Novel Lipid Mediators as a Promising Therapeutic Strategy for Ischemic Stroke
Main Article Content
Ludmila Belayev, MD
http://orcid.org/0000-0001-8687-9340
Madigan M. Reid
Nicolas G. Bazan, MD, PhD
http://orcid.org/0000-0002-9243-5444
http://orcid.org/0000-0001-8687-9340
Madigan M. Reid
Nicolas G. Bazan, MD, PhD
http://orcid.org/0000-0002-9243-5444
Abstract
Despite displaying efficacy in experimental stroke studies, neuroprotection has failed in clinical trials. The translational difficulties include a limited methodological agreement between preclinical and clinical studies and the heterogeneity of stroke in humans compared to standardized strokes in animal models. Promising neuroprotective approaches based on a deeper understanding of the complex pathophysiology of ischemic stroke, such as blocking pro-inflammatory pathways plus pro-survival mediators, are now evaluated in preclinical studies. Combinatorial therapy has become increasingly attractive in recent years as recognizing the complexity of stroke progression becomes evident. The paper aimed to test the hypothesis that blocking pro-inflammatory platelet-activating factor receptor (PAF-R) with LAU-0901 plus administering a selected docosanoid, aspirin-triggered neuroprotectin D1 (AT-NPD1), which activates cell-survival pathways after middle cerebral artery occlusion (MCAo), would lead to neurological recovery. We have demonstrated that LAU-0901 plus AT-NPD1 treatment affords high-grade neuroprotection in MCAo, equaling or exceeding that afforded by LAU-0901 or AT-NPD1 alone at considerably moderate doses, and it has a broad therapeutic window extending to 6 hours after stroke onset.
Keywords:
Stroke, Ischemic Stroke, Therapeutic Strategy for Ischemic Stroke, Lipid Mediators, Therapeutic Strategy
Article Details
How to Cite
BELAYEV, Ludmila; REID, Madigan M.; BAZAN, Nicolas G..
Novel Lipid Mediators as a Promising Therapeutic Strategy for Ischemic Stroke.
Medical Research Archives, [S.l.], v. 11, n. 1, jan. 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/3333>. Date accessed: 21 dec. 2024.
doi: https://doi.org/10.18103/mra.v11i1.3333.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Minnerup J, Sutherland BA, Buchan AM, Kleinschnitz C. Neuroprotection for stroke: current status and future perspectives. Int J Mol Sci. 2012;13(9):11753-11772.
2. Paul S, Candelario-Jalil E. Emerging neuroprotective strategies for the treatment of ischemic stroke: An overview of clinical and preclinical studies. Experimental Neurology. 2021;335:113518.
3. Kuriakose D, Xiao Z. Pathophysiology and Treatment of Stroke: Present Status and Future Perspectives. International Journal of Molecular Sciences. 2020;21(20):7609.
4. Sekerdag E, Solaroglu I, Gursoy-Ozdemir Y. Cell Death Mechanisms in Stroke and Novel Molecular and Cellular Treatment Options. Curr Neuropharmacol. 2018;16(9):1396-1415.
5. Arai K, Lok J, Guo S, Hayakawa K, Xing C, Lo EH. Cellular mechanisms of neurovascular damage and repair after stroke. J Child Neurol. 2011;26(9):1193-1198.
6. Mac Grory B, Saldanha IJ, Mistry EA, et al. Thrombolytic therapy for wake-up stroke: A systematic review and meta-analysis. Eur J Neurol. 2021;28(6):2006-2016.
7. 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;59(3):467-477.
8. Boltze J, Lukomska B, Jolkkonen J, consortium MI. Mesenchymal Stromal Cells in Stroke: Improvement of Motor Recovery or Functional Compensation? J Cereb Blood Flow Metab. 2014;34(8):1420-1421.
