徐 凡，雷 鳴，龍 隆，龔其海，高健美

(遵義醫(yī)學(xué)院1.藥學(xué)院、2.基礎(chǔ)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(jīng)保護(hù)作用研究進(jìn)展

徐 凡1，雷 鳴1，龍 隆1，龔其海2，高健美1

(遵義醫(yī)學(xué)院1.藥學(xué)院、2.基礎(chǔ)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(jīng)系統(tǒng)疾病發(fā)生及發(fā)展過程中的作用備受關(guān)注，其抑制劑可發(fā)揮神經(jīng)保護(hù)作用，機(jī)制與抑制PDE5后產(chǎn)生的抗中風(fēng)、抗氧化、抗神經(jīng)炎癥及改善認(rèn)知障礙等作用有關(guān)。該文結(jié)合國內(nèi)外研究報道，系統(tǒng)地綜述了PDE5抑制劑的神經(jīng)保護(hù)作用及其相關(guān)作用機(jī)制。

磷酸二酯酶5抑制劑；神經(jīng)保護(hù)；抗中風(fēng)；抗神經(jīng)炎癥；抗氧化；改善認(rèn)知障礙；研究進(jìn)展

大腦在缺血、缺氧條件下會發(fā)生一系列的瀑布級聯(lián)反應(yīng)，從而導(dǎo)致神經(jīng)系統(tǒng)疾病的發(fā)生發(fā)展，神經(jīng)保護(hù)則是對級聯(lián)反應(yīng)的各個環(huán)節(jié)加以影響和調(diào)控，保護(hù)及修復(fù)受損的神經(jīng)組織，并使之恢復(fù)或部分恢復(fù)原有功能[1]。目前，神經(jīng)保護(hù)藥物主要包括氧自由基清除劑依達(dá)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(fā)現(xiàn)有磷酸二酯酶5(phosphodiesterase 5，PDE5)的存在，并且發(fā)現(xiàn)傳統(tǒng)的PDE5抑制劑，如西地那非和他達(dá)那非以及新報道的PDE5抑制劑優(yōu)克那非和淫羊藿苷(icariin，ICA)都可透過血腦屏障，在中風(fēng)、阿爾茨海默病(Alzheimer’s disease，AD)等神經(jīng)系統(tǒng)疾病中發(fā)揮保護(hù)作用，其機(jī)制與抑制PDE5后產(chǎn)生的抗中風(fēng)、抗氧化、抗神經(jīng)炎癥及改善認(rèn)知障礙等作用有關(guān)[4-5]。本文結(jié)合國內(nèi)外研究結(jié)果及所在團(tuán)隊的研究工作，系統(tǒng)綜述了PDE5抑制劑的神經(jīng)保護(hù)作用，旨在為更好地開發(fā)利用PDE5抑制劑防治中樞神經(jīng)系統(tǒng)疾病提供依據(jù)。

