Ischemic stroke, prevalent among the elderly, necessitates attention to reperfusion injury post treatment. Limited drug access to the brain, owing to the blood–brain barrier, restricts clinical applications. Identifying efficient drug carriers capable of penetrating this barrier is crucial. Blood–brain barrier transporters play a vital role in nutrient transport to the brain. Recently, nanoparticles emerged as drug carriers, enhancing drug permeability via surface-modified ligands. This article introduces the blood–brain barrier structure, elucidates reperfusion injury pathogenesis, compiles ischemic stroke treatment drugs, explores nanomaterials for drug encapsulation and emphasizes their advantages over conventional drugs. Utilizing nanoparticles as drug-delivery systems offers targeting and efficiency benefits absent in traditional drugs. The prospects for nanomedicine in stroke treatment are promising.

Keywords:

Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

1. Ghaffari A, Akbarfahimi M, Rostami HR. Discriminative factors for post-stroke depression. Asian J. Psychiatr. 48, 101863 (2020).
MedlineGoogle Scholar
2. Fifield KE, Vanderluit JL. Rapid degeneration of neurons in the penumbra region following a small, focal ischemic stroke. Eur. J. Neurosci. 52(4), 3196–3214 (2020).
MedlineGoogle Scholar
3. Kluge MG, Jones K, Kooi Ong L et al. Age-dependent disturbances of neuronal and glial protein expression profiles in areas of secondary neurodegeneration post-stroke. Neuroscience 393, 185–195 (2018).
Medline CASGoogle Scholar
4. Chamorro Á, Lo EH, Renú A, Van Leyen K, Lyden PD. The future of neuroprotection in stroke. J. Neurol. Neurosurg. Psychiatry 92(2), 129–135 (2021).
MedlineGoogle Scholar
5. Chen Z, Liu P, Xia X, Wang L, Li X. The underlying mechanism of PM2.5-induced ischemic stroke. Environ. Pollut. 310, 119827 (2022).
Medline CASGoogle Scholar
6. Wu Q, Yan R, Sun J. Probing the drug delivery strategies in ischemic stroke therapy. Drug Deliv. 27(1), 1644–1655 (2020).
MedlineGoogle Scholar
7. Kakaletsis N, Ntaios G, Milionis H et al. Time of blood pressure in target range in acute ischemic stroke. J. Hypertens. 41(2), 303–309 (2023).
Medline CASGoogle Scholar
8. Zubair AS, Sheth KN. Hemorrhagic conversion of acute ischemic stroke. Neurotherapeutics 20(3), 705–711 (2023).
MedlineGoogle Scholar
9. Katsanos AH, Malhotra K, Goyal N et al. Intravenous thrombolysis prior to mechanical thrombectomy in large vessel occlusions. Ann. Neurol. 86(3), 395–406 (2019).
MedlineGoogle Scholar
10. Xu ZH, Deng QW, Zhai Q et al. Clinical significance of stroke nurse in patients with acute ischemic stroke receiving intravenous thrombolysis. BMC Neurol. 21(1), 359 (2021).
Medline CASGoogle Scholar
11. Xu Y, Chen D, Liu P et al. A triple fusion tissue-type plasminogen activator (TriF-ΔtPA) enhanced thrombolysis in carotid embolism-induced stroke model. Int. J. Pharm. 637, 122878 (2023).
Medline CASGoogle Scholar
12. Capitanescu C, Macovei Oprescu AM, Ionita D et al. Molecular processes in the streptokinase thrombolytic therapy. J. Enzyme Inhib. Med. Chem. 31(6), 1411–1414 (2016).
Medline CASGoogle Scholar
13. Florova G, De Vera CJ, Emerine RL et al. Targeting the PAI-1 mechanism with a small peptide increases the efficacy of alteplase in a rabbit model of chronic empyema. Pharmaceutics 15(5), DOI: 10.3390/pharmaceutics15051498 (2023).
MedlineGoogle Scholar
14. Zhang N, Li C, Zhou D et al. Cyclic RGD functionalized liposomes encapsulating urokinase for thrombolysis. Acta Biomater. 70, 227–236 (2018).