9. Saleh MC, Connell BJ, Rajagopal D, et al. Co-administration of resveratrol and lipoic acid, or their synthetic combination, enhances neuroprotection in a rat model of ischemia/reperfusion. PLoS One. 2014;9(1):e87865.
10. Hwang S, Choi J, Kim M. Combining Human Umbilical Cord Blood Cells With Erythropoietin Enhances Angiogenesis/Neurogenesis and Behavioral Recovery After Stroke. Front Neurol. 2019;10:357.
11. Ishrat T, Fouda AY, Pillai B, et al. Dose-response, therapeutic time-window and tPA-combinatorial efficacy of compound 21: A randomized, blinded preclinical trial in a rat model of thromboembolic stroke. J Cereb Blood Flow Metab. 2019;39(8):1635-1647.
12. Panetta T, Marcheselli VL, Braquet P, Spinnewyn B, Bazan NG. Effects of a platelet activating factor antagonist (BN 52021) on free fatty acids, diacylglycerols, polyphosphoinositides and blood flow in the gerbil brain: inhibition of ischemia-reperfusion induced cerebral injury. Biochem Biophys Res Commun. 1987;149(2):580-587.
13. Marcheselli VL, Rossowska MJ, Domingo MT, Braquet P, Bazan NG. Distinct platelet-activating factor binding sites in synaptic endings and in intracellular membranes of rat cerebral cortex. J Biol Chem. 1990;265(16):9140-9145.
14. Bazan NG, Squinto SP, Braquet P, Panetta T, Marcheselli VL. Platelet-activating factor and polyunsaturated fatty acids in cerebral ischemia or convulsions: intracellular PAF-binding sites and activation of a fos/jun/AP-1 transcriptional signaling system. Lipids. 1991;26(12):1236-1242.
15. Clark GD, Happel LT, Zorumski CF, Bazan NG. Enhancement of hippocampal excitatory synaptic transmission by platelet-activating factor. Neuron. 1992;9(6):1211-1216.
16. Kato K, Clark GD, Bazan NG, Zorumski CF. Platelet-activating factor as a potential retrograde messenger in CA1 hippocampal long-term potentiation. Nature. 1994;367(6459):175-179.
17. Bazan NG, Zorumski CF, Clark GD. The activation of phospholipase A2 and release of arachidonic acid and other lipid mediators at the synapse: the role of platelet-activating factor. J Lipid Mediat. 1993;6(1-3):421-427.
18. Jerusalinsky D, Fin C, Quillfeldt JA, et al. Effect of antagonists of platelet-activating factor receptors on memory of inhibitory avoidance in rats. Behav Neural Biol. 1994;62(1):1-3.
19. Izquierdo I, Fin C, Schmitz PK, et al. Memory enhancement by intrahippocampal, intraamygdala, or intraentorhinal infusion of platelet-activating factor measured in an inhibitory avoidance task. Proc Natl Acad Sci USA. 1995;92(11):5047-5051.
20. Bazan NG, Sunkel C, Marcheselli VL, Builla-G J. 2,4,6-trimethyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid esters as neuroprotective drugs. Published online May 20, 2003.
21. Bazan NG. Inflammation. A signal terminator. Nature. 1995;374(6522):501-502.
22. Ashraf MA, Nookala V. Biochemistry of Platelet Activating Factor. In: StatPearls. StatPearls Publishing; 2022.
23. Chen C, Bazan NG. Lipid signaling: Sleep, synaptic plasticity, and neuroprotection. Prostaglandins & Other Lipid Mediators. 2005;77(1):65-76.
24. Mukherjee PK, DeCoster MA, Campbell FZ, Davis RJ, Bazan NG. Glutamate Receptor Signaling Interplay Modulates Stress-sensitive Mitogen-activated Protein Kinases and Neuronal Cell Death*. Journal of Biological Chemistry. 1999;274(10):6493-6498.
25. Tian X, Bazan NG. Neuroprotection by Platelet-Activating Factor Antagonism. Annals of the New York Academy of Sciences. 2005;1053(1):455-456.
