The Role of Maresin1 and Maresin2 Serum Levels in Prediction of Prognosis in Thrombectomised ischemic Stroke Patients

Abstract

Objective: Although endovascular treatment (EVT) is widely accepted as the standard approach for acute ischemic stroke (IS), the prognostic determinants are not yet fully clarified. This study was designed to investigate the prognostic value of serum Maresin-1 (MaR1) and Maresin-2 (MaR2) levels in IS patients treated with EVT. Method: In this prospective study at Dicle University Faculty of Medicine, Department of Neurology, Stroke Center, 59 IS patients undergoing EVT and 24 healthy controls were enrolled between March 1 and August 1, 2024. Serum levels of MaR1, MaR2, albumin, hemoglobin A1C, neutrophils, platelets, lipid profile, vitamin D, C-reactive protein, and ferritin were measured. Clinical data included baseline NIHSS, 3-month mRS, TICI recanalization, and pre-stroke comorbidities. Multivariable logistic regression analyses were performed to evaluate associations between MaR1, MaR2, stroke severity, and mortality. Results: MaR1 and MaR2 concentrations were markedly reduced in the ischemic stroke group compared with healthy controls (p = 0.04 and p = 0.02). In parsimonious multivariable logistic regression analyses for 3-month mortality, neither MaR1 nor MaR2 showed an independent association, although both demonstrated borderline relationships after adjustment for age and baseline NIHSS. In contrast, stroke severity analysis revealed that higher MaR1 levels were independently associated with increased stroke severity (OR = 2.123; 95% CI, 1.18–3.25; p = 0.047), whereas MaR2 was not. Additionally, lower serum albumin levels emerged as an independent predictor of greater stroke severity in both models. Conclusions: These findings suggest that MaR1 may reflect stroke severity rather than mortality, while albumin represents a key systemic determinant of disease severity. Maresins appear to act as inflammation-related biomarkers whose prognostic effects are modulated by overall metabolic and inflammatory status.

Keywords

• MaR1 and stroke
• MaR2 and stroke
• NIHSS and MaR1
• Stroke Prognosis and maresin

Trombektomi uygulanan iskemik inme hastalarında Maresin-1 ve Maresin-2 Serum düzeylerinin Prognozun öngörülmesindeki rolü

Abstract

Amaç: Akut iskemik inmede (İS) endovasküler tedavi (EVT) standart yaklaşım olmakla birlikte, prognozu etkileyen faktörler hâlâ tam olarak aydınlatılamamıştır. Bu çalışma, EVT uygulanan İS hastalarında serum Maresin-1 (MaR1) ve Maresin-2 (MaR2) düzeylerinin prognostik önemini değerlendirmeyi amaçlamıştır. Yöntemler: Bu prospektif çalışmada, Dicle Üniversitesi Tıp Fakültesi, Nöroloji Ana Bilim Dalı, İnme Merkezi’nde 1 Mart–1 Ağustos 2024 tarihleri arasında EVT uygulanan 59 İS hastası ve 24 sağlıklı kontrol değerlendirilmiştir. Serum MaR1, MaR2, albümin, hemoglobin A1c, nötrofil, trombosit, lipid profili, D vitamini, C-reaktif protein ve ferritin düzeyleri ölçülmüştür. Klinik veriler arasında başlangıç NIHSS skoru, 3. ay mRS değeri, TICI reküperasyon düzeyi ve inme öncesi komorbiditeler yer almıştır. MaR1, MaR2, inme ciddiyeti ve mortalite arasındaki ilişkileri incelemek için çok değişkenli lojistik regresyon analizleri yapılmıştır. Bulgular: MaR1 ve MaR2 düzeyleri, iskemik inme grubunda sağlıklı kontrollere kıyasla anlamlı olarak daha düşüktü (sırasıyla p = 0,04 ve p = 0,02). Üç aylık mortalite için yapılan parsimoniyöz çok değişkenli lojistik regresyon analizlerinde, yaş ve başlangıç NIHSS skoru ile düzeltme sonrasında MaR1 ve MaR2’nin bağımsız bir ilişki göstermediği, ancak sınırda ilişkiler sergilediği izlendi. Buna karşılık, inme şiddeti analizinde yüksek MaR1 düzeylerinin daha ağır inme ile bağımsız olarak ilişkili olduğu saptandı (OR = 2,123; %95 GA: 1,18–3,25; p = 0,047), MaR2 için ise anlamlı bir ilişki gözlenmedi. Ayrıca düşük serum albümin düzeyleri, her iki modelde de artmış inme şiddetinin bağımsız bir belirleyicisi olarak bulundu. Sonuç: Bu bulgular, MaR1’in mortaliteden ziyade inme şiddetini yansıtan bir biyobelirteç olabileceğini, albüminin ise hastalık şiddetinde önemli bir sistemik belirleyici olduğunu düşündürmektedir. Maresinlerin prognostik etkilerinin, genel metabolik ve inflamatuvar durum tarafından modüle edilen inflamasyon ilişkili biyobelirteçler olarak değerlendirilmesi gerektiği kanaatine varılmıştır.

Keywords

• Mar1 ve inme
• maR2 ve inme
• NIHSS and MaR1
• inme prognozu ve maresin.