Medline CASGoogle Scholar
15. Zuba V, Furon J, Bellemain-Sagnard M et al. The choroid plexus: a door between the blood and the brain for tissue-type plasminogen activator. Fluids Barriers CNS 19(1), 80 (2022).
Medline CASGoogle Scholar
16. Chen S, Chen D, Liu Y et al. Enhanced clot lysis by a single point mutation in a reteplase variant. Br. J. Haematol. 196(4), 1076–1085 (2022).
Medline CASGoogle Scholar
17. Johansen MC, Campbell BCV. ANA Investigates: tenecteplase. Ann. Neurol. 90(1), 1–3 (2021).
MedlineGoogle Scholar
18. Wang LC, Wei WY, Ho PC, Wu PY, Chu YP, Tsai KJ. Somatosensory cortical electrical stimulation after reperfusion attenuates ischemia/reperfusion injury of rat brain. Front. Aging Neurosci. 13, 741168 (2021). •• Provides a detailed introduction to the pathogenesis of stroke.
Medline CASGoogle Scholar
19. Garden GA, Campbell BM. Glial biomarkers in human central nervous system disease. Glia 64(10), 1755–1771 (2016).
MedlineGoogle Scholar
20. Gauberti M, Lapergue B, De Martinez Lizarrondo S et al. Ischemia–reperfusion injury after endovascular thrombectomy for ischemic stroke. Stroke 49(12), 3071–3074 (2018).
MedlineGoogle Scholar
21. Chang CY, Chen JY, Wu MH, Hu ML. Therapeutic treatment with vitamin C reduces focal cerebral ischemia-induced brain infarction in rats by attenuating disruptions of blood–brain barrier and cerebral neuronal apoptosis. Free Radic. Biol. Med. 155, 29–36 (2020).
Medline CASGoogle Scholar
22. Geier EG, Chen EC, Webb A et al. Profiling solute carrier transporters in the human blood–brain barrier. Clin. Pharmacol. Ther. 94(6), 636–639 (2013).
Medline CASGoogle Scholar
23. Latif S, Kang YS. Blood–brain barrier solute carrier transporters and motor neuron disease. Pharmaceutics 14(10), DOI: 10.3390/pharmaceutics14102167 (2022).
Google Scholar
24. Zhang W, Sigdel G, Mintz KJ et al. Carbon dots: a future blood–brain barrier penetrating nanomedicine and drug nanocarrier. Int. J. Nanomed. 16, 5003–5016 (2021).
MedlineGoogle Scholar
25. Mochizuki T, Mizuno T, Kurosawa T et al. Functional investigation of solute carrier family 35, member F2, in three cellular models of the primate blood–brain barrier. Drug Metab. Dispos. 49(1), 3–11 (2021).
Medline CASGoogle Scholar
26. Van Lengerich B, Zhan L, Xia D et al. A TREM2-activating antibody with a blood–brain barrier transport vehicle enhances microglial metabolism in Alzheimer’s disease models. Nat. Neurosci. 26(3), 416–429 (2023).
Medline CASGoogle Scholar
27. Feng W, Chen Y. Chemoreactive nanomedicine. J. Mater. Chem. B 8(31), 6753–6764 (2020).
Medline CASGoogle Scholar
28. Nagase T, Kin K, Yasuhara T. Targeting neurogenesis in seeking novel treatments for ischemic stroke. Biomedicines 11(10), DOI: 10.3390/biomedicines11102773 (2023).
MedlineGoogle Scholar
29. Sofias AM, Lammers T. Multidrug nanomedicine. Nat. Nanotechnol. 18(2), 104–106 (2023). •• Introduces the molecular properties of nanomaterials, providing a reference for the synthesis and loading of nanomedicines.
Medline CASGoogle Scholar
30. Yu W, Yin N, Yang Y et al. Rescuing ischemic stroke by biomimetic nanovesicles through accelerated thrombolysis and sequential ischemia–reperfusion protection. Acta Biomater. 140, 625–640 (2022).
