Clinical Significance of DKK2 Protein in Cerebral Ischemia-reperfusion Injury

NCT ID: NCT05585255

Last Updated: 2024-03-25

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Total Enrollment

108 participants

Study Classification

OBSERVATIONAL

Study Start Date

2022-09-01

Study Completion Date

2024-09-30

Brief Summary

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The study is a two-center prospective cohort clinical trial. The primary purpose of this trial is to identify the pattern of DKK2 serum levels in ischemic stroke patients after revascularization therapy and determine the correlation between serum DKK2 levels and prognosis.

Detailed Description

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Ischemic stroke refers to ischaemic and hypoxic necrosis of brain tissue caused by narrowing or occlusion of the blood vessels in the brain and accounts for approximately 80% of all strokes. It is characterized by high morbidity, mortality, disability, and recurrence rates. Reperfusion is currently the most effective treatment for the acute phase of ischaemic stroke, including pharmacological thrombolysis and mechanical embolization. Although successful revascularization can reperfuse areas of cerebral ischemia, it can cause acute cerebrovascular damage while restoring blood supply to brain tissue, leading to disruption of the blood-brain barrier (BBB), increased risk of cerebral edema and hemorrhagic transformation, and increased inflammation of neural tissue, which can further damage brain tissue. Targeted reduction of endothelial damage from ischemia-reperfusion will therefore effectively protect neurons from subsequent damage, thereby minimizing neurological impairment after stroke and maximizing the benefit of revascularisation therapy.

The Wnt signaling pathway has been identified by several research groups worldwide as a key regulatory pathway in the maintenance of cerebrovascular and neural cell function. The DKK (Dickkopf-related protein) family of proteins is the most representative group of classical Wnt signaling pathway inhibitors. DKK proteins competitively bind to the Wnt co-receptor LRP5/6, thereby inhibiting the activity of Wnt proteins and exerting their inhibitory effects on the Wnt/β-catenin signaling pathway. We initially found that DKK2 serum levels increased significantly after 4.5 h of recanalization therapy in 20 patients with large vessel occlusive acute stroke, and decreased after 24 h. Increased DKK2 levels were strongly associated with an unfavorable prognosis. This was corroborated in animal models as well, DKK2 expression levels in ischaemic brain tissue and peripheral blood were both significantly elevated and rapidly upregulated within 6-12 h of the onset of cerebral ischemia-reperfusion in mice. In vitro cellular assays showed that DKK2 protein significantly inhibited the activity of the Wnt/β-catenin signaling pathway. We further study showed that upregulation of DKK2 protein levels in the blood of mice by intravenous administration of adenovirus expressing DKK2 protein significantly increased cerebral infarction and neurological impairment in mice with stroke. The increased expression of DKK2 protein in brain tissue is the main reason for the downregulation of Wnt/β-catenin signaling pathway activity after ischemia/reperfusion, which leads to blood-brain barrier damage, neuronal cell death, and neuroinflammation, and ultimately promotes brain tissue damage and neurological dysfunction. It is a new target for drug therapy and has great scientific significance and clinical application prospects.

This clinical study is conducted at Dongguan Hospital of Southern Medical University and Nanfang Hospital of Southern Medical University. Acute ischemic stroke patients with large vessel occlusion who received mechanical thrombectomy therapy and are successfully revascularized will be included and followed up for 90 d, along with testing serum levels of DKK2 protein to explore its correlation with the prognosis of enrolled patients. Venous blood samples will be collected before, and 24 h, 48 h, and 72 h after revascularization treatment in enrolled patients. Venous blood samples will be collected before and 0h, 24 h, 48 h, and 72 h after revascularisation treatment to test serum KKD2 level, and cranial CT examination will be performed before, 24 h, and 72 h after revascularization treatment to detect the occurrence of the transformation of hemorrhage, the severity of cerebral edema, and midline shift after revascularisation treatment. Blood-brain barrier injury-related indicators (MMP-9, ICAM-1) and inflammation-related indicators (IL-6, IL-1β, TNF-α, IL-10) will be measured at each time point of DKK2 testing. NIHSS scores will be evaluated before, 0h (immediately after revascularization treatment), 24 h, 48 h, 72 h, and 7 d after revascularization treatment. The mRS scores will be followed up at 30 days and 90 days after the onset to clarify the relationship between serum DKK2 levels and large vessel occlusion. We aim to investigate the mechanism of DKK2 causing adverse clinical outcomes such as BBB leakage, cerebral edema, and hemorrhagic transformation at a real-world clinical level by collecting blood samples, clinical follow-up, and neurological scoring from stroke patients by measuring DKK2 levels and brain imaging parameters for quantitative assessment.

