Tetramethylpyrazine Attenuates Oxygen-glucose Deprivation-induced Neuronal Damage through Inhibition of the HIF-1α/BNIP3 Pathway: from Network Pharmacological Finding to Experimental Validation-Reference-Cited by-全球学者库

Tetramethylpyrazine Attenuates Oxygen-glucose Deprivation-induced Neuronal Damage through Inhibition of the HIF-1α/BNIP3 Pathway: from Network Pharmacological Finding to Experimental Validation

Published:2023-02 Issue:7 Volume:29 Page:543-554
ISSN:1381-6128
Container-title:Current Pharmaceutical Design
language:en
Short-container-title:CPD

Author:

Xu Shixin¹²,Zhang Nannan¹³,Cao Lanlan¹²,Liu Lu¹⁴,Deng Hao¹²,Hua Shengyu⁵,Zhang Yunsha⁶

Affiliation:

1. Medical Experiment Center, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China

2. Tianjin Key Laboratory of Translational Research of TCM Prescription and Syndrome, Tianjin, China

3. Dongcheng District Community Health Service Management Center, Beijing, China

4. Binhai New Area Hospital of TCM, Fourth Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China

5. Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China

6. School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China

Abstract

Aims:A network pharmacological analysis combined with experimental validation was used to investigate the neuroprotective mechanism of the natural product Tetramethylpyrazine (TMP).Background:Protecting neurons is critical for acute ischemic stroke treatment. Tetramethylpyrazine is a bioactive component extracted from Chuanxiong. The neuroprotective potential of TMP has been reported, but a systematic analysis of its mechanism has not been performed.Objective:Based on the hints of network pharmacology and bioinformatics analysis, the mechanism by which TMP alleviates oxygen-glucose deprivation-induced neuronal damage through inhibition of the HIF-1α/BNIP3 pathway was verified.Methods:In this study, we initially used network pharmacology and bioinformatics analyses to elucidate the mechanisms involved in TMP's predictive targets on a system level. The HIF-1α/BNIP3 pathway mediating the cellular response to hypoxia and apoptosis was considered worthy of focus in the bioinformatic analysis. An oxygen-glucose deprivation (OGD)-induced PC12 cell injury model was established for functional and mechanical validation. Cell viability, lactate dehydrogenase leakage, intracellular reactive oxygen species, percentage of apoptotic cells, and Caspase-3 activity were determined to assess the TMP's protective effects. Transfection with siRNA/HIF-1α or pcDNA/HIF-1α plasmids to silence or overexpress hypoxia-inducible factor 1α (HIF-1α). The role of HIF-1α in OGD-injured cells was observed first. After that, TMP's regulation of the HIF-1α/BNIP3 pathway was investigated. The pcDNA3.1/HIF-1α-positive plasmids were applied in rescue experiments.Results:The results showed that TMP dose-dependently attenuated OGD-induced cell injury. The expression levels of HIF-1α, BNIP3, and the Bax/Bcl-2 increased significantly with increasing OGD duration. Overexpression of HIF-1α decreased cell viability, increased BNIP3 expression, and Bax/Bcl-2 ratio; siRNA-HIF-1α showed the opposite effect. TMP treatment suppressed HIF-1α, BNIP3 expression, and the Bax/Bcl-2 ratio and was reversed by HIF-1α overexpression.Conclusion:Our study shows that TMP protects OGD-damaged PC12 cells by inhibiting the HIF-1α/BNIP3 pathway, which provides new insights into the mechanism of TMP and its neuroprotective potential.

Publisher

Bentham Science Publishers Ltd.

Subject

Drug Discovery,Pharmacology

Reference41 articles.