Medline CASGoogle Scholar
31. Quan X, Han Y, Lu P et al. Annexin V-modified platelet-biomimetic nanomedicine for targeted therapy of acute ischemic stroke. Adv. Healthc. Mater. 11(16), e2200416 (2022).
Medline CASGoogle Scholar
32. Chen J, Jin J, Li K, Shi L, Wen X, Fang F. Progresses and prospects of neuroprotective agents-loaded nanoparticles and biomimetic material in ischemic stroke. Front. Cell. Neurosci. 16, 868323 (2022).
Medline CASGoogle Scholar
33. Wu D, Chen Q, Chen X, Han F, Chen Z, Wang Y. The blood–brain barrier: structure, regulation, and drug delivery. Signal Transduct. Target. Ther. 8(1), 217 (2023).
MedlineGoogle Scholar
34. Guo M, Sun X, Chen J, Cai T. Pharmaceutical cocrystals: a review of preparations, physicochemical properties and applications. Acta Pharm. Sin. B 11(8), 2537–2564 (2021).
Medline CASGoogle Scholar
35. Sasson E, Anzi S, Bell B et al. Nano-scale architecture of blood–brain barrier tight-junctions. eLife 10, e63253 (2021).
Medline CASGoogle Scholar
36. Faria-Pereira A, Morais VA. Synapses: the brain's energy-demanding sites. Int. J. Mol. Sci. 23(7), 3627 (2022).
Medline CASGoogle Scholar
37. Nguyen YTK, Ha HTT, Nguyen TH, Nguyen LN. The role of SLC transporters for brain health and disease. Cell Mol. Life Sci. 79(1), 20 (2021).
MedlineGoogle Scholar
38. Grube M, Hagen P, Jedlitschky G. Neurosteroid transport in the brain: role of ABC and SLC transporters. Front. Pharmacol. 9, 354 (2018).
MedlineGoogle Scholar
39. Brenza TM, Schlichtmann BW, Bhargavan B et al. Biodegradable polyanhydride-based nanomedicines for blood to brain drug delivery. J. Biomed. Mater. Res. A 106(11), 2881–2890 (2018).
Medline CASGoogle Scholar
40. Chen SQ, Wang C, Tao S, Wang YX, Hu FQ, Yuan H. Rational design of redox-responsive and p-gp-inhibitory lipid nanoparticles with high entrapment of paclitaxel for tumor therapy. Adv. Healthc. Mater. 7(17), e1800485 (2018).
MedlineGoogle Scholar
41. Pathan N, Shende P. Tailoring of P-glycoprotein for effective transportation of actives across blood–brain-barrier. J. Control. Rel. 335, 398–407 (2021).
Medline CASGoogle Scholar
42. Bai X, Moraes TF, Reithmeier RAF. Structural biology of solute carrier (SLC) membrane transport proteins. Mol. Membr. Biol. 34(1–2), 1–32 (2017).
MedlineGoogle Scholar
43. Seo E, Jee B, Chung JH et al. Repression of SLC22A3 by the AR-V7/YAP1/TAZ axis in enzalutamide-resistant castration-resistant prostate cancer. FEBS J. 290(6), 1645–1662 (2023).
Medline CASGoogle Scholar
44. Ullman JC, Arguello A, Getz JA et al. Brain delivery and activity of a lysosomal enzyme using a blood–brain barrier transport vehicle in mice. Sci. Transl. Med. 12(545), DOI: 10.1126/scitranslmed.aay1163 (2020).
Google Scholar
45. Zhao Z, Ukidve A, Krishnan V, Mitragotri S. Effect of physicochemical and surface properties on in vivo fate of drug nanocarriers. Adv. Drug Deliv. Rev. 143, 3–21 (2019).
Medline CASGoogle Scholar
46. Anand A, Sugumaran A, Narayanasamy D. Brain targeted delivery of anticancer drugs: prospective approach using solid lipid nanoparticles. IET Nanobiotechnol. 13(4), 353–362 (2019).
MedlineGoogle Scholar
47. Du Y, Gao J, Zhang H et al. Brain-targeting delivery of MMB4 DMS using carrier-free nanomedicine CRT-MMB4@MDZ. Drug Deliv. 28(1), 1822–1835 (2021).