1 PDE5抑制劑對腦中風(fēng)后神經(jīng)血管修復(fù)的作用

中風(fēng)的治療主要通過促進(jìn)血管重構(gòu)以恢復(fù)大腦的供血和阻斷神經(jīng)細(xì)胞死亡的級聯(lián)反應(yīng)來實現(xiàn)[6]。Zhang等[7]將內(nèi)皮細(xì)胞與PDE5抑制劑西地那非共培養(yǎng)后發(fā)現(xiàn)，西地那非可誘導(dǎo)內(nèi)皮細(xì)胞形成類毛細(xì)血管，表明西地那非有促進(jìn)血管發(fā)生的潛能。隨后，此課題組采用大腦中動脈梗死誘導(dǎo)大鼠中風(fēng)模型后發(fā)現(xiàn)，西地那非可明顯促進(jìn)中風(fēng)大鼠神經(jīng)功能的恢復(fù)，并增加大鼠腦皮質(zhì)區(qū)域血管密度，促進(jìn)內(nèi)皮細(xì)胞的增殖以及突觸素的免疫活性[8]。甘靖等[9]發(fā)現(xiàn)西地那非可改善大鼠腦缺血/再灌注后急性期神經(jīng)功能，其機(jī)制可能與海馬前體神經(jīng)細(xì)胞標(biāo)記物微管相關(guān)蛋白陽性細(xì)胞及血管內(nèi)皮生長因子的表達(dá)增加有關(guān)。同樣，他達(dá)那非也可促進(jìn)大鼠腦栓塞模型的神經(jīng)功能恢復(fù)[10]。Li等[11]通過衡量中風(fēng)大鼠的核磁共振圖像和功能表現(xiàn)來評價西地那非對中風(fēng)的治療效果，并應(yīng)用血管內(nèi)皮屏障抗原染色來進(jìn)行腦血管的形態(tài)學(xué)和量化分析，發(fā)現(xiàn)西地那非可選擇性地增加缺血周邊區(qū)腦血流量以及血管活性。但無論是西地那非還是他達(dá)那非，均不能有效減少中風(fēng)病灶的大小[9-10]。在大腦發(fā)育過程中，腦室內(nèi)的神經(jīng)干細(xì)胞(neuron stem cell, NSC)分化成神經(jīng)細(xì)胞，而后遷移至皮層，聚集形成皮質(zhì)神經(jīng)元[12]。Zhang等[13]采用溴脫氧尿苷標(biāo)記神經(jīng)元的方法，發(fā)現(xiàn)用西地那非處理(中風(fēng)后2 h或24 h)中風(fēng)大鼠后，可大幅增加其室下區(qū)及齒狀回的新生神經(jīng)元，且某些神經(jīng)元可表現(xiàn)出成熟神經(jīng)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(fēng)小鼠NSC標(biāo)記物巢蛋白、成熟神經(jīng)元及少突膠質(zhì)細(xì)胞的表達(dá)[14]。體外實驗數(shù)據(jù)表明，西地那非可直接作用于NSC，通過促進(jìn)干細(xì)胞增殖與分化來增強(qiáng)神經(jīng)發(fā)生作用[15]。研究表明，PDE5抑制劑西地那非與他達(dá)那非均能在中風(fēng)后提高腦環(huán)磷鳥嘌呤核苷(cyclic guanosinc monophosphate, cGMP)的濃度，從而作用于血管內(nèi)皮細(xì)胞、NSC和少突細(xì)胞，進(jìn)而促進(jìn)中風(fēng)誘導(dǎo)的血管發(fā)生、神經(jīng)發(fā)生及突觸再生過程[4]。

2 PDE5抑制劑的抗神經(jīng)炎癥作用

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

3 PDE5抑制劑的抗氧化作用

氧化應(yīng)激條件下可產(chǎn)生過多活性氧(reactive oxygen species, ROS)產(chǎn)物，從而導(dǎo)致線粒體的功能和結(jié)構(gòu)遭到破壞，最終導(dǎo)致神經(jīng)細(xì)胞死亡[22]?；罨男∧z質(zhì)細(xì)胞通過分泌ROS，促使神經(jīng)退行性病變的發(fā)生及發(fā)展[23]。然而，Park等[24]認(rèn)為，活化的小膠質(zhì)細(xì)胞并非ROS產(chǎn)生的主要來源，而大多由NADPH氧化酶產(chǎn)生。有報道稱，PDE5抑制劑西地那非通過抑制NADPH氧化酶的表達(dá)，從而明顯減少了肺動脈上皮中的負(fù)氧離子[25-26]。同時，西地那非可下調(diào)gp91phox和細(xì)胞內(nèi)ROS水平，gp91phox是NADPH氧化酶的一個具有催化作用的關(guān)鍵亞基[17]。最近，Sung等[27]用晚期糖基化終末產(chǎn)物誘導(dǎo)HT-22海馬神經(jīng)細(xì)胞發(fā)生氧化應(yīng)激反應(yīng)，使其喪失線粒體功能，給予西地那非后可保護(hù)其線粒體功能，此外，還能減少因氧化應(yīng)激引起的細(xì)胞凋亡。進(jìn)一步研究發(fā)現(xiàn)，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(hù)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(dá)[28]。綜上，可以推測PDE5抑制劑抗氧化的機(jī)制可能與增高cGMP水平，從而抑制NADPH氧化酶的表達(dá)有關(guān)。

