Inflammation in ischemic stroke patients with type 2 diabetes – Part II: Potential therapeutic targets
Zhang L, Chen Y, Xu J, et al. Inflammation in ischemic stroke patients with type 2 diabetes – Part II: Potential therapeutic targets. Adv Neuro. doi: 10.36922/an.1694
© 2024 Author(s). This is an Open-Access article distributed under the terms of the Creative Commons Attribution License, permitting distribution, and reproduction in any medium, provided the original work is properly cited.
Stroke is the leading cause of disability and the second leading cause of death worldwide. Diabetes mellitus is a critical independent cardiovascular risk factor in patients, irrespective of age, smoking, and hypertension. Approximately one-third of first-time ischemic stroke patients have diabetes. Inflammation is among the most important pathological mechanisms in atheroma formation, the damage cascades of the acute phase, as well as during the subacute and chronic phases after stroke. Diabetes, as a common risk factor for stroke, is often present for a long time before a stroke occurs, causing low-grade inflammation, and disrupting the proper functioning of the neurovascular units. These proinflammatory processes and maladaptive immune mechanisms are further accelerated after cerebral ischemia and worsen the stroke outcome in diabetic patients. Clinical treatments for ischemic stroke are currently focused on restoring cerebral blood flow (reperfusion) in the acute phase, including thrombolysis and mechanical thrombectomy, which are not applicable to patients that fall outside of the treatment window and/or without large-vessel occlusion. There are few approved treatments targeting cellular injury caused by inflammation. There are even fewer data on effective treatment for diabetic stroke targeting inflammation. This paper presents the first part of a review focusing on the temporospatial aspects of inflammation in ischemic stroke pathophysiology in stroke patients with type 2 diabetes.
- GBD 2016 Lifetime Risk of Stroke Collaborators, Feigin VL, Nguyen G, et al. Global, regional, and country-specific lifetime risks of stroke, 1990 and 2016. N Engl J Med. 2018;379(25):2429-2437. doi: 10.1056/NEJMoa1804492
- Mulnier HE, Seaman HE, Raleigh VS, et al. Risk of stroke in people with type 2 diabetes in the UK: A study using the General Practice Research Database. Diabetologia. 2006;49(12):2859-2865. doi: 10.1007/s00125-006-0493-z
- Lee J, Yun JS, Ko SH. Advanced glycation end products and their effect on vascular complications in type 2 diabetes mellitus. Nutrients. 2022;14(15):3086. doi: 10.3390/nu14153086
- Chawla D, Bansal S, Banerjee BD, Madhu SV, Kalra OP, Tripathi AK. Role of advanced glycation end product (AGE)-induced receptor (RAGE) expression in diabetic vascular complications. Microvasc Res. 2014;95:1-6. doi: 10.1016/j.mvr.2014.06.010
- Koska J, Saremi A, Howell S, et al. Advanced glycation end products, oxidation products, and incident cardiovascular events in patients with type 2 diabetes. Diabetes Care. 2018;41(3):570-576. doi: 10.2337/dc17-1740
- Diabetes Control and Complications Trial (DCCT)/ Epidemiology of Diabetes Interventions and Complications (EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular outcomes in type 1 diabetes: The DCCT/EDIC study 30-year follow-up. Diabetes Care. 2016;39(5):686-693. doi: 10.2337/dc15-1990