Medline CASGoogle Scholar
48. Chen X, Zhao Y, He C et al. Identification of a novel GLUT1 inhibitor with in vitro and in vivo anti-tumor activity. Int. J. Biol. Macromol. 216, 768–778 (2022).
Medline CASGoogle Scholar
49. Strubbe-Rivera JO, Chen J, West BA, Parent KN, Wei GW, Bazil JN. Modeling the effects of calcium overload on mitochondrial ultrastructural remodeling. Appl. Sci. 11(5), DOI: 10.3390/app11052071 (2021). •• Introduces the destructive effect of free radicals on cells themselves, including the process of distance, which is very detailed.
Google Scholar
50. Wen B, Xu K, Huang R et al. Preserving mitochondrial function by inhibiting GRP75 ameliorates neuron injury under ischemic stroke. Mol. Med. Rep. 25(5), DOI: 10.3892/mmr.2022.12681 (2022).
Google Scholar
51. Collard CD, Gelman S. Pathophysiology, clinical manifestations, and prevention of ischemia-reperfusion injury. Anesthesiology 94, 1133–1138 (2001).
Medline CASGoogle Scholar
52. Yao J, Peng H, Qiu Y et al. Nanoplatform-mediated calcium overload for cancer therapy. J. Mater. Chem. B 10(10), 1508–1519 (2022).
Medline CASGoogle Scholar
53. Gorica E, Calderone V. Arachidonic acid derivatives and neuroinflammation. CNS Neurol. Disord. Drug Targets 21(2), 118–129 (2022).
Medline CASGoogle Scholar
54. Menezes LB, Segat BB, Tolentino H et al. ROS scavenging of SOD/CAT mimics probed by EPR and reduction of lipid peroxidation in S. cerevisiae and mouse liver, under severe hydroxyl radical stress condition. J. Inorg. Biochem. 239, 112062 (2023).
Medline CASGoogle Scholar
55. Du W, Wang J, Zhou L et al. Transferrin-targeted iridium nanoagglomerates with multi-enzyme activities for cerebral ischemia–reperfusion injury therapy. Acta Biomater. 166, 524–535 (2023).
Medline CASGoogle Scholar
56. Kapoor M, Sharma N, Sandhir R, Nehru B. Effect of the NADPH oxidase inhibitor apocynin on ischemia–reperfusion hippocampus injury in rat brain. Biomed. Pharmacother. 97, 458–472 (2018).
Medline CASGoogle Scholar
57. Tang X, Zhong W, Tu Q, Ding B. NADPH oxidase mediates the expression of MMP-9 in cerebral tissue after ischemia–reperfusion damage. Neurol. Res. 36(2), 118–125 (2014).
MedlineGoogle Scholar
58. Fujii J, Osaki T. Involvement of nitric oxide in protecting against radical species and autoregulation of M1-polarized macrophages through metabolic remodeling. Molecules 28(2), DOI: 10.3390/molecules28020814 (2023).
Google Scholar
59. Fedotcheva T, Shimanovsky N, Fedotcheva N. Specific features of mitochondrial dysfunction under conditions of ferroptosis induced by t-butylhydroperoxide and iron: protective role of the inhibitors of lipid peroxidation and mitochondrial permeability transition pore opening. Membranes 13(4), DOI: 10.3390/membranes13040372 (2023).
MedlineGoogle Scholar
60. Łukawski K, Czuczwar SJ. Oxidative stress and neurodegeneration in animal models of seizures and epilepsy. Antioxidants 12(5), DOI: 10.3390/antiox12051049 (2023).
MedlineGoogle Scholar
61. Lee KH, Ha SJ, Woo JS et al. Exenatide prevents morphological and structural changes of mitochondria following ischaemia–reperfusion injury. Heart Lung Circ. 26(5), 519–523 (2017).
MedlineGoogle Scholar
62. Peng JF, Salami OM, Habimana O, Xie YX, Yao H, Yi GH. Targeted mitochondrial drugs for treatment of ischemia–reperfusion injury. Curr. Drug Targets 23(16), 1526–1536 (2022).