4 PDE5抑制劑可改善認(rèn)知障礙

亨廷頓病(Huntington′s disease, HD)早期可出現(xiàn)認(rèn)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(fā)現(xiàn)其濃度異常降低，但PDE5水平則無明顯變化。進(jìn)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(xué)習(xí)記憶功能，并認(rèn)為cGMP水平的調(diào)節(jié)可作為治療HD認(rèn)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(fā)展也有關(guān)，早期AD患者中cGMP的減少可加劇認(rèn)知障礙及淀粉樣蛋白的沉積[30]，但缺乏臨床治療AD的相關(guān)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(rèn)知功能改變情況，發(fā)現(xiàn)西地那非可明顯降低Tg2576與J20小鼠的逃避潛伏期[31-32]，促進(jìn)TgAPP/PS1小鼠對新穎物體的探索[16]。進(jìn)一步研究表明，PDE5/cGMP信號通路可能參與改善AD小鼠認(rèn)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(zhuǎn)錄因子環(huán)磷酸腺苷反應(yīng)部分結(jié)合蛋白(cAMP-response element binding protein, CREB)及其下游腦源性神經(jīng)營養(yǎng)因子(brain derived neurotrophic factor, BDNF)及活性調(diào)節(jié)細(xì)胞骨架聯(lián)合的蛋白(recombinant activity regulated cytoskeleton associated protein, Arc)表達(dá)[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(jìn)而改善認(rèn)知障礙。

5 新報道的PDE5抑制劑

西地那非類似物優(yōu)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(yīng)較少[33]。優(yōu)克那非也具有抗中風(fēng)、抗神經(jīng)炎癥、促進(jìn)神經(jīng)發(fā)生及改善認(rèn)知障礙等神經(jīng)保護(hù)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(zhì)，在它被證實可抑制PDE5之前，就有研究發(fā)現(xiàn)其具有保護(hù)大腦缺血性損傷的功效，表明ICA具有潛在神經(jīng)保護(hù)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(jīng)保護(hù)作用的研究，發(fā)現(xiàn)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(dá)，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(rèn)知障礙，減少神經(jīng)細(xì)胞凋亡來發(fā)揮神經(jīng)保護(hù)作用[41]。此外，ICA能夠通過對抗神經(jīng)炎癥反應(yīng)來預(yù)防腦缺血/再灌注損傷[42]。體外實驗中，我們采用氧糖剝奪/復(fù)氧細(xì)胞模型證明ICA可通過抗凋亡及調(diào)節(jié)自噬起到神經(jīng)保護(hù)作用[43]。然而，ICA會在體內(nèi)代謝為淫羊藿次苷Ⅱ(icariside Ⅱ, ICSⅡ)[44]，則有理由假設(shè)ICS Ⅱ也有類似神經(jīng)保護(hù)效應(yīng)。我們的研究證實了ICSⅡ可通過降低中風(fēng)大鼠及AD大鼠海馬的PDE5蛋白產(chǎn)生，從而改善其神經(jīng)功能及認(rèn)知障礙，減少促炎性因子及神經(jīng)元的死亡，進(jìn)而發(fā)揮神經(jīng)保護(hù)作用[45-46]。

6 展望

大量臨床前實驗證實PDE5抑制劑具有神經(jīng)保護(hù)作用，效果顯著，且不良反應(yīng)較少。本文結(jié)合國內(nèi)外研究結(jié)果及所在團(tuán)隊研究報道，系統(tǒng)地綜述了PDE5抑制劑抗中風(fēng)、抗氧化、抗神經(jīng)炎癥及改善認(rèn)知障礙等神經(jīng)保護(hù)作用及相關(guān)機(jī)制。這為更好地開發(fā)利用PDE5抑制劑在臨床防治中樞神經(jīng)系統(tǒng)疾病的深入研究提供了線索，對開發(fā)新型PDE5抑制劑具有現(xiàn)實的指導(dǎo)意義。

[1] 嚴(yán) 鈺,丁啟龍. 中藥單體及有效部位的神經(jīng)保護(hù)作用機(jī)制研究進(jìn)展[J]. 藥學(xué)進(jìn)展，2007, 31(4): 154-8.

[1] Yan Y, Ding Q L. Advances in the mechanistic study on neuroprotective actions of the monomers and active components from Chinese traditional medicines[J].ProgPharmSci, 2007, 31(4): 154-8.