- Boussageon R, Bejan-Angoulvant T, Saadatian-Elahi M, et al. Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes: Meta-analysis of randomised controlled trials. BMJ. 2011;343:d4169. doi: 10.1136/bmj.d4169
- Muller TD, Finan B, Bloom SR, et al. Glucagon-like peptide 1 (GLP-1). Mol Metab. 2019;30:72-130. doi: 10.1016/j.molmet.2019.09.010
- Sattar N, Lee MMY, Kristensen SL, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: A systematic review and meta-analysis of randomised trials. Lancet Diabetes Endocrinol. 2021;9(10):653-662. doi: 10.1016/S2213-8587(21)00203-5
- Giugliano D, Scappaticcio L, Longo M, et al. GLP-1 receptor agonists and cardiorenal outcomes in type 2 diabetes: An updated meta-analysis of eight CVOTs. Cardiovasc Diabetol. 2021;20(1):189. doi: 10.1186/s12933-021-01366-8
- Cork SC, Richards JE, Holt MK, Gribble FM, Reimann F, Trapp S. Distribution and characterisation of Glucagon-like peptide-1 receptor expressing cells in the mouse brain. Mol Metab. 2015;4(10):718-731. doi: 10.1016/j.molmet.2015.07.008
- Hunter K, Holscher C. Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis. BMC Neurosci. 2012;13:33. doi: 10.1186/1471-2202-13-33
- Kopp KO, Glotfelty EJ, Li Y, Greig NH. Glucagon-like peptide-1 (GLP-1) receptor agonists and neuroinflammation: Implications for neurodegenerative disease treatment. Pharmacol Res. 2022;186:106550. doi: 10.1016/j.phrs.2022.106550
- Rizzo M, Chandalia M, Patti AM, et al. Liraglutide decreases carotid intima-media thickness in patients with type 2 diabetes: 8-month prospective pilot study. Cardiovasc Diabetol. 2014;13:49. doi: 10.1186/1475-2840-13-49
- Kapoor I, Sarvepalli SM, D’Alessio D, Grewal DS, Hadziahmetovic M. GLP-1 receptor agonists and diabetic retinopathy: A meta-analysis of randomized clinical trials. Surv Ophthalmol. 2023;68(6):1071-1083. doi: 10.1016/j.survophthal.2023.07.002
- Patoulias DI, Boulmpou A, Teperikidis E, et al. Cardiovascular efficacy and safety of dipeptidyl peptidase-4 inhibitors: A meta-analysis of cardiovascular outcome trials. World J Cardiol. 2021;13(10):585-592. doi: 10.4330/wjc.v13.i10.585
- Schmidt AM. Diabetes mellitus and cardiovascular disease. Arterioscler Thromb Vasc Biol. 2019;39(4):558-568. doi: 10.1161/ATVBAHA.119.310961
- Xia C, Goud A, D’Souza J, et al. DPP4 inhibitors and cardiovascular outcomes: Safety on heart failure. Heart Fail Rev. 2017;22(3):299-304. doi: 10.1007/s10741-017-9617-4
- Frak W, Hajdys J, Radzioch E, et al. Cardiovascular diseases: Therapeutic potential of SGLT-2 inhibitors. Biomedicines. 2023;11(7):2085. doi: 10.3390/biomedicines11072085
- Huang K, Luo X, Liao B, Li G, Feng J. Insights into SGLT2 inhibitor treatment of diabetic cardiomyopathy: Focus on the mechanisms. Cardiovasc Diabetol. 2023;22(1):86. doi: 10.1186/s12933-023-01816-5
- Gourdy P, Darmon P, Dievart F, Halimi JM, Guerci B. Combining glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) in patients with type 2 diabetes mellitus (T2DM). Cardiovasc Diabetol. 2023;22(1):79. doi: 10.1186/s12933-023-01798-4
- Eckel RH, Bornfeldt KE, Goldberg IJ. Cardiovascular disease in diabetes, beyond glucose. Cell Metab. 2021;33(8):1519-1545. doi: 10.1016/j.cmet.2021.07.001
- Paridari P, Jabermoradi S, Gholamzadeh R, et al. Can metformin use reduce the risk of stroke in diabetic patients? A systematic review and meta-analysis. Diabetes Metab Syndr. Feb 2023;17(2):102721. doi: 10.1016/j.dsx.2023.102721