Medline CASGoogle Scholar
63. Speijer D. How mitochondria showcase evolutionary mechanisms and the importance of oxygen. BioEssays 45(6), e2300013 (2023).
Medline CASGoogle Scholar
64. Yin X, Wang J, Yang S et al. SAM50 exerts neuroprotection by maintaining the mitochondrial structure during experimental cerebral ischemia/reperfusion injury in rats. CNS Neurosci. Ther. 28(12), 2230–2244 (2022).
Medline CASGoogle Scholar
65. Monzel AS, Enríquez JA, Picard M. Multifaceted mitochondria: moving mitochondrial science beyond function and dysfunction. Nat. Metab. 5(4), 546–562 (2023).
MedlineGoogle Scholar
66. Guan X, Wei D, Liang Z et al. FDCA attenuates neuroinflammation and brain injury after cerebral ischemic stroke. ACS Chem. Neurosci. DOI: 10.1021/acschemneuro.3c00456 (2023).
Google Scholar
67. Wang J, Hu Z, Yang S et al. Inflammatory cytokines and cells are potential markers for patients with cerebral apoplexy in intensive care unit. Exp. Ther. Med. 16, 1014–1020 (2018).
MedlineGoogle Scholar
68. Wytrykowska A, Prosba-Mackiewicz M, Nyka WM. IL-1β, TNF-α, and IL-6 levels in gingival fluid and serum of patients with ischemic stroke. J. Oral Sci. 58(4), 509–513 (2016).
Medline CASGoogle Scholar
69. Yoshida M, Kato N, Uemura T et al. Time dependent transition of the levels of protein-conjugated acrolein (PC-Acro), IL-6 and CRP in plasma during stroke. eNeurologicalSci 7, 18–24 (2017).
MedlineGoogle Scholar
70. Thammisetty SS, Pedragosa J, Weng YC, Calon F, Planas A, Kriz J. Age-related deregulation of TDP-43 after stroke enhances NF-κB-mediated inflammation and neuronal damage. J. Neuroinflamm. 15(1), DOI: 10.1186/s12974-018-1350-y (2018).
MedlineGoogle Scholar
71. Chen R, Jiang G, Liu Y et al. Predictive effects of S100β and CRP levels on hemorrhagic transformation in patients with AIS after intravenous thrombolysis: a concise review based on our center experience. Medicine 102(38), DOI: 10.1097/md.0000000000035149 (2023).
Google Scholar
72. Zhang D, Yuan D, Shen J et al. Up-regulation of VCAM1 relates to neuronal apoptosis after intracerebral hemorrhage in adult rats. Neurochem. Res. 40(5), 1042–1052 (2015).
Medline CASGoogle Scholar
73. Wang D, Li L, Zhang Q et al. Combination of electroacupuncture and constraint-induced movement therapy enhances functional recovery after ischemic stroke in rats. J. Mol. Neurosci. 71(10), 2116–2125 (2021).
Medline CASGoogle Scholar
74. Lim S, Kim TJ, Kim YJ, Kim C, Ko SB, Kim BS. Senolytic therapy for cerebral ischemia–reperfusion injury. Int. J. Mol. Sci. 22(21), DOI: 10.3390/ijms222111967 (2021).
Google Scholar
75. Liu YS, Zhang GY, Hou Y. Theoretical and experimental investigation of the antioxidation mechanism of loureirin C by radical scavenging for treatment of stroke. Molecules 28(1), DOI: 10.3390/molecules28010380 (2023).
Google Scholar
76. Preskorn SH. CNS drug development, lessons learned, part 4: the role of brain circuitry and genes – tasimelteon as an example. J. Psychiatr. 23(6), 425–430 (2017).
Google Scholar
77. Xiong LL, Chen L, Deng IB, Zhou XF, Wang TH. P75 neurotrophin receptor as a therapeutic target for drug development to treat neurological diseases. Eur. J. Neurosci. 56(8), 5299–5318 (2022).