[2] Teich A F, Sakurai M, Patel M, et al. PDE5 exists in human neurons and is a viable therapeutic target for neurologic disease[J].JAlzheimersDis, 2016, 52(1): 295-302.

[3] Shimizu-Albergine M, Rybalkin S D, Rybalkina I G, et al. Individual cerebellar purkinje cells express different cGMP phosphodiesterases(PDEs):invivophosphorylation of cGMP-specific PDE(PDE5) as an indicator of cGMP-dependent protein kinase(PKG) activation[J].JNeurosci, 2003, 23(16): 6452-9.

[4] Zhang R L, Zhang Z G, Chopp M. Targeting nitric oxide in the subacute restorative treatment of ischemic stroke[J].ExpertOpinInvestigDrugs, 2013, 22(7): 843-51.

[5] Peixoto C A, Nunes A K, Garcia-Osta A. Phosphodiesterase-5 inhibitors: action on the signaling pathways of neuroinflammation, neurodegeneration, and cognition[J].MediatorsInflamm, 2015, 2015(2): 1-17.

[6] 高 梅，劉 睿，杜冠華. 缺血性中風(fēng)治療新策略—靶向神經(jīng)血管單元[J]. 中國臨床藥理與治療學(xué)，2008, 13(7): 813-21.

[6] Gao M, Liu R, Du G H. Therapeutic strategies for stroke: targeting the neurovascular unit[J].ChinJClinPharmTherap, 2008, 13(7): 813-21.

[7] Zhang R, Wang L, Zhang L, et al. Nitric oxide enhances angiogenesis via the synthesis of vascular endothelial growth factor and cGMP after stroke in the rat[J].CircRes, 2003, 92(3): 308-13.

[8] Zhang L, Zhang R L, Wang Y, et al. Functional recovery in aged and young rats after embolic stroke: treatment with a phosphodiesterase type 5 inhibitor[J].Stroke, 2005, 36(4): 847-52.

[9] 甘 靖，范周田. 磷酸二酯酶5抑制劑促進(jìn)大鼠腦缺血/再灌注后神經(jīng)及血管再生的研究[J]. 中華老年心腦血管病雜志，2012, 14(12): 1312-5.

[9] Gan J, Fan Z T. Phosphodiesterase 5 inhibitor sildenafil stimulates neurogenesis and revascularization in rats following cerebral/ischemia reperfusion[J].ChinJGeriatrHeartBrainVesDis, 2012, 14(12): 1312-5.

[10]Zhang L, Zhang Z, Zhang R L, et al. Tadalafil, a long-acting type 5 phosphodiesterase isoenzyme inhibitor, improves neurological functional recovery in a rat model of embolic stroke[J].BrainRes, 2006, 1118(1): 192-8.

[11]Li L, Jiang Q, Zhang L, et al. Angiogenesis and improved cerebral blood flow in the ischemic boundary area detected by MRI after administration of sildenafil to rats with embolic stroke[J].BrainRes, 2007, 1132(1): 185-92.

[12]Alvarez-Buylla A , Lim D A. For the long run: maintaining germinal niches in the adult brain[J].Neuron, 2004, 41(5): 683-6.

[13]Zhang R, Wang Y, Zhang L, et al. Sildenafil (Viagra) induces neurogenesis and promotes functional recovery after stroke in rats[J].Stroke, 2002, 33(11): 2675-80.

[14]Zhang R L, Chopp M, Roberts C, et al. Sildenafil enhances neurogenesis and oligodendrogenesis in ischemic brain of middle-aged mouse[J].PLoSOne, 2012, 7(10): e48141.

[15]Zhang R L, Zhang Z, Zhang L, et al. Delayed treatment with sildenafil enhances neurogenesis and improves functional recovery in aged rats after focal cerebral ischemia[J].JNeurosciRes, 2006, 83(7):1213-9.

[16]王洪超，李偉偉，李雪飛, 等. 鞘內(nèi)西地那非能減輕神經(jīng)病理性疼痛大鼠的痛覺高敏[J]. 中國藥理學(xué)通報，2012, 28(7): 982-5.

[16]Wang H C, Li W W, Li X F, et al. Attenuating effect of intrathecal sildenafil on hyperalgesia in rats with neuropathic pain[J].ChinPharmacolBull, 2012, 28(7): 982-5.