- Nakatsuji H, Kobayashi H, Kishida K, et al. Binding of adiponectin and C1q in human serum, and clinical significance of the measurement of C1q-adiponectin/total adiponectin ratio. Metabolism. 2013;62(1):109-120. doi: 10.1016/j.metabol.2012.06.006
- Gairolla J, Kler R, Modi M, Khurana D. Leptin and adiponectin: pathophysiological role and possible therapeutic target of inflammation in ischemic stroke. Rev Neurosci. 2017;28(3):295-306. doi: 10.1515/revneuro-2016-0055
- Bidulescu A, Dinh PC Jr., Sarwary S, et al. Associations of leptin and adiponectin with incident type 2 diabetes and interactions among African Americans: The Jackson heart study. BMC Endocr Disord. 2020;20(1):31. doi: 10.1186/s12902-020-0511-z
- Zhao S, Kusminski CM, Elmquist JK, Scherer PE. Leptin: Less is more. Diabetes. 2020;69(5):823-829. doi: 10.2337/dbi19-0018
- Cioffi JA, Shafer AW, Zupancic TJ, et al. Novel B219/OB receptor isoforms: Possible role of leptin in hematopoiesis and reproduction. Nat Med. 1996;2(5):585-589. doi: 10.1038/nm0596-585
- Sanchez-Margalet V, Martin-Romero C, Santos-Alvarez J, Goberna R, Najib S, Gonzalez-Yanes C. Role of leptin as an immunomodulator of blood mononuclear cells: Mechanisms of action. Clin Exp Immunol. 2003;133(1):11-19. doi: 10.1046/j.1365-2249.2003.02190.x
- Nakata M, Yada T, Soejima N, Maruyama I. Leptin promotes aggregation of human platelets via the long form of its receptor. Diabetes. 1999;48(2):426-429. doi: 10.2337/diabetes.48.2.426
- Abderrazak A, Syrovets T, Couchie D, et al. NLRP3 inflammasome: From a danger signal sensor to a regulatory node of oxidative stress and inflammatory diseases. Redox Biol. 2015;4:296-307. doi: 10.1016/j.redox.2015.01.008
- Look AHEAD Research Group, Gregg E, Jakicic J, et al. Association of the magnitude of weight loss and changes in physical fitness with long-term cardiovascular disease outcomes in overweight or obese people with type 2 diabetes: A post-hoc analysis of the Look AHEAD randomised clinical trial. Lancet Diabetes Endocrinol. 2016;4(11):913-921. doi: 10.1016/S2213-8587(16)30162-0
- Zhao S, Zhu Y, Schultz RD, et al. Partial leptin reduction as an insulin sensitization and weight loss strategy. Cell Metab. 2019;30(4):706-719.e6. doi: 10.1016/j.cmet.2019.08.005
- Civitarese AE, Jenkinson CP, Richardson D, et al. Adiponectin receptors gene expression and insulin sensitivity in non-diabetic Mexican Americans with or without a family history of Type 2 diabetes. Diabetologia. 2004;47(5):816-820. doi: 10.1007/s00125-004-1359-x
- Bluher M, Bullen JW Jr., Lee JH, et al. Circulating adiponectin and expression of adiponectin receptors in human skeletal muscle: Associations with metabolic parameters and insulin resistance and regulation by physical training. J Clin Endocrinol Metab. 2006;91(6):2310-2316. doi: 10.1210/jc.2005-2556
- Bodles AM, Banga A, Rasouli N, Ono F, Kern PA, Owens RJ. Pioglitazone increases secretion of high-molecular-weight adiponectin from adipocytes. Am J Physiol Endocrinol Metab. 2006;291(5):E1100-E1105. doi: 10.1152/ajpendo.00187.2006
- Liu J, Wang LN. Peroxisome proliferator-activated receptor gamma agonists for preventing recurrent stroke and other vascular events in people with stroke or transient ischaemic attack. Cochrane Database Syst Rev. 2023;1(1):CD010693. doi: 10.1002/14651858.CD010693.pub6