1. Kassebaum N.J.; Arora M.; Barber R.M.; Bhutta Z.A.; Brown J.; Carter A.; Casey D.C.; Charlson F.J.; Coates M.M.; Coggeshall M.; Cornaby L.; Dandona L.; Dicker D.J.; Erskine H.E.; Ferrari A.J.; Fitzmaurice C.; Foreman K.; Forouzanfar M.H.; Fullman N.; Gething P.W.; Goldberg E.M.; Graetz N.; Haagsma J.A.; Hay S.I.; Johnson C.O.; Kemmer L.; Khalil I.A.; Kinfu Y.; Kutz M.J.; Kyu H.H.; Leung J.; Liang X.; Lim S.S.; Lozano R.; Mensah G.A.; Mikesell J.; Mokdad A.H.; Mooney M.D.; Naghavi M.; Nguyen G.; Nsoesie E.; Pigott D.M.; Pinho C.; Rankin Z.; Reinig N.; Salomon J.A.; Sandar L.; Smith A.; Sorensen R.J.D.; Stanaway J.; Steiner C.; Teeple S.; Troeger C.; Truelsen T.; VanderZanden A.; Wagner J.A.; Wanga V.; Whiteford H.A.; Zhou M.; Zoeckler L.; Abajobir A.A.; Abate K.H.; Abbafati C.; Abbas K.M.; Abd-Allah F.; Abraham B.; Abubakar I.; Abu-Raddad L.J.; Abu-Rmeileh N.M.E.; Achoki T.; Ackerman I.N.; Adebiyi A.O.; Adedeji I.A.; Adsuar J.C.; Afanvi K.A.; Afshin A.; Agardh E.E.; Agarwal A.; Agarwal S.K.; Ahmed M.B.; Kiadaliri A.A.; Ahmadieh H.; Akseer N.; Al-Aly Z.; Alam K.; Alam N.K.M.; Aldhahri S.F.; Alegretti M.A.; Aleman A.V.; Alemu Z.A.; Alexander L.T.; Ali R.; Alkerwi A.; Alla F.; Allebeck P.; Allen C.; Alsharif U.; Altirkawi K.A.; Martin E.A.; Alvis-Guzman N.; Amare A.T.; Amberbir A.; Amegah A.K.; Amini H.; Ammar W.; Amrock S.M.; Anderson G.M.; Anderson B.O.; Antonio C.A.T.; Anwari P.; Ärnlöv J.; Arsenijevic V.S.A.; Artaman A.; Asayesh H.; Asghar R.J.; Avokpaho E.F.G.A.; Awasthi A.; Quintanilla B.P.A.; Azzopardi P.; Bacha U.; Badawi A.; Balakrishnan K.; Banerjee A.; Barac A.; Barker-Collo S.L.; Bärnighausen T.; Barregard L.; Barrero L.H.; Basu S.; Bayou T.A.; Beardsley J.; Bedi N.; Beghi E.; Bell B.; Bell M.L.; Benjet C.; Bennett D.A.; Bensenor I.M.; Berhane A.; Bernabé E.; Betsu B.D.; Beyene A.S.; Bhala N.; Bhansali A.; Bhatt S.; Biadgilign S.; Bienhoff K.; Bikbov B.; Abdulhak A.A.B.; Biryukov S.; Bisanzio D.; Bjertness E.; Blore J.D.; Borschmann R.; Boufous S.; Bourne R.R.A.; Brainin M.; Brazinova A.; Breitborde N.J.K.; Brugha T.S.; Buchbinder R.; Buckle G.C.; Butt Z.A.; Calabria B.; Campos-Nonato I.R.; Campuzano J.C.; Carabin H.; Carapetis J.R.; Cárdenas R.; Carrero J.J.; Castañeda-Orjuela C.A.; Rivas J.C.; Catalá-López F.; Cavalleri F.; Chang J-C.; Chiang P.P-C.; Chibalabala M.; Chibueze C.E.; Chisumpa V.H.; Choi J-Y.J.; Choudhury L.; Christensen H.; Ciobanu L.G.; Colistro V.; Colomar M.; Colquhoun S.M.; Cortinovis M.; Crump J.A.; Damasceno A.; Dandona R.; Dargan P.I.; das Neves J.; Davey G.; Davis A.C.; Leo D.D.; Degenhardt L.; Gobbo L.C.D.; Derrett S.; Jarlais D.C.D.; deVeber G.A.; Dharmaratne S.D.; Dhillon P.K.; Ding E.L.; Doyle K.E.; Driscoll T.R.; Duan L.; Dubey M.; Duncan B.B.; Ebrahimi H.; Ellenbogen R.G.; Elyazar I.; Endries A.Y.; Ermakov S.P.; Eshrati B.; Esteghamati A.; Estep K.; Fahimi S.; Farid T.A.; Farinha C.S.S.; Faro A.; Farvid M.S.; Farzadfar F.; Feigin V.L.; Fereshtehnejad S-M.; Fernandes