References

1. 1.Alexandru R, Terecoasă EO, Băjenaru OA, Tiu C.Etiologic classification of ischemic stroke: Where dowe stand? Clin Neurol Neurosurg. 2017;155:1-9.
2. 2.Mozaffarian D, Benjamin EJ, Go AS, et al. Heartdisease and stroke statistics—2016 update: A reportfrom the American Heart Association. Circulation.2016;133:e38-360.
3. 3.Şengeze N, Giray S. The relationship betweenmean platelet volume, platelet count, plateletlymphocyte ratio, and recanalization success in first-pass thrombectomy of middle cerebral arteryocclusions. Turk J Neurol. 2020;26:133-7.
4. 4.Serhan CN. Resolution phase of inflammation:Novel endogenous anti-inflammatory and pro-resolving lipid mediators and pathways. Annu RevImmunol. 2007;25:101-37.
5. 5.Serhan CN, Chiang N, Dalli J, Levy BD. Lipidmediators in the resolution of inflammation. ColdSpring Harb Perspect Biol. 2014;7:a016311.
6. 6.Serhan CN, Petasis NA. Resolvins and protectins ininflammation-resolution. Chem Rev.2011;111:5922-43.
7. 7.Serhan CN, Dalli J, Karamnov S, et al. Macrophageproresolving mediator maresin 1 stimulates tissueregeneration and controls pain. FASEB J.2012;26:1755-65.
8. 8.Wei J, Su W, Zhao Y, et al. Maresin 1 promotesnerve regeneration and alleviates neuropathic painafter nerve injury. J Neuroinflammation.2022;19:32.

9. 9.Miao T, Huang B, He N, et al. Decreased plasmamaresin 1 concentration is associated with diabeticfoot ulcer. Mediators Inflamm. 2020;2020:4539035.
10. 10.Saito-Sasaki N, Sawada Y, Nakamura M. Maresin-1 and inflammatory disease. Int J Mol Sci.2022;23:1367.
11. 11.Wang Y, Leppert A, Tan S, et al. Maresin 1attenuates pro-inflammatory activation induced byβ-amyloid and stimulates its uptake. J Cell Mol Med.2021;25:434-47.
12. 12.Francos-Quijorna I, Santos-Nogueira E, GronertK, et al. Maresin 1 promotes inflammatoryresolution, neuroprotection, and functionalneurological recovery after spinal cord injury. JNeurosci. 2017;37:11731-43.
13. 13.Xian W, Li T, Li L, Hu L, Cao J. Maresin 1attenuates the inflammatory response andmitochondrial damage in mice with cerebralischemia/reperfusion in a SIRT1-dependentmanner. Brain Res. 2019;1711:83-90.
14. 14.Fattori V, Pinho-Ribeiro FA, Staurengo-Ferrari L,et al. The specialised pro-resolving lipid mediatormaresin 1 reduces inflammatory pain with a long-lasting analgesic effect. Br J Pharmacol.2019;176:1728-44.
15. 15.Lopes RV, Baggio DF, Ferraz CR, et al. Maresin-2inhibits inflammatory and neuropathic trigeminalpain and reduces neuronal activation in thetrigeminal ganglion. Curr Res Neurobiol.2023;4:100093.
16. 16.Zhang J, Li C, Shuai W, et al. Maresin-2 fine-tunesULK1 O-GlcNAcylation to improve post-myocardialinfarction remodeling. Eur J Pharmacol.2024;962:176223.
17. 17.Chen YC, Ma NX, Pei ZF, et al. A NeuroD1 AAV-based gene therapy for functional brain repair afterischemic injury through in vivo astrocyte-to-neuronconversion. Mol Ther. 2020;28:217-34.
18. 18.Hu X, Wu D, He X, et al. circGSK3β promotesmetastasis in esophageal squamous cell carcinomaby augmenting β-catenin signaling. Mol Cancer.2019;18:160.
19. 19.Karaaslan F, Demir F, Yılmaz R, Akıl E. Totaloxidant/antioxidant status, copper and zinc levels inacute ischemic stroke patients after mechanicalthrombectomy. Clin Neurol Neurosurg.2023;229:107718.
20. 20.Ren X, Hu H, Farooqi I, Simpkins JW. Bloodsubstitution therapy rescues the brain of mice fromischemic damage. Nat Commun. 2020;11:4078.
21. 21.Zhao Y, Zhang X, Chen X, Wei Y. Neuronal injuriesin cerebral infarction and ischemic stroke: Frommechanisms to treatment. Int J Mol Med.2022;49:15.
22. 22.Qiu Y, Wu Y, Zhao H, Sun H, Gao S. Maresin 1mitigates renal ischemia/reperfusion injury in micevia inhibition of the TLR4/MAPK/NF-κB pathwaysand activation of the Nrf2 pathway. Drug Des DevelTher. 2019;13:739-45.
23. 23.Yin P, Wang S, Wei Y, et al. Maresin 1 decreasedmicroglial chemotaxis and amelioratedinflammation induced by amyloid-β42 in neuron-microglia co-culture models. J Alzheimers Dis.2020;73:503-15.
24. 24.Yu CX, Shi ZA, Ou GC, et al. Maresin-2 alleviatesallergic airway inflammation in mice by inhibitingthe activation of NLRP3 inflammasome, Th2immune response and oxidative stress. MolImmunol. 2022;146:78-86.
25. 25.Albayrak S, Aydin MA, Ugur K, et al. Subfatin,asprosin, alamandine and maresin-1 in cerebralischemia, intracranial and subarachnoidhemorrhages. Eur Rev Med Pharmacol Sci.2023;27:4471-80.
26. 26.Daubail B, Jacquin A, Guilland JC, et al. Serum 25-hydroxyvitamin D predicts severity and prognosis instroke patients. Eur J Neurol. 2013;20:57-61.
27. 27.Zhou H, Wang A, Meng X, et al. Low serumalbumin levels predict poor outcome in patientswith acute ischaemic stroke or transient ischaemicattack. Stroke Vasc Neurol. 2021;6:458-66.
28. 28.Zhao M, Xian W, Liu W, et al. Maresin 1 alleviatesneuroinflammation by inhibiting caspase-3/GSDME-mediated pyroptosis in a cerebralischemia–reperfusion model. J Stroke CerebrovascDis. 2024;33:107789.