- Zhao D, Sohouli MH, Rohani P, et al. The effect of metformin on adipokines levels: A systematic review and meta-analysis of randomized-controlled trials. Diabetes Res Clin Pract. 2023;207:111076. doi: 10.1016/j.diabres.2023.111076
- Flynn MC, Kraakman MJ, Tikellis C, et al. Transient intermittent hyperglycemia accelerates atherosclerosis by promoting myelopoiesis. Circ Res. 2020;127(7):877-892. doi: 10.1161/CIRCRESAHA.120.316653
- Bjork P, Bjork A, Vogl T, et al. Identification of human S100A9 as a novel target for treatment of autoimmune disease via binding to quinoline-3-carboxamides. PLoS Biol. 2009;7(4):e97. doi: 10.1371/journal.pbio.1000097
- Imazio M, Nidorf M. Colchicine and the heart. Eur Heart J. 2021;42(28):2745-2760. doi: 10.1093/eurheartj/ehab221
- Nidorf SM, Fiolet ATL, Mosterd A, et al. Colchicine in patients with chronic coronary disease. N Engl J Med. 2020;383(19):1838-1847. doi: 10.1056/NEJMoa2021372
- Puig N, Sole A, Aguilera-Simon A, et al. Novel therapeutic approaches to prevent atherothrombotic ischemic stroke in patients with carotid atherosclerosis. Int J Mol Sci. 2023;24(18):14325. doi: 10.3390/ijms241814325
- Boczar KE, Shin S, deKemp RA, et al. The Canadian study of arterial inflammation in patients with diabetes and recent vascular events, evaluation of colchicine effectiveness (CADENCE): Protocol for a randomised, double-blind, placebo-controlled trial. BMJ Open. 2023;13(11):e074463. doi: 10.1136/bmjopen-2023-074463
- Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377(12):1119-1131. doi: 10.1056/NEJMoa1707914
- Hudson BI, Kalea AZ, Del Mar Arriero M, et al. Interaction of the RAGE cytoplasmic domain with diaphanous-1 is required for ligand-stimulated cellular migration through activation of Rac1 and Cdc42. J Biol Chem. 2008;283(49):34457-34468. doi: 10.1074/jbc.M801465200
- Senatus L, Egana-Gorrono L, Lopez-Diez R, et al. DIAPH1 mediates progression of atherosclerosis and regulates hepatic lipid metabolism in mice. Commun Biol. 2023;6(1):280. doi: 10.1038/s42003-023-04643-2
- Ridker PM, Danielson E, Fonseca FAH, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195-2207. doi: 10.1056/NEJMoa0807646
- Alikiaii B, Heidari Z, Bagherniya M, Askari G, Sathyapalan T, Sahebkar A. The effect of statins on C-reactive protein in stroke patients: A systematic review of clinical trials. Mediators Inflamm. 2021;2021:7104934. doi: 10.1155/2021/7104934
- Distel E, Barrett TJ, Chung K, et al. miR33 inhibition overcomes deleterious effects of diabetes mellitus on atherosclerosis plaque regression in mice. Circ Res. 2014;115(9):759-769. doi: 10.1161/CIRCRESAHA.115.304164
- Enlimomab Acute Stroke Trial Investigators. Use of anti- ICAM-1 therapy in ischemic stroke: Results of the enlimomab acute stroke trial. Neurology. 2001;57(8):1428-1434. doi: 10.1212/wnl.57.8.1428
- Mocco J, Choudhri T, Huang J, et al. HuEP5C7 as a humanized monoclonal anti-E/P-selectin neurovascular protective strategy in a blinded placebo-controlled trial of nonhuman primate stroke. Circ Res. 2002;91(10):907-914. doi: 10.1161/01.res.0000042063.15901.20
- National Institute of Neurological Disorders and Stroke (NINDS). E-Selectin Nasal Spray to Prevent Stroke Recurrence. Bethesda, MD: National Library of Medicine (US); 2000. Available from: https://clinicaltrials.gov/show/ NCT00012454 [Last accessed on 2016 May 21].