Conditions

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Ischemic Stroke, Acute Ischemia-reperfusion Injury Cerebral Edema

Study Design

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Observational Model Type

COHORT

Study Time Perspective

PROSPECTIVE

Study Groups

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Acute ischemic stroke patients

Acute ischemic stroke patients with large vessel occlusion who received mechanical thrombectomy therapy and are successfully revascularized

enzyme-linked immunosorbent assay(ELISA)

Intervention Type DIAGNOSTIC_TEST

After allowing to stand at room temperature for 2h, blood samples are centrifuged at 4 ℃ for 15 min (12000 rpm) to collect the supernatant. Then, the levels of DKK2, IL-6, IL-1β, TNF-α, and IL-10 in the supernatants are tested by ELISA detection.

Interventions

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enzyme-linked immunosorbent assay(ELISA)

After allowing to stand at room temperature for 2h, blood samples are centrifuged at 4 ℃ for 15 min (12000 rpm) to collect the supernatant. Then, the levels of DKK2, IL-6, IL-1β, TNF-α, and IL-10 in the supernatants are tested by ELISA detection.

Intervention Type DIAGNOSTIC_TEST

Eligibility Criteria

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Inclusion Criteria

1. Age ≥ 18 years, \< 80 years, sex not limited;
2. Definite clinical diagnosis of acute ischemic stroke;
3. Baseline NIHSS score ≥ 6 and ≤ 25;
4. CTA/MRA/DSA examination suggests large vessel occlusion in the anterior circulation (internal carotid artery, M1/M2 segment of the middle cerebral artery);
5. The criteria for receiving endovascular treatment in accordance with the Chinese Guidelines for Early Endovascular Intervention in Acute Ischemic Stroke 2018 and have successful revascularization (TICI ≥ grade 2b);
6. Subjects or their legal representatives agree to the treatment and sign the informed consent form.

Exclusion Criteria

1. Patients with combined posterior circulation infarction;
2. The mRS ≥ 2 points before the current episode;
3. Patients who are to be treated with or have been treated with anticoagulants;
4. Patients with existing or active organ bleeding within 6 months of enrollment, including cerebral hemorrhage, subarachnoid hemorrhage, gastrointestinal tract hemorrhage, fundus hemorrhage, etc;
5. The presence of other intracranial pathologies, such as cerebrovascular malformations, cerebral venous lesions, tumors, and other diseases involving the cranium;
6. Severe organ dysfunction or failure;
7. Those with severe hematologic disorders or severe coagulation abnormalities;
8. Those with a history of severe trauma or major surgical procedures within 6 months prior to enrollment;
9. Pregnant or lactating women;
10. Patients with a life expectancy of less than 3 months or who for other reasons are unable to complete the study;
11. Unwillingness to be followed up or poor compliance with treatment;
12. Other conditions that the investigator considers unsuitable for enrollment.
Minimum Eligible Age

18 Years

Maximum Eligible Age

79 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Nanfang Hospital, Southern Medical University

OTHER

Sponsor Role lead

Responsible Party

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Huang Kaibin

associate chief physician

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Zhu Shi, PHD

Role: STUDY_CHAIR

Dongguan Hospital of Southern Medical University

Locations

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Dongguan Hospital of Southern Medical University

Dongguan, Guangdong, China

Site Status RECRUITING

Nanfang Hospital of Southern Medical University

Guangzhou, Guangdong, China

Site Status RECRUITING

Countries

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China

Central Contacts

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Kaibin Huang, PHD

Role: CONTACT

020-62787664

Zhu Shi, PHD

Role: CONTACT

0769-28636833

Facility Contacts

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Zhu Shi, PHD

Role: primary

0769-22679351

Kaibin Huang, PHD

Role: primary

(+86) 020-62787664

References

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GBD 2016 Stroke Collaborators. Global, regional, and national burden of stroke, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019 May;18(5):439-458. doi: 10.1016/S1474-4422(19)30034-1. Epub 2019 Mar 11.

Reference Type BACKGROUND
PMID: 30871944 (View on PubMed)

Zhou M, Wang H, Zeng X, Yin P, Zhu J, Chen W, Li X, Wang L, Wang L, Liu Y, Liu J, Zhang M, Qi J, Yu S, Afshin A, Gakidou E, Glenn S, Krish VS, Miller-Petrie MK, Mountjoy-Venning WC, Mullany EC, Redford SB, Liu H, Naghavi M, Hay SI, Wang L, Murray CJL, Liang X. Mortality, morbidity, and risk factors in China and its provinces, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2019 Sep 28;394(10204):1145-1158. doi: 10.1016/S0140-6736(19)30427-1. Epub 2019 Jun 24.