26. Rawish E, Nording H, Münte T, Langer HF. Platelets as Mediators of Neuroinflammation and Thrombosis. Frontiers in Immunology. 2020;11.
27. Vadas P, Gold M, Perelman B, et al. Platelet-activating factor, PAF acetylhydrolase, and severe anaphylaxis. N Engl J Med. 2008;358(1):28-35.
28. Li T, Zhang X, Jiang P, et al. Platelet-activating factor receptor antagonists of natural origin for acute ischemic stroke: a systematic review of current evidence. Frontiers in Pharmacology. 2022;13.
29. Belayev L, Khoutorova L, Atkins K, Cherqui A, Alvarez-Builla J, Bazan NG. LAU-0901, a novel platelet-activating factor receptor antagonist, confers enduring neuroprotection in experimental focal cerebral ischemia in the rat. Brain Research. 2009;1253:184-190.
30. Belayev L, Khoutorova L, Atkins K, Gordon WC, Alvarez-Builla J, Bazan NG. LAU-0901, a novel platelet-activating factor antagonist, is highly neuroprotective in cerebral ischemia. Experimental Neurology. 2008;214(2):253-258.
31. Serhan CN, Fredman G, Yang R, et al. Novel proresolving aspirin-triggered DHA pathway. Chem Biol. 2011;18(8):976-987.
32. Bazan NG, Eady TN, Khoutorova L, et al. Novel aspirin-triggered neuroprotectin D1 attenuates cerebral ischemic injury after experimental stroke. Experimental Neurology. 2012;236(1):122-130.
33. Jayaraj RL, Azimullah S, Beiram R, Jalal FY, Rosenberg GA. Neuroinflammation: friend and foe for ischemic stroke. J Neuroinflammation. 2019;16.
34. Khadankhuu B, Fei Y, Li X, Fang W, Li Y. 10-O-(N N-Dimethylaminoethyl)-Ginkgolide B Methane-Sulfonate (XQ-1H) Ameliorates Cerebral Ischemia Via Suppressing Neuronal Apoptosis. Journal of Stroke and Cerebrovascular Diseases. 2021;30(9):105987.
35. Belayev L, Obenaus A, Mukherjee PK, et al. Blocking pro-inflammatory platelet-activating factor receptors and activating cell survival pathways: A novel therapeutic strategy in experimental ischemic stroke. Brain Circulation. 2020;6(4):260.
36. Reid MM, Obenaus A, Mukherjee PK, et al. Synergistic neuroprotection by a PAF antagonist plus a docosanoid in experimental ischemic stroke: Dose-response and therapeutic window. J Stroke Cerebrovasc Dis. 2022;31(8):106585.
37. Arai K, Lok J, Guo S, Hayakawa K, Xing C, Lo EH. Cellular Mechanisms of Neurovascular Damage and Repair After Stroke. J Child Neurol. 2011;26(9):1193-1198.
38. Calandria JM, Bazan NG. Neuroprotectin D1 modulates the induction of pro-inflammatory signaling and promotes retinal pigment epithelial cell survival during oxidative stress. Adv Exp Med Biol. 2010;664:663-670.
2. Paul S, Candelario-Jalil E. Emerging neuroprotective strategies for the treatment of ischemic stroke: An overview of clinical and preclinical studies. Experimental Neurology. 2021;335:113518.
3. Kuriakose D, Xiao Z. Pathophysiology and Treatment of Stroke: Present Status and Future Perspectives. International Journal of Molecular Sciences. 2020;21(20):7609.
4. Sekerdag E, Solaroglu I, Gursoy-Ozdemir Y. Cell Death Mechanisms in Stroke and Novel Molecular and Cellular Treatment Options. Curr Neuropharmacol. 2018;16(9):1396-1415.
