development and progression of neurological disease. PDE5 inhibitors show significant effect of neruoprotection, which may be related with some effects such as resistance to stroke, anti-oxidation, inhibition of neuroinflammation and amelioration of cognitive deficits. Based on the domestic and overseas researches about PDE5, this review systematically summarized the neuroprotection of PDE5 and their related mechanisms.

phosphodiesterase 5 inhibitors; neuroprotection; anti-stroke; anti-neuroinflammation; anti-oxidation; amelioration of cognitive deficits; research progress

2016-12-07,

2017-01-06

國家自然科學基金資助項目(No 81560666)；貴州省淫羊藿開發利用科技創新人才團隊[No 黔科合人才團隊(2015)4023號]

徐 凡(1993-)，男，碩士生，研究方向：神經藥理學，E-mail: xufan_jakie@163.com； 高健美(1979-)，女，博士，副教授，碩士生導師，研究方向：神經藥理學，通訊作者，E-mail: gaojianmei@zmc.edu.cn

時間：2017-4-24 11:19

http://kns.cnki.net/kcms/detail/34.1086.R.20170424.1119.006.html

10.3969/j.issn.1001-1978.2017.05.003

A

1001-1978(2017)05-0603-04

R-05；R338.64；R345.61；R364.5；R741.05；R743.305；R977.3