Medline CASGoogle Scholar
78. Zhao N, Gao Y, Jia H, Jiang X. Anti-apoptosis effect of traditional Chinese medicine in the treatment of cerebral ischemia–reperfusion injury. Apoptosis 28(5–6), 702–729 (2023).
Medline CASGoogle Scholar
79. Matsuoka Y, Yamada KI. Detection and structural analysis of lipid-derived radicals in vitro and in vivo. Free Radic. Res. 55(4), 441–449 (2021).
Medline CASGoogle Scholar
80. Lee IS, Kullmann S, Scheffler K, Preissl H, Enck P. Fat label compared with fat content: gastrointestinal symptoms and brain activity in functional dyspepsia patients and healthy controls. Am. J. Clin. Nutr. 108(1), 127–135 (2018).
MedlineGoogle Scholar
81. Morita M, Naito Y, Itoh Y, Niki E. Comparative study on the plasma lipid oxidation induced by peroxynitrite and peroxyl radicals and its inhibition by antioxidants. Free Radic. Res. 53(11–12), 1101–1113 (2019).
Medline CASGoogle Scholar
82. Yoo JY, Lee YJ, Kim YJ et al. Multiple low-dose radiation-induced neuronal cysteine transporter expression and oxidative stress are rescued by N-acetylcysteine in neuronal SH-SY5Y cells. Neurotoxicology 95, 205–217 (2023).
Medline CASGoogle Scholar
83. Shibuya K, Otani R, Suzuki YI, Kuwabara S, Kiernan MC. Neuronal hyperexcitability and free radical toxicity in amyotrophic lateral sclerosis: established and future targets. Pharmaceuticals 15(4), DOI: 10.3390/ph15040433 (2022).
MedlineGoogle Scholar
84. Homma T, Kobayashi S, Sato H, Fujii J. Edaravone, a free radical scavenger, protects against ferroptotic cell death in vitro. Exp. Cell Res. 384(1), 111592 (2019).
Medline CASGoogle Scholar
85. Fogelholm R, Palomäki H, Erilä T, Rissanen A, Kaste M. Blood pressure, nimodipine, and outcome of ischemic stroke. Acta Neurol. Scand. 109(3), 200–204 (2004).
Medline CASGoogle Scholar
86. Yu Y, Feng J, Lian N et al. Hydrogen gas alleviates blood–brain barrier impairment and cognitive dysfunction of septic mice in an Nrf2-dependent pathway. Int. Immunopharmacol. 85(106585), 21 (2020).
Google Scholar
87. Rao AK, Vaidyula VR, Bagga S et al. Effect of antiplatelet agents clopidogrel, aspirin, and cilostazol on circulating tissue factor procoagulant activity in patients with peripheral arterial disease. Thromb. Haemost. 96(6), 738–743 (2006).
Medline CASGoogle Scholar
88. Zhao Z, Ma Y, Liu Q et al. Effects of different doses of clopidogrel plus early rehabilitation therapy on motor function and inflammatory factors in patients with ischemic stroke. Evid. Based Complement. Alternat. Med. 2022, 9692382 (2022).
MedlineGoogle Scholar
89. Liu Y, Yin Y, Lu QL et al. Vinpocetine in the treatment of poststroke cognitive dysfunction: a protocol for systematic review and meta-analysis. Medicine 98(6), e13685 (2019).
MedlineGoogle Scholar
90. Milcan A, Arslan E, Bagdatoglu OT et al. The effect of alprostadil on ischemia–reperfusion injury of peripheral nerve in rats. Pharmacol. Res. 49(1), 67–72 (2004).
Medline CASGoogle Scholar
91. Li D, Zhao S, Zhu B et al. Cinepazide maleate promotes recovery from spinal cord injury by inhibiting inflammation and prolonging neuronal survival. Drug Dev. Res. 84(4), 736–746 (2023).
Medline CASGoogle Scholar
92. Zhang J, Zhang X, Shang Y, Zhang L. Effect of cinepazide maleate on serum inflammatory factors of ICU patients with severe cerebral hemorrhage after surgery. Evid. Based Complement. Alternat. Med. 2021, 6562140 (2021).