5. Arai K, Lok J, Guo S, Hayakawa K, Xing C, Lo EH. Cellular mechanisms of neurovascular damage and repair after stroke. J Child Neurol. 2011;26(9):1193-1198.
6. Mac Grory B, Saldanha IJ, Mistry EA, et al. Thrombolytic therapy for wake-up stroke: A systematic review and meta-analysis. Eur J Neurol. 2021;28(6):2006-2016.
7. 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;59(3):467-477.
8. Boltze J, Lukomska B, Jolkkonen J, consortium MI. Mesenchymal Stromal Cells in Stroke: Improvement of Motor Recovery or Functional Compensation? J Cereb Blood Flow Metab. 2014;34(8):1420-1421.
9. Saleh MC, Connell BJ, Rajagopal D, et al. Co-administration of resveratrol and lipoic acid, or their synthetic combination, enhances neuroprotection in a rat model of ischemia/reperfusion. PLoS One. 2014;9(1):e87865.
10. Hwang S, Choi J, Kim M. Combining Human Umbilical Cord Blood Cells With Erythropoietin Enhances Angiogenesis/Neurogenesis and Behavioral Recovery After Stroke. Front Neurol. 2019;10:357.
11. Ishrat T, Fouda AY, Pillai B, et al. Dose-response, therapeutic time-window and tPA-combinatorial efficacy of compound 21: A randomized, blinded preclinical trial in a rat model of thromboembolic stroke. J Cereb Blood Flow Metab. 2019;39(8):1635-1647.
12. Panetta T, Marcheselli VL, Braquet P, Spinnewyn B, Bazan NG. Effects of a platelet activating factor antagonist (BN 52021) on free fatty acids, diacylglycerols, polyphosphoinositides and blood flow in the gerbil brain: inhibition of ischemia-reperfusion induced cerebral injury. Biochem Biophys Res Commun. 1987;149(2):580-587.
13. Marcheselli VL, Rossowska MJ, Domingo MT, Braquet P, Bazan NG. Distinct platelet-activating factor binding sites in synaptic endings and in intracellular membranes of rat cerebral cortex. J Biol Chem. 1990;265(16):9140-9145.
14. Bazan NG, Squinto SP, Braquet P, Panetta T, Marcheselli VL. Platelet-activating factor and polyunsaturated fatty acids in cerebral ischemia or convulsions: intracellular PAF-binding sites and activation of a fos/jun/AP-1 transcriptional signaling system. Lipids. 1991;26(12):1236-1242.
15. Clark GD, Happel LT, Zorumski CF, Bazan NG. Enhancement of hippocampal excitatory synaptic transmission by platelet-activating factor. Neuron. 1992;9(6):1211-1216.
16. Kato K, Clark GD, Bazan NG, Zorumski CF. Platelet-activating factor as a potential retrograde messenger in CA1 hippocampal long-term potentiation. Nature. 1994;367(6459):175-179.
17. Bazan NG, Zorumski CF, Clark GD. The activation of phospholipase A2 and release of arachidonic acid and other lipid mediators at the synapse: the role of platelet-activating factor. J Lipid Mediat. 1993;6(1-3):421-427.
18. Jerusalinsky D, Fin C, Quillfeldt JA, et al. Effect of antagonists of platelet-activating factor receptors on memory of inhibitory avoidance in rats. Behav Neural Biol. 1994;62(1):1-3.
19. Izquierdo I, Fin C, Schmitz PK, et al. Memory enhancement by intrahippocampal, intraamygdala, or intraentorhinal infusion of platelet-activating factor measured in an inhibitory avoidance task. Proc Natl Acad Sci USA. 1995;92(11):5047-5051.
20. Bazan NG, Sunkel C, Marcheselli VL, Builla-G J. 2,4,6-trimethyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid esters as neuroprotective drugs. Published online May 20, 2003.