J.G.; Fernandes J.C.; Fischer F.; Fitchett J.R.A.; Foigt N.; Fowkes F.G.R.; Franklin R.C.; Friedman J.; Frostad J.; Fürst T.; Futran N.D.; Gabbe B.; Gankpé F.G.; Garcia-Basteiro A.L.; Gebrehiwot T.T.; Gebremedhin A.T.; Geleijnse J.M.; Gibney K.B.; Gillum R.F.; Ginawi I.A.M.; Giref A.Z.; Giroud M.; Gishu M.D.; Giussani G.; Godwin W.W.; Gomez-Dantes H.; Gona P.; Goodridge A.; Gopalani S.V.; Gotay C.C.; Goto A.; Gouda H.N.; Gugnani H.; Guo Y.; Gupta R.; Gupta R.; Gupta V.; Gutiérrez R.A.; Hafezi-Nejad N.; Haile D.; Hailu A.D.; Hailu G.B.; Halasa Y.A.; Hamadeh R.R.; Hamidi S.; Hammami M.; Handal A.J.; Hankey G.J.; Harb H.L.; Harikrishnan S.; Haro J.M.; Hassanvand M.S.; Hassen T.A.; Havmoeller R.; Hay R.J.; Hedayati M.T.; Heredia-Pi I.B.; Heydarpour P.; Hoek H.W.; Hoffman D.J.; Horino M.; Horita N.; Hosgood H.D.; Hoy D.G.; Hsairi M.; Huang H.; Huang J.J.; Iburg K.M.; Idrisov B.T.; Innos K.; Inoue M.; Jacobsen K.H.; Jauregui A.; Jayatilleke A.U.; Jeemon P.; Jha V.; Jiang G.; Jiang Y.; Jibat T.; Jimenez-Corona A.; Jin Y.; Jonas J.B.; Kabir Z.; Kajungu D.K.; Kalkonde Y.; Kamal R.; Kan H.; Kandel A.; Karch A.; Karema C.K.; Karimkhani C.; Kasaeian A.; Katibeh M.; Kaul A.; Kawakami N.; Kazi D.S.; Keiyoro P.N.; Kemp A.H.; Kengne A.P.; Keren A.; Kesavachandran C.N.; Khader Y.S.; Khan A.R.; Khan E.A.; Khang Y-H.; Khoja T.A.M.; Khubchandani J.; Kieling C.; Kim C.; Kim D.; Kim Y.J.; Kissoon N.; Kivipelto M.; Knibbs L.D.; Knudsen A.K.; Kokubo Y.; Kolte D.; Kopec J.A.; Koul P.A.; Koyanagi A.; Defo B.K.; Kuchenbecker R.S.; Bicer B.K.; Kuipers E.J.; Kumar G.A.; Kwan G.F.; Lalloo R.; Lallukka T.; Larsson A.; Latif A.A.; Lavados P.M.; Lawrynowicz A.E.B.; Leasher J.L.; Leigh J.; Leung R.; Li Y.; Li Y.; Lipshultz S.E.; Liu P.Y.; Liu Y.; Lloyd B.K.; Logroscino G.; Looker K.J.; Lotufo P.A.; Lucas R.M.; Lunevicius R.; Lyons R.A.; Razek H.M.A.E.; Mahdavi M.; Majdan M.; Majeed A.; Malekzadeh R.; Malta D.C.; Marcenes W.; Martinez-Raga J.; Masiye F.; Mason-Jones A.J.; Matzopoulos R.; Mayosi B.M.; McGrath J.J.; McKee M.; Meaney P.A.; Mehari A.; Melaku Y.A.; Memiah P.; Memish Z.A.; Mendoza W.; Meretoja A.; Meretoja T.J.; Mesfin Y.M.; Mhimbira F.A.; Millear A.; Miller T.R.; Mills E.J.; Mirarefin M.; Mirrakhimov E.M.; Mitchell P.B.; Mock C.N.; Mohammad K.A.; Mohammadi A.; Mohammed S.; Monasta L.; Hernandez J.C.M.; Montico M.; Moradi-Lakeh M.; Mori R.; Mueller U.O.; Mumford J.E.; Murdoch M.E.; Murthy G.V.S.; Nachega J.B.; Naheed A.; Naldi L.; Nangia V.; Newton J.N.; Ng M.; Ngalesoni F.N.; Nguyen Q.L.; Nisar M.I.; Pete P.M.N.; Nolla J.M.; Norheim O.F.; Norman R.E.; Norrving B.; Obermeyer C.M.; Ogbo F.A.; Oh I-H.; Oladimeji O.; Olivares P.R.; Olusanya B.O.; Olusanya J.O.; Oren E.; Ortiz A.; Ota E.; Oyekale A.S.; Pa M.; Park E-K.; Parsaeian M.; Patten S.B.; Patton G.C.; Pedro J.M.; Pereira D.M.; Perico N.; Pesudovs K.; Petzold M.; Phillips M.R.; Piel F.B.; Pillay J.D.; Pishgar F.; Plass D.; Polinder S.; Popova S.; Poulton R.G.; Pourmalek F.; Prasad N.M.; Qorbani