Reference Type BACKGROUND
PMID: 31248666 (View on PubMed)

Phipps MS, Cronin CA. Management of acute ischemic stroke. BMJ. 2020 Feb 13;368:l6983. doi: 10.1136/bmj.l6983.

Reference Type BACKGROUND
PMID: 32054610 (View on PubMed)

Ma H, Campbell BCV, Parsons MW, Churilov L, Levi CR, Hsu C, Kleinig TJ, Wijeratne T, Curtze S, Dewey HM, Miteff F, Tsai CH, Lee JT, Phan TG, Mahant N, Sun MC, Krause M, Sturm J, Grimley R, Chen CH, Hu CJ, Wong AA, Field D, Sun Y, Barber PA, Sabet A, Jannes J, Jeng JS, Clissold B, Markus R, Lin CH, Lien LM, Bladin CF, Christensen S, Yassi N, Sharma G, Bivard A, Desmond PM, Yan B, Mitchell PJ, Thijs V, Carey L, Meretoja A, Davis SM, Donnan GA; EXTEND Investigators. Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke. N Engl J Med. 2019 May 9;380(19):1795-1803. doi: 10.1056/NEJMoa1813046.

Reference Type BACKGROUND
PMID: 31067369 (View on PubMed)

Albers GW, Marks MP, Kemp S, Christensen S, Tsai JP, Ortega-Gutierrez S, McTaggart RA, Torbey MT, Kim-Tenser M, Leslie-Mazwi T, Sarraj A, Kasner SE, Ansari SA, Yeatts SD, Hamilton S, Mlynash M, Heit JJ, Zaharchuk G, Kim S, Carrozzella J, Palesch YY, Demchuk AM, Bammer R, Lavori PW, Broderick JP, Lansberg MG; DEFUSE 3 Investigators. Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging. N Engl J Med. 2018 Feb 22;378(8):708-718. doi: 10.1056/NEJMoa1713973. Epub 2018 Jan 24.

Reference Type BACKGROUND
PMID: 29364767 (View on PubMed)

Patel P, Yavagal D, Khandelwal P. Hyperacute Management of Ischemic Strokes: JACC Focus Seminar. J Am Coll Cardiol. 2020 Apr 21;75(15):1844-1856. doi: 10.1016/j.jacc.2020.03.006.

Reference Type BACKGROUND
PMID: 32299596 (View on PubMed)

Yang P, Zhang Y, Zhang L, Zhang Y, Treurniet KM, Chen W, Peng Y, Han H, Wang J, Wang S, Yin C, Liu S, Wang P, Fang Q, Shi H, Yang J, Wen C, Li C, Jiang C, Sun J, Yue X, Lou M, Zhang M, Shu H, Sun D, Liang H, Li T, Guo F, Ke K, Yuan H, Wang G, Yang W, Shi H, Li T, Li Z, Xing P, Zhang P, Zhou Y, Wang H, Xu Y, Huang Q, Wu T, Zhao R, Li Q, Fang Y, Wang L, Lu J, Li Y, Fu J, Zhong X, Wang Y, Wang L, Goyal M, Dippel DWJ, Hong B, Deng B, Roos YBWEM, Majoie CBLM, Liu J; DIRECT-MT Investigators. Endovascular Thrombectomy with or without Intravenous Alteplase in Acute Stroke. N Engl J Med. 2020 May 21;382(21):1981-1993. doi: 10.1056/NEJMoa2001123. Epub 2020 May 6.

Reference Type BACKGROUND
PMID: 32374959 (View on PubMed)

Moskowitz MA, Lo EH, Iadecola C. The science of stroke: mechanisms in search of treatments. Neuron. 2010 Jul 29;67(2):181-98. doi: 10.1016/j.neuron.2010.07.002.

Reference Type BACKGROUND
PMID: 20670828 (View on PubMed)

Shi K, Zou M, Jia DM, Shi S, Yang X, Liu Q, Dong JF, Sheth KN, Wang X, Shi FD. tPA Mobilizes Immune Cells That Exacerbate Hemorrhagic Transformation in Stroke. Circ Res. 2021 Jan 8;128(1):62-75. doi: 10.1161/CIRCRESAHA.120.317596. Epub 2020 Oct 19.