MedlineGoogle Scholar
93. Li L, Lou X, Zhang K, Yu F, Zhao Y, Jiang P. Hydrochloride fasudil attenuates brain injury in ICH rats. Transl. Neurosci. 11(1), 75–86 (2020).
Medline CASGoogle Scholar
94. Kecskés S, Menyhárt Á, Bari F, Farkas E. Nimodipine augments cerebrovascular reactivity in aging but runs the risk of local perfusion reduction in acute cerebral ischemia. Front. Aging Neurosci. 15, 1175281 (2023).
Medline CASGoogle Scholar
95. Yuan LL, Chen TY, Huang ZQ. Effects of paroxetine hydrochloride combined with idebenone on inflammatory factors and antioxidant molecules in treatment of depression after ischemic stroke. Pak. J. Med. Sci. 39(1), 17–22 (2023).
MedlineGoogle Scholar
96. Özalp B, Elbey H, Aydın H, Tekkesin MS, Uzun H. The effect of coenzyme Q10 on venous ischemia reperfusion injury. J. Surg. Res. 204(2), 304–310 (2016).
Medline CASGoogle Scholar
97. Lu CJ, Guo YZ, Zhang Y et al. Coenzyme Q10 ameliorates cerebral ischemia reperfusion injury in hyperglycemic rats. Pathol. Res. Pract. 213(9), 1191–1199 (2017).
Medline CASGoogle Scholar
98. Overgaard K. The effects of citicoline on acute ischemic stroke: a review. J. Stroke Cerebrovasc. Dis. 23(7), 1764–1769 (2014).
MedlineGoogle Scholar
99. Shavlovskaya OA. The assessment of the efficacy of citicoline in the early and recovery stages of stroke. Zh. Nevrol. Psikhiatr. Im. SS Korsakova 116(6), 93–97 (2016).
Medline CASGoogle Scholar
100. Stein DJ, Daniels WM, Savitz J, Harvey BH. Brain-derived neurotrophic factor: the neurotrophin hypothesis of psychopathology. CNS Spectr. 13(11), 945–949 (2008).
MedlineGoogle Scholar
101. Hishiyama S, Kotoda M, Ishiyama T, Mitsui K, Matsukawa T. Neuroprotective effects of neurotropin in a mouse model of hypoxic–ischemic brain injury. J. Anesth. 33(4), 495–500 (2019).
MedlineGoogle Scholar
102. Wang J, Sun R, Li Z, Pan Y. Combined bone marrow stromal cells and oxiracetam treatments ameliorates acute cerebral ischemia/reperfusion injury through TRPC6. Acta Biochim. Biophys Sin. 51(8), 767–777 (2019).
CASGoogle Scholar
103. Ricci S, Celani MG, Cantisani TA, Righetti E. Piracetam for acute ischaemic stroke. Cochrane Database Syst. Rev. 2012(9), CD000419 (2012).
MedlineGoogle Scholar
104. Azouz AA, Hersi F, Ali FEM, Hussein Elkelawy AMM, Omar HA. Renoprotective effect of vinpocetine against ischemia/reperfusion injury: modulation of NADPH oxidase/Nrf2, IKKβ/NF-κB p65, and cleaved caspase-3 expressions. J. Biochem. Mol. Toxicol. 36(7), e23046 (2022).
Medline CASGoogle Scholar
105. Ren Y, Ma X, Wang T et al. The cerebroprotein hydrolysate-I plays a neuroprotective effect on cerebral ischemic stroke by inhibiting MEK/ERK1/2 signaling pathway in rats. Neuropsychiatr. Dis. Treat. 17, 2199–2208 (2021).
MedlineGoogle Scholar
106. Sui R, Zang L, Bai Y. Administration of troxerutin and cerebroprotein hydrolysate injection alleviates cerebral ischemia/reperfusion injury by down-regulating caspase molecules. Neuropsychiatr. Dis. Treat. 15, 2345–2352 (2019).
Medline CASGoogle Scholar
107. Fukuta T, Ikeda-Imafuku M, Iwao Y. Development of edaravone ionic liquids and their application for the treatment of cerebral ischemia/reperfusion injury. Mol. Pharm. 20(6), 3115–3126 (2023).