[17]Zhao S, Zhang L, Lian G, et al. Sildenafil attenuates LPS-induced pro-inflammatory responses through down-regulation of intracellular ROS-related MAPK/NF-kappaB signaling pathways in N9 microglia[J].IntImmunopharmacol, 2011, 11(4): 468-74.

[18]Iadecola C, Anrather J. The immunology of stroke: from mechanisms to translation[J].NatMed, 2011, 17(7): 796-808.

[19]Moretti R, Leger P L, Besson V C, et al. Sildenafil, a cyclic GMP phosphodiesterase inhibitor, induces microglial modulation after focal ischemia in the neonatal mouse brain[J].JNeuroinflammation, 2016, 13(1): 1-12.

[20]Hernandez-Rabaza V, Agusti A, Cabrera-Pastor A, et al. Sildenafil reduces neuroinflammation and restores spatial learning in rats with hepatic encephalopathy: underlying mechanisms[J].JNeuroinflammation, 2015, 12(1): 1-12.

[21]Raposo C, Nunes A K, Luna R L, et al. Sildenafil(Viagra) protective effects on neuroinflammation: the role of iNOS/NO system in an inflammatory demyelination model[J].MediatorsInflamm, 2013, 2013(1): 321460.

[22]Lemasters J J, Nieminen A L, Qian T, et al. The mitochondrial permeability transition in cell death: a common mechanism in necrosis, apoptosis and autophagy[J].BiochimBiophysActa, 1998, 1366(1-2): 177-96.

[23]Rodriguez-Perez A I, Borrajo A, Rodriguez-Pallares J, et al. Interaction between NADPH-oxidase and Rho-kinase in angiotensin II-induced microglial activation[J].Glia, 2015, 63(3): 466-82.

[24]Park J, Min J S, Kim B, et al. Mitochondrial ROS govern the LPS-induced pro-inflammatory response in microglia cells by regulating MAPK and NF-kappaB pathways[J].NeurosciLett, 2015, 584: 191-6.

[25]Hotston M R, Jeremy J Y, Bloor J, et al. Sildenafil inhibits the up-regulation of phosphodiesterase type 5 elicited with nicotine and tumour necrosis factor-alpha in cavernosal vascular smooth muscle cells: mediation by superoxide[J].BJUInt, 2007, 99(3): 612-8.

[26]Jeremy J Y, Koupparis A, Muzaffar S, et al. Is the therapeutic action of sildenafil mediated partly through the inhibition of superoxide formation[J].BJUInt, 2005, 5(7): 930-1.

[27]Sung S K, Woo J S, Kim Y H, et al. Sildenafil ameliorates advanced glycation end products-induced mitochondrial dysfunction in HT-22 hippocampal neuronal cells[J].JKoreanNeurosurgSoc, 2016, 59(3): 259-68.

[28]Muzaffar S, Shukla N, Jeremy J Y. Nicotinamide adenine dinucleotide phosphate oxidase: a promiscuous therapeutic target for cardiovascular drugs[J].TrendsCardiovascMed, 2005, 15(8): 278-82.

[29]Saavedra A, Giralt A, Arumi H, et al. Regulation of hippocampal cGMP levels as a candidate to treat cognitive deficits in Huntington′s disease[J].PLoSOne, 2013, 8(9): 5932-40.

[30]Ugarte A, Gil-Bea F, Garcia-Barroso C, et al. Decreased levels of guanosine 3′, 5′-monophosphate(cGMP) in cerebrospinal fluid(CSF) are associated with cognitive decline and amyloid pathology in Alzheimer′s disease[J].NeuropatholApplNeurobiol, 2015, 41(4): 471-82.

[31]Garcia-Barroso C, Ricobaraza A, Pascual-Lucas M, et al. Tadalafil crosses the blood-brain barrier and reverses cognitive dysfunction in a mouse model of AD[J].Neuropharmacology, 2013, 64(1): 114-23.

[32]Cuadrado-Tejedor M, Hervias I, Ricobaraza A, et al. Sildenafil restores cognitive function without affecting beta-amyloid burden in a mouse model of Alzheimer′s disease[J].BrJPharmacol, 2011, 164(8): 2029-41.