M.; Rabiee R.H.S.; Radfar A.; Rafay A.; Rahimi K.; Rahimi-Movaghar V.; Rahman M.; Rahman M.H.U.; Rahman S.U.; Rai D.; Rai R.K.; Rajsic S.; Raju M.; Ram U.; Ranganathan K.; Refaat A.H.; Reitsma M.B.; Remuzzi G.; Resnikoff S.; Reynolds A.; Ribeiro A.L.; Ricci S.; Roba H.S.; Rojas-Rueda D.; Ronfani L.; Roshandel G.; Roth G.A.; Roy A.; Sackey B.B.; Sagar R.; Sanabria J.R.; Sanchez-Niño M.D.; Santos I.S.; Santos J.V.; Sarmiento-Suarez R.; Sartorius B.; Satpathy M.; Savic M.; Sawhney M.; Schmidt M.I.; Schneider I.J.C.; Schutte A.E.; Schwebel D.C.; Seedat S.; Sepanlou S.G.; Servan-Mori E.E.; Shahraz S.; Shaikh M.A.; Sharma R.; She J.; Sheikhbahaei S.; Shen J.; Sheth K.N.; Shibuya K.; Shigematsu M.; Shin M-J.; Shiri R.; Sigfusdottir I.D.; Silva D.A.S.; Silverberg J.I.; Simard E.P.; Singh A.; Singh J.A.; Singh P.K.; Skirbekk V.; Skogen J.C.; Soljak M.; Søreide K.; Sorensen R.J.D.; Sreeramareddy C.T.; Stathopoulou V.; Steel N.; Stein D.J.; Stein M.B.; Steiner T.J.; Stovner L.J.; Stranges S.; Stroumpoulis K.; Sunguya B.F.; Sur P.J.; Swaminathan S.; Sykes B.L.; Szoeke C.E.I.; Tabarés-Seisdedos R.; Tandon N.; Tanne D.; Tavakkoli M.; Taye B.; Taylor H.R.; Ao B.J.T.; Tegegne T.K.; Tekle D.Y.; Terkawi A.S.; Tessema G.A.; Thakur J.S.; Thomson A.J.; Thorne-Lyman A.L.; Thrift A.G.; Thurston G.D.; Tobe-Gai R.; Tonelli M.; Topor-Madry R.; Topouzis F.; Tran B.X.; Truelsen T.; Dimbuene Z.T.; Tsilimbaris M.; Tura A.K.; Tuzcu E.M.; Tyrovolas S.; Ukwaja K.N.; Undurraga E.A.; Uneke C.J.; Uthman O.A.; van Gool C.H.; van Os J.; Vasankari T.; Vasconcelos A.M.N.; Venketasubramanian N.; Violante F.S.; Vlassov V.V.; Vollset S.E.; Wagner G.R.; Wallin M.T.; Wang L.; Weichenthal S.; Weiderpass E.; Weintraub R.G.; Werdecker A.; Westerman R.; Wijeratne T.; Wilkinson J.D.; Williams H.C.; Wiysonge C.S.; Woldeyohannes S.M.; Wolfe C.D.A.; Won S.; Xu G.; Yadav A.K.; Yakob B.; Yan L.L.; Yano Y.; Yaseri M.; Ye P.; Yip P.; Yonemoto N.; Yoon S-J.; Younis M.Z.; Yu C.; Zaidi Z.; Zaki M.E.S.; Zeeb H.; Zodpey S.; Zonies D.; Zuhlke L.J.; Vos T.; Lopez A.D.; Murray C.J.L.; Global, regional, and national disability-adjusted life-years (DALYs) for 315 diseases and injuries and healthy life expectancy (HALE), 1990-2015: A systematic analysis for the global burden of disease study 2015. Lancet 2016,388(10053),1603-1658

2. Moskowitz M.A.; Lo E.H.; Iadecola C.; The science of stroke: Mechanisms in search of treatments. Neuron 2010,67(2),181-198

3. Baron J.C.; Protecting the ischaemic penumbra as an adjunct to thrombectomy for acute stroke. Nat Rev Neurol 2018,14(6),325-337

4. Chen Z.; Zhang C.; Gao F.; Fu Q.; Fu C.; He Y.; Zhang J.; A systematic review on the rhizome of Ligusticum chuanxiong Hort (Chuanxiong). Food Chem Toxicol 2018,119,309-325

5. Zhao Y.; Liu Y.; Chen K.; Mechanisms and clinical application of tetramethylpyrazine (an interesting natural compound isolated from Ligusticum wallichii): Current status and perspective. Oxid Med Cell Longev 2016,2016,1-9