- Elkind MSV, Veltkamp R, Montaner J, et al. Natalizumab in acute ischemic stroke (ACTION II): A randomized, placebo-controlled trial. Neurology. 2020;95(8):e1091-e1104. doi: 10.1212/WNL.0000000000010038
- Krams M, Lees KR, Hacke W, et al. Acute stroke therapy by inhibition of neutrophils (ASTIN): An adaptive dose-response study of UK-279,276 in acute ischemic stroke. Stroke. 2003;34(11):2543-2548. doi: 10.1161/01.STR.0000092527.33910.89
- Levard D, Buendia I, Lanquetin A, Glavan M, Vivien D, Rubio M. Filling the gaps on stroke research: Focus on inflammation and immunity. Brain Behav Immun. 2021;91:649-667. doi: 10.1016/j.bbi.2020.09.025
- Fu Y, Zhang N, Ren L, et al. Impact of an immune modulator fingolimod on acute ischemic stroke. Proc Natl Acad Sci U S A. 2014;111(51):18315-18320. doi: 10.1073/pnas.1416166111
- Veltkamp R, Gill D. Clinical trials of immunomodulation in ischemic stroke. Neurotherapeutics. 2016;13(4):791-800. doi: 10.1007/s13311-016-0458-y
- Yuan B, Meng X, Wang A, et al. Effect of different doses of colchicine on high sensitivity C-reactive protein in patients with acute minor stroke or transient ischemic attack: A pilot randomized controlled trial. Eur J Pharm Sci. 2022;178:106288. doi: 10.1016/j.ejps.2022.106288
- Wang Y, Li J, Johnston SC, et al. Colchicine in High-risk patients with acute minor-to-moderate ischemic stroke or transient ischemic attack (CHANCE-3): Rationale and design of a multicenter randomized placebo-controlled trial. Int J Stroke. 2023;18(7):873-878. doi: 10.1177/17474930231172312
- Zhang YP, Cui QY, Zhang TM, et al. Chloroquine pretreatment attenuates ischemia-reperfusion injury in the brain of ob/ob diabetic mice as well as wildtype mice. Brain Res. 2020;1726:146518. doi: 10.1016/j.brainres.2019.146518
- Ruan C, Guo H, Gao J, et al. Neuroprotective effects of metformin on cerebral ischemia-reperfusion injury by regulating PI3K/Akt pathway. Brain Behav. 2021;11(10):e2335. doi: 10.1002/brb3.2335
- Pawletko K, Jedrzejowska-Szypulka H, Bogus K, et al. After ischemic stroke, minocycline promotes a protective response in neurons via the RNA-binding protein HuR, with a positive impact on motor performance. Int J Mol Sci. 2023;24(11):9446. doi: 10.3390/ijms24119446
- Singhealth Foundation. Neuroprotection with Minocycline Therapy for Acute Stroke Recovery Trial (NeuMAST). Bethesda, MD: National Library of Medicine (US); 2000. Available from: https://clinicaltrials.gov/show/ NCT00930020 [Last accessed on 2016 May 21].
- Smith CJ, Hulme S, Vail A, et al. SCIL-STROKE (Subcutaneous interleukin-1 receptor antagonist in ischemic stroke): A randomized controlled phase 2 Trial. Stroke. 2018;49(5):1210-1216. doi: 10.1161/STROKEAHA.118.020750
- Strang AC, Bisoendial RJ, Kootte RS, et al. Pro-atherogenic lipid changes and decreased hepatic LDL receptor expression by tocilizumab in rheumatoid arthritis. Atherosclerosis. 2013;229(1):174-181. doi: 10.1016/j.atherosclerosis.2013.04.031
- Lok KZ, Basta M, Manzanero S, Arumugam TV. Intravenous immunoglobulin (IVIg) dampens neuronal toll-like receptor-mediated responses in ischemia. J Neuroinflammation. 2015;12:73. doi: 10.1186/s12974-015-0294-8
- Jin W, Wu Y, Chen N, et al. Early administration of MPC-n(IVIg) selectively accumulates in ischemic areas to protect inflammation-induced brain damage from ischemic stroke. Theranostics. 2021;11(17):8197-8217. doi: 10.7150/thno.58947
- Hong P, Li FX, Gu RN, et al. Inhibition of NLRP3 inflammasome ameliorates cerebral ischemia-reperfusion injury in diabetic mice. Neural Plast. 2018;2018:9163521. doi: 10.1155/2018/9163521
- Hong P, Gu RN, Li FX, et al. NLRP3 inflammasome as a potential treatment in ischemic stroke concomitant with diabetes. J Neuroinflammation. 2019;16(1):121. doi: 10.1186/s12974-019-1498-0
- Ward R, Li W, Abdul Y, et al. NLRP3 inflammasome inhibition with MCC950 improves diabetes-mediated cognitive impairment and vasoneuronal remodeling after ischemia. Pharmacol Res. 2019;142:237-250. doi: 10.1016/j.phrs.2019.01.035
- Zeng J, Wang Y, Luo Z, et al. TRIM9-mediated resolution of neuroinflammation confers neuroprotection upon ischemic stroke in mice. Cell Rep. 2019;27(2):549-560.e6. doi: 10.1016/j.celrep.2018.12.055