Reference Type BACKGROUND
PMID: 33070717 (View on PubMed)

Wang R, Zhu Y, Liu Z, Chang L, Bai X, Kang L, Cao Y, Yang X, Yu H, Shi MJ, Hu Y, Fan W, Zhao BQ. Neutrophil extracellular traps promote tPA-induced brain hemorrhage via cGAS in mice with stroke. Blood. 2021 Jul 8;138(1):91-103. doi: 10.1182/blood.2020008913.

Reference Type BACKGROUND
PMID: 33881503 (View on PubMed)

El-Benna J, Hurtado-Nedelec M, Marzaioli V, Marie JC, Gougerot-Pocidalo MA, Dang PM. Priming of the neutrophil respiratory burst: role in host defense and inflammation. Immunol Rev. 2016 Sep;273(1):180-93. doi: 10.1111/imr.12447.

Reference Type BACKGROUND
PMID: 27558335 (View on PubMed)

Chen R, Zhang X, Gu L, Zhu H, Zhong Y, Ye Y, Xiong X, Jian Z. New Insight Into Neutrophils: A Potential Therapeutic Target for Cerebral Ischemia. Front Immunol. 2021 Jul 14;12:692061. doi: 10.3389/fimmu.2021.692061. eCollection 2021.

Reference Type BACKGROUND
PMID: 34335600 (View on PubMed)

Jian Z, Liu R, Zhu X, Smerin D, Zhong Y, Gu L, Fang W, Xiong X. The Involvement and Therapy Target of Immune Cells After Ischemic Stroke. Front Immunol. 2019 Sep 11;10:2167. doi: 10.3389/fimmu.2019.02167. eCollection 2019.

Reference Type BACKGROUND
PMID: 31572378 (View on PubMed)

O'Collins VE, Macleod MR, Donnan GA, Horky LL, van der Worp BH, Howells DW. 1,026 experimental treatments in acute stroke. Ann Neurol. 2006 Mar;59(3):467-77. doi: 10.1002/ana.20741.

Reference Type BACKGROUND
PMID: 16453316 (View on PubMed)

Zhou Z, Lu J, Liu WW, Manaenko A, Hou X, Mei Q, Huang JL, Tang J, Zhang JH, Yao H, Hu Q. Advances in stroke pharmacology. Pharmacol Ther. 2018 Nov;191:23-42. doi: 10.1016/j.pharmthera.2018.05.012. Epub 2018 May 25.

Reference Type BACKGROUND
PMID: 29807056 (View on PubMed)

Elkins J, Veltkamp R, Montaner J, Johnston SC, Singhal AB, Becker K, Lansberg MG, Tang W, Chang I, Muralidharan K, Gheuens S, Mehta L, Elkind MSV. Safety and efficacy of natalizumab in patients with acute ischaemic stroke (ACTION): a randomised, placebo-controlled, double-blind phase 2 trial. Lancet Neurol. 2017 Mar;16(3):217-226. doi: 10.1016/S1474-4422(16)30357-X. Epub 2017 Feb 15.

Reference Type BACKGROUND
PMID: 28229893 (View on PubMed)

Nusse R, Clevers H. Wnt/beta-Catenin Signaling, Disease, and Emerging Therapeutic Modalities. Cell. 2017 Jun 1;169(6):985-999. doi: 10.1016/j.cell.2017.05.016.

Reference Type BACKGROUND
PMID: 28575679 (View on PubMed)

Clevers H, Nusse R. Wnt/beta-catenin signaling and disease. Cell. 2012 Jun 8;149(6):1192-205. doi: 10.1016/j.cell.2012.05.012.

Reference Type BACKGROUND
PMID: 22682243 (View on PubMed)

Routledge D, Scholpp S. Mechanisms of intercellular Wnt transport. Development. 2019 May 15;146(10):dev176073. doi: 10.1242/dev.176073.

Reference Type BACKGROUND
PMID: 31092504 (View on PubMed)

Chang J, Mancuso MR, Maier C, Liang X, Yuki K, Yang L, Kwong JW, Wang J, Rao V, Vallon M, Kosinski C, Zhang JJ, Mah AT, Xu L, Li L, Gholamin S, Reyes TF, Li R, Kuhnert F, Han X, Yuan J, Chiou SH, Brettman AD, Daly L, Corney DC, Cheshier SH, Shortliffe LD, Wu X, Snyder M, Chan P, Giffard RG, Chang HY, Andreasson K, Kuo CJ. Gpr124 is essential for blood-brain barrier integrity in central nervous system disease. Nat Med. 2017 Apr;23(4):450-460. doi: 10.1038/nm.4309. Epub 2017 Mar 13.