[33]Wang J, Jiang Y, Wang Y, et al. A rapid and sensitive LC-MS/MS assay to quantify yonkenafil in rat plasma with application to preclinical pharmacokinetics studies[J].JPharmBiomedAnal, 2008, 47(47): 985-9.

[34]Zhu L, Yang J Y, Xue X, et al. A novel phosphodiesterase-5 inhibitor: yonkenafil modulates neurogenesis, gliosis to improve cognitive function and ameliorates amyloid burden in an APP/PS1 transgenic mice model[J].MechAgeingDev, 2015, 150: 34-45.

[35]Zhao S, Yang J, Wang L, et al. NF-kappaB upregulates type 5 phosphodiesterase in N9 microglial cells: inhibition by sildenafil and yonkenafil[J].MolNeurobiol, 2016, 53(4): 2647-58.

[36]Chen X, Wang N, Liu Y, et al. Yonkenafil: a novel phosphodiesterase type 5 inhibitor induces neuronal network potentiation by a cGMP-dependent Nogo-R axis in acute experimental stroke[J].ExpNeurol, 2014, 261: 267-77.

[37]Zhu H R, Wang Z Y, Zhu X L, et al. Icariin protects against brain injury by enhancing SIRT1-dependent PGC-1alpha expression in experimental stroke[J].Neuropharmacology, 2010, 59(1-2): 70-6.

[38]廖 暉，Jacob R. 經(jīng)NO-cGMP-PDE5通路治療勃起功能障礙的中藥研究進(jìn)展[J]. 中華男科醫(yī)學(xué)雜志，2012，18(3)：260-5.

[38]Liao H, Jacob R. Chinese herbal drugs for erectile dysfunction through NO-cGMP-PDE5 signaling pathway[J].NatJAndrol, 2012, 18(3): 260-5.

[39]Jin F, Gong Q H, Xu Y S, et al. Icariin, a phosphodiesterase-5 inhibitor, improves learning and memory in APP/PS1 transgenic mice by stimulation of NO/cGMP signalling[J].IntJNeuropsychopharmacol, 2014, 17(6): 871-81.

[40]Li F, Dong H X, Gong Q H, et al. Icariin decreases both APP and Abeta levels and increases neurogenesis in the brain of Tg2576 mice[J].Neuroscience, 2015, 304: 29-35.

[41]Zong N, Li F, Deng Y Y, et al. Icariin, a major constituent from epimedium brevicornum, attenuates ibotenic acid-induced excitotoxicity in rat hippocampus[J].BehavBrainRes, 2016, 313: 111-9.

[42]Xiong D, Deng Y, Huang B, et al. Icariin attenuates cerebral ischemia-reperfusion injury through inhibition of inflammatory response mediated by NF-kappaB, PPARalpha and PPARgamma in rats[J].IntImmunopharmacol, 2016, 30: 157-62.

[43]Mo Z T, Zhai Y R, Gong Q H, et al. Icariin attenuates OGD/R-induced autophagy via Bcl-2-dependent cross talk between apoptosis and autophagy in PC12 cells[J].Evid-BasedComplementAlternatMed, 2016, 2016:4343084.

[44]Cai W J, Huang J H, Zhang S Q, et al. Icariin and its derivative icariside II extend health span via insulin/IGF-1 pathway in C. Elegans[J].PLoSOne, 2011, 6(12): e28835.

[45]Deng Y, Xiong D, Yin C, et al. Icariside II protects against cerebral ischemia-reperfusion injury in rats via nuclear factor-kappaB inhibition and peroxisome proliferator-activated receptor up-regulation[J].NeurochemInt, 2016, 96: 56-61.

[46]Yin C, Deng Y, Gao J, et al. Icariside II, a novel phosphodiesterase-5 inhibitor, attenuates streptozotocin-induced cognitive deficits in rats[J].Neuroscience, 2016, 328: 69-79.

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(xué)基金資助項目(No 81560666)；貴州省淫羊藿開發(fā)利用科技創(chuàng)新人才團(tuán)隊[No 黔科合人才團(tuán)隊(2015)4023號]

徐 凡(1993-)，男，碩士生，研究方向：神經(jīng)藥理學(xué)，E-mail: xufan_jakie@163.com； 高健美(1979-)，女，博士，副教授，碩士生導(dǎo)師，研究方向：神經(jīng)藥理學(xué)，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