- Nikolic D, Jankovic M, Petrovic B, Novakovic I. Genetic aspects of inflammation and immune response in stroke. Int J Mol Sci. 2020;21(19):7409. doi: 10.3390/ijms21197409
- Wang H, Li J, Zhang H, et al. Regulation of microglia polarization after cerebral ischemia. Front Cell Neurosci. 2023;17:1182621. doi: 10.3389/fncel.2023.1182621
- Li L, Gan H, Jin H, et al. Astragaloside IV promotes microglia/macrophages M2 polarization and enhances neurogenesis and angiogenesis through PPARgamma pathway after cerebral ischemia/reperfusion injury in rats. Int Immunopharmacol. 2021;92:107335. doi: 10.1016/j.intimp.2020.107335
- Cuartero MI, Ballesteros I, Moraga A, et al. N2 neutrophils, novel players in brain inflammation after stroke: Modulation by the PPARgamma agonist rosiglitazone. Stroke. 2013;44(12):3498-3508. doi: 10.1161/STROKEAHA.113.002470
- Tian X, Liu H, Xiang F, Xu L, Dong Z. 𝛽-caryophyllene protects against ischemic stroke by promoting polarization of microglia toward M2 phenotype via the TLR4 pathway. Life Sci. 2019;237:116915. doi: 10.1016/j.lfs.2019.116915
- Amantea D, Petrelli F, Greco R, et al. Azithromycin affords neuroprotection in rat undergone transient focal cerebral ischemia. Front Neurosci. 2019;13:1256. doi: 10.3389/fnins.2019.01256
- Hernandez-Jimenez M, Abad-Santos F, Cotgreave I, et al. Safety and efficacy of ApTOLL in patients with ischemic stroke undergoing endovascular treatment: A phase 1/2 randomized clinical trial. JAMA Neurol. 2023;80(8):779-788. doi: 10.1001/jamaneurol.2023.1660
- Wei N, Yu SP, Gu XH, et al. The involvement of autophagy pathway in exaggerated ischemic brain damage in diabetic mice. CNS Neurosci Ther. 2013;19(10):753-763. doi: 10.1111/cns.12123
- D’Souza B, D’Souza V, Sowmya S, et al. A comparative study on oxidative stress and antioxidant status in ischemic stroke patients with and without diabetes. Indian J Clin Biochem. 2008;23(3):218-222. doi: 10.1007/s12291-008-0049-8
- Bemeur C, Ste-Marie L, Montgomery J. Increased oxidative stress during hyperglycemic cerebral ischemia. Neurochem Int. 2007;50(7-8):890-904. doi: 10.1016/j.neuint.2007.03.002
- Soloniuk DS, Perkins E, Wilson JR. Use of allopurinol and deferoxamine in cellular protection during ischemia. Surg Neurol. 1992;38(2):110-113. doi: 10.1016/0090-3019(92)90087-4
- Sugimoto K, Iadecola C. Delayed effect of administration of COX-2 inhibitor in mice with acute cerebral ischemia. Brain Res. 2003;960(1-2):273-276. doi: 10.1016/s0006-8993(02)03805-2
- Dawson J, Quinn T, Harrow C, et al. Allopurinol and nitric oxide activity in the cerebral circulation of those with diabetes: A randomized trial. Diabetes Care. 2009;32(1):135-137. doi: 10.2337/dc08-1179
- Dawson J, Robertson M, Dickie DA, et al. Xanthine oxidase inhibition and white matter hyperintensity progression following ischaemic stroke and transient ischaemic attack (XILO-FIST): A multicentre, double-blinded, randomised, placebo-controlled trial. EClinicalMedicine. 2023;57:101863. doi: 10.1016/j.eclinm.2023.101863
- Lees KR, Zivin JA, Ashwood T, et al. NXY-059 for acute ischemic stroke. N Engl J Med. 2006;354(6):588-600. doi: 10.1056/NEJMoa052980
- Xu J, Wang A, Meng X, et al. Edaravone dexborneol versus edaravone alone for the treatment of acute ischemic stroke: A phase III, randomized, double-blind, comparative trial. Stroke. 2021;52(3):772-780. doi: 10.1161/STROKEAHA.120.031197
- Shuaib A, Lees KR, Lyden P, et al. NXY-059 for the treatment of acute ischemic stroke. N Engl J Med. 2007;357(6):562-571. doi: 10.1056/NEJMoa070240
- Kobayashi S, Fukuma S, Ikenoue T, Fukuhara S, Kobayashi S. Effect of edaravone on neurological symptoms in real-world patients with acute ischemic stroke. Stroke. 2019;50(7):1805-1811. doi: 10.1161/STROKEAHA.118.024351
- Ji J, Zhang R, Li H, Zhu J, Pan Y, Guo Q. Analgesic and anti-inflammatory effects and mechanism of action of borneol on photodynamic therapy of acne. Environ Toxicol Pharmacol. 2020;75:103329. doi: 10.1016/j.etap.2020.103329
- Zhao L, Hu FX. α-Lipoic acid treatment of aged type 2 diabetes mellitus complicated with acute cerebral infarction. Eur Rev Med Pharmacol Sci. 2014;18(23):3715-3719.