Medline CASGoogle Scholar
108. Schnaar RL. Gangliosides of the vertebrate nervous system. J. Mol. Biol. 428(16), 3325–3336 (2016).
Medline CASGoogle Scholar
109. Li L, Medina-Menéndez C, García-Corzo L et al. SoxD genes are required for adult neural stem cell activation. Cell Rep. 38(5), 110313 (2022).
Medline CASGoogle Scholar
110. Tian Z, Zhao Q, Biswas S, Deng W. Methods of reactivation and reprogramming of neural stem cells for neural repair. Methods 133, 3–20 (2018).
Medline CASGoogle Scholar
111. Chiang MC, Cheng YC, Chen SJ, Yen CH, Huang RN. Metformin activation of AMPK-dependent pathways is neuroprotective in human neural stem cells against amyloid-beta-induced mitochondrial dysfunction. Exp. Cell Res. 347(2), 322–331 (2016). • Introduces the BCL2 gene related to neuroprotective effects, and describes that the emerging hydrogen gas can also promote its expression.
Medline CASGoogle Scholar
112. Shi W, Bi S, Dai Y, Yang K, Zhao Y, Zhang Z. Clobetasol propionate enhances neural stem cell and oligodendrocyte differentiation. Exp. Ther. Med. 18(2), 1258–1266 (2019).
Medline CASGoogle Scholar
113. Vicario N, Bernstock JD, Spitale FM et al. Clobetasol modulates adult neural stem cell growth via canonical Hedgehog pathway activation. Int. J. Mol. Sci. 20(8), DOI: 10.3390/ijms20081991 (2019).
Google Scholar
114. Lin B, Lu L, Wang Y et al. Nanomedicine directs neuronal differentiation of neural stem cells via silencing long noncoding RNA for stroke therapy. Nano Lett. 21(1), 806–815 (2021).
Medline CASGoogle Scholar
115. Soares R, Ribeiro FF, Xapelli S et al. Tauroursodeoxycholic acid enhances mitochondrial biogenesis, neural stem cell pool, and early neurogenesis in adult rats. Mol. Neurobiol. 55(5), 3725–3738 (2018).
Medline CASGoogle Scholar
116. Fernandes MB, Costa M, Ribeiro MF et al. Reprogramming of lipid metabolism as a new driving force behind tauroursodeoxycholic acid-induced neural stem cell proliferation. Front. Cell. Dev. Biol. 8, 335 (2020).
MedlineGoogle Scholar
117. Kemp JA, Shim MS, Heo CY, Kwon YJ. ‘Combo’ nanomedicine: co-delivery of multi-modal therapeutics for efficient, targeted, and safe cancer therapy. Adv. Drug Deliv. Rev. 98, 3–18 (2016).
Medline CASGoogle Scholar
118. Bilia AR, Piazzini V, Guccione C et al. Improving on nature: the role of nanomedicine in the development of clinical natural drugs. Planta Med. 83(5), 366–381 (2017).
Medline CASGoogle Scholar
119. Abbasi S, Sato Y, Kajimoto K, Harashima H. New design strategies for controlling the rate of hydrophobic drug release from nanoemulsions in blood circulation. Mol. Pharm. 17(10), 3773–3782 (2020).
Medline CASGoogle Scholar
120. Tuguntaev RG, Hussain A, Fu C et al. Bioimaging guided pharmaceutical evaluations of nanomedicines for clinical translations. J. Nanobiotechnol. 20(1), 236 (2022).
MedlineGoogle Scholar
121. Vanden-Hehir S, Tipping WJ, Lee M, Brunton VG, Williams A, Hulme AN. Raman imaging of nanocarriers for drug delivery. Nanomaterials 9(3), DOI: 10.3390/nano9030341 (2019).
MedlineGoogle Scholar
122. Sarkar A, Fatima I, Jamal QMS et al. Nanoparticles as a carrier system for drug delivery across blood brain barrier. Curr. Drug Metab. 18(2), 129–137 (2017).
Medline CASGoogle Scholar
123. Xu XR, Carrim N, Neves MAD et al. Platelets