21. Bazan NG. Inflammation. A signal terminator. Nature. 1995;374(6522):501-502.
22. Ashraf MA, Nookala V. Biochemistry of Platelet Activating Factor. In: StatPearls. StatPearls Publishing; 2022.
23. Chen C, Bazan NG. Lipid signaling: Sleep, synaptic plasticity, and neuroprotection. Prostaglandins & Other Lipid Mediators. 2005;77(1):65-76.
24. Mukherjee PK, DeCoster MA, Campbell FZ, Davis RJ, Bazan NG. Glutamate Receptor Signaling Interplay Modulates Stress-sensitive Mitogen-activated Protein Kinases and Neuronal Cell Death*. Journal of Biological Chemistry. 1999;274(10):6493-6498.
25. Tian X, Bazan NG. Neuroprotection by Platelet-Activating Factor Antagonism. Annals of the New York Academy of Sciences. 2005;1053(1):455-456.
26. Rawish E, Nording H, Münte T, Langer HF. Platelets as Mediators of Neuroinflammation and Thrombosis. Frontiers in Immunology. 2020;11.
27. Vadas P, Gold M, Perelman B, et al. Platelet-activating factor, PAF acetylhydrolase, and severe anaphylaxis. N Engl J Med. 2008;358(1):28-35.
28. Li T, Zhang X, Jiang P, et al. Platelet-activating factor receptor antagonists of natural origin for acute ischemic stroke: a systematic review of current evidence. Frontiers in Pharmacology. 2022;13.
29. Belayev L, Khoutorova L, Atkins K, Cherqui A, Alvarez-Builla J, Bazan NG. LAU-0901, a novel platelet-activating factor receptor antagonist, confers enduring neuroprotection in experimental focal cerebral ischemia in the rat. Brain Research. 2009;1253:184-190.
30. Belayev L, Khoutorova L, Atkins K, Gordon WC, Alvarez-Builla J, Bazan NG. LAU-0901, a novel platelet-activating factor antagonist, is highly neuroprotective in cerebral ischemia. Experimental Neurology. 2008;214(2):253-258.
31. Serhan CN, Fredman G, Yang R, et al. Novel proresolving aspirin-triggered DHA pathway. Chem Biol. 2011;18(8):976-987.
32. Bazan NG, Eady TN, Khoutorova L, et al. Novel aspirin-triggered neuroprotectin D1 attenuates cerebral ischemic injury after experimental stroke. Experimental Neurology. 2012;236(1):122-130.
33. Jayaraj RL, Azimullah S, Beiram R, Jalal FY, Rosenberg GA. Neuroinflammation: friend and foe for ischemic stroke. J Neuroinflammation. 2019;16.
34. Khadankhuu B, Fei Y, Li X, Fang W, Li Y. 10-O-(N N-Dimethylaminoethyl)-Ginkgolide B Methane-Sulfonate (XQ-1H) Ameliorates Cerebral Ischemia Via Suppressing Neuronal Apoptosis. Journal of Stroke and Cerebrovascular Diseases. 2021;30(9):105987.
35. Belayev L, Obenaus A, Mukherjee PK, et al. Blocking pro-inflammatory platelet-activating factor receptors and activating cell survival pathways: A novel therapeutic strategy in experimental ischemic stroke. Brain Circulation. 2020;6(4):260.
36. Reid MM, Obenaus A, Mukherjee PK, et al. Synergistic neuroprotection by a PAF antagonist plus a docosanoid in experimental ischemic stroke: Dose-response and therapeutic window. J Stroke Cerebrovasc Dis. 2022;31(8):106585.
37. Arai K, Lok J, Guo S, Hayakawa K, Xing C, Lo EH. Cellular Mechanisms of Neurovascular Damage and Repair After Stroke. J Child Neurol. 2011;26(9):1193-1198.
38. Calandria JM, Bazan NG. Neuroprotectin D1 modulates the induction of pro-inflammatory signaling and promotes retinal pigment epithelial cell survival during oxidative stress. Adv Exp Med Biol. 2010;664:663-670.