- Tan DX, Manchester LC, Qin L, Reiter RJ. Melatonin: A mitochondrial targeting molecule involving mitochondrial protection and dynamics. Int J Mol Sci. 2016;17(12):2124. doi: 10.3390/ijms17122124
- Xu Q, Cheung RTF. Melatonin mitigates type 1 diabetes-aggravated cerebral ischemia-reperfusion injury through anti-inflammatory and anti-apoptotic effects. Brain Behav. 2023;13(9):e3118. doi: 10.1002/brb3.3118
- Yu W, Ren C, Ji X. A review of remote ischemic conditioning as a potential strategy for neural repair poststroke. CNS Neurosci Ther. 2023;29(2):516-524. doi: 10.1111/cns.14064
- Liu C, Zhang C, Du H, Geng X, Zhao H. Remote ischemic preconditioning protects against ischemic stroke in streptozotocin-induced diabetic mice via anti-inflammatory response and anti-apoptosis. Brain Res. 2019;1724:146429. doi: 10.1016/j.brainres.2019.146429
- Kan X, Yan Z, Wang F, et al. Efficacy and safety of remote ischemic conditioning for acute ischemic stroke: A comprehensive meta-analysis from randomized controlled trials. CNS Neurosci Ther. 2023;29(9):2445-2456. doi: 10.1111/cns.14240
- Zhao W, Hausenloy DJ, Hess DC, Yellon DM, Ji X. Remote ischemic conditioning: Challenges and opportunities. Stroke. 2023;54(8):2204-2207. doi: 10.1161/STROKEAHA.123.043279
- Westendorp WF, Vermeij JD, Smith CJ, et al. Preventive antibiotic therapy in acute stroke patients: A systematic review and meta-analysis of individual patient data of randomized controlled trials. Eur Stroke J. 2021;6(4):385-394. doi: 10.1177/23969873211056445
- Wen H, Weymann KB, Wood L, Wang QM. Inflammatory signaling in post-stroke fatigue and depression. Eur Neurol. 2018;80(3-4):138-148. doi: 10.1159/000494988
- Caiaffo V, Oliveira BD, de Sa FB, Evencio Neto J. Anti-inflammatory, antiapoptotic, and antioxidant activity of fluoxetine. Pharmacol Res Perspect. 2016;4(3):e00231. doi: 10.1002/prp2.231
- Schneider CL, Prentiss EK, Busza A, Williams ZR, Mahon BZ, Sahin B. FLUORESCE: A pilot randomized clinical trial of fluoxetine for vision recovery after acute ischemic stroke. J Neuroophthalmol. 2023;43(2):237-242. doi: 10.1097/WNO.0000000000001654
- Knox MG, Demaerschalk BM, Alcott SB, Marks LA, Wingerchuk DM, O’Carroll CB. Does the initiation of fluoxetine postacute stroke result in improved functional recovery?: A critically appraised topic. Neurologist. 2021;26(3):112-115. doi: 10.1097/NRL.0000000000000314
- Li N, Hua J. Interactions between mesenchymal stem cells and the immune system. Cell Mol Life Sci. 2017;74(13):2345-2360. doi: 10.1007/s00018-017-2473-5
- He J, Liu J, Huang Y, Tang X, Xiao H, Hu Z. Oxidative stress, inflammation, and autophagy: Potential targets of mesenchymal stem cells-based therapies in ischemic stroke. Front Neurosci. 2021;15:641157. doi: 10.3389/fnins.2021.641157