Reference Type BACKGROUND
PMID: 28288111 (View on PubMed)

Ji YB, Gao Q, Tan XX, Huang XW, Ma YZ, Fang C, Wang SN, Qiu LH, Cheng YX, Guo FY, Chang J. Lithium alleviates blood-brain barrier breakdown after cerebral ischemia and reperfusion by upregulating endothelial Wnt/beta-catenin signaling in mice. Neuropharmacology. 2021 Mar 15;186:108474. doi: 10.1016/j.neuropharm.2021.108474. Epub 2021 Jan 29.

Reference Type BACKGROUND
PMID: 33524408 (View on PubMed)

Ta S, Rong X, Guo ZN, Jin H, Zhang P, Li F, Li Z, Lin L, Zheng C, Gu Q, Zhang Y, Liu W, Yang Y, Chang J. Variants of WNT7A and GPR124 are associated with hemorrhagic transformation following intravenous thrombolysis in ischemic stroke. CNS Neurosci Ther. 2021 Jan;27(1):71-81. doi: 10.1111/cns.13457. Epub 2020 Sep 29.

Reference Type BACKGROUND
PMID: 32991049 (View on PubMed)

Song D, Zhang X, Chen J, Liu X, Xue J, Zhang L, Lan X. Wnt canonical pathway activator TWS119 drives microglial anti-inflammatory activation and facilitates neurological recovery following experimental stroke. J Neuroinflammation. 2019 Dec 6;16(1):256. doi: 10.1186/s12974-019-1660-8.

Reference Type BACKGROUND
PMID: 31810470 (View on PubMed)

Wei ZZ, Zhang JY, Taylor TM, Gu X, Zhao Y, Wei L. Neuroprotective and regenerative roles of intranasal Wnt-3a administration after focal ischemic stroke in mice. J Cereb Blood Flow Metab. 2018 Mar;38(3):404-421. doi: 10.1177/0271678X17702669. Epub 2017 Apr 21.

Reference Type BACKGROUND
PMID: 28430000 (View on PubMed)

Wang W, Li M, Wang Y, Wang Z, Zhang W, Guan F, Chen Q, Wang J. GSK-3beta as a target for protection against transient cerebral ischemia. Int J Med Sci. 2017 Mar 11;14(4):333-339. doi: 10.7150/ijms.17514. eCollection 2017.

Reference Type BACKGROUND
PMID: 28553165 (View on PubMed)

Wu MV, Hen R. The young and the restless: regulation of adult neurogenesis by Wnt signaling. Cell Stem Cell. 2013 Feb 7;12(2):139-40. doi: 10.1016/j.stem.2013.01.013.

Reference Type BACKGROUND
PMID: 23395437 (View on PubMed)

Busceti CL, Biagioni F, Aronica E, Riozzi B, Storto M, Battaglia G, Giorgi FS, Gradini R, Fornai F, Caricasole A, Nicoletti F, Bruno V. Induction of the Wnt inhibitor, Dickkopf-1, is associated with neurodegeneration related to temporal lobe epilepsy. Epilepsia. 2007 Apr;48(4):694-705. doi: 10.1111/j.1528-1167.2007.01055.x.

Reference Type BACKGROUND
PMID: 17437412 (View on PubMed)

Cappuccio I, Calderone A, Busceti CL, Biagioni F, Pontarelli F, Bruno V, Storto M, Terstappen GT, Gaviraghi G, Fornai F, Battaglia G, Melchiorri D, Zukin RS, Nicoletti F, Caricasole A. Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is required for the development of ischemic neuronal death. J Neurosci. 2005 Mar 9;25(10):2647-57. doi: 10.1523/JNEUROSCI.5230-04.2005.

Reference Type BACKGROUND
PMID: 15758175 (View on PubMed)

Mastroiacovo F, Busceti CL, Biagioni F, Moyanova SG, Meisler MH, Battaglia G, Caricasole A, Bruno V, Nicoletti F. Induction of the Wnt antagonist, Dickkopf-1, contributes to the development of neuronal death in models of brain focal ischemia. J Cereb Blood Flow Metab. 2009 Feb;29(2):264-76. doi: 10.1038/jcbfm.2008.111. Epub 2008 Oct 1.

Reference Type BACKGROUND
PMID: 18827832 (View on PubMed)

Other Identifiers

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NFEC-2022-273

Identifier Type: -

Identifier Source: org_study_id

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