- Li J, Zhang Q, Wang W, Lin F, Wang S, Zhao J. Mesenchymal stem cell therapy for ischemic stroke: A look into treatment mechanism and therapeutic potential. J Neurol. 2021;268(11):4095-4107. doi: 10.1007/s00415-020-10138-5
- Cordeau P Jr., Lalancette-Hebert M, Weng YC, Kriz J. Live imaging of neuroinflammation reveals sex and estrogen effects on astrocyte response to ischemic injury. Stroke. 2008;39(3):935-942. doi: 10.1161/STROKEAHA.107.501460
- Chernykh ER, Shevela EY, Starostina NM, et al. Safety and therapeutic potential of M2 macrophages in stroke treatment. Cell Transplant. 2016;25(8):1461-1471. doi: 10.3727/096368915X690279
- Doyle KP, Quach LN, Sole M, et al. B-lymphocyte-mediated delayed cognitive impairment following stroke. J Neurosci. 2015;35(5):2133-2145. doi: 10.1523/JNEUROSCI.4098-14.2015
- Thapa R, Afzal O, Alfawaz Altamimi AS, et al. Galangin as an inflammatory response modulator: An updated overview and therapeutic potential. Chem Biol Interact. 2023;378:110482. doi: 10.1016/j.cbi.2023.110482
- Xu H, Wang E, Chen F, Xiao J, Wang M. Neuroprotective phytochemicals in experimental ischemic stroke: Mechanisms and potential clinical applications. Oxid Med Cell Longev. 2021;2021:6687386. doi: 10.1155/2021/6687386
- Zhu T, Wang L, Feng Y, Sun G, Sun X. Classical active ingredients and extracts of Chinese herbal medicines: Pharmacokinetics, pharmacodynamics, and molecular mechanisms for ischemic stroke. Oxid Med Cell Longev. 2021;2021:8868941. doi: 10.1155/2021/8868941
- Zhou P, Du S, Zhou L, et al. Tetramethylpyrazine2’Osodium ferulate provides neuroprotection against neuroinflammation and brain injury in MCAO/R rats by suppressing TLR-4/NF-kappaB signaling pathway. Pharmacol Biochem Behav. 2019;176:33-42. doi: 10.1016/j.pbb.2018.08.010
- Tsai FJ, Ho TJ, Cheng CF, et al. Effect of Chinese herbal medicine on stroke patients with type 2 diabetes. J Ethnopharmacol. 2017;200:31-44. doi: 10.1016/j.jep.2017.02.024
- Ritzel RM, Lai YJ, Crapser JD, et al. Aging alters the immunological response to ischemic stroke. Acta Neuropathol. 2018;136(1):89-110. doi: 10.1007/s00401-018-1859-2
- Buga AM, Di Napoli M, Popa-Wagner A. Preclinical models of stroke in aged animals with or without comorbidities: Role of neuroinflammation. Biogerontology. 2013;14(6):651-662. doi: 10.1007/s10522-013-9465-0
- Yamashiro K, Kurita N, Urabe T, Hattori N. Role of the gut microbiota in stroke pathogenesis and potential therapeutic implications. Ann Nutr Metab. 2021;77 Suppl 2(Suppl 2):36-44. doi: 10.1159/000516398
- Delrue C, Delanghe JR, Speeckaert MM. The role of sRAGE in cardiovascular diseases. Adv Clin Chem. 2023;117:53-102. doi: 10.1016/bs.acc.2023.08.005
- Baker EW, Kinder HA, West FD. Neural stem cell therapy for stroke: A multimechanistic approach to restoring neurological function. Brain Behav. 2019;9(3):e01214. doi: 10.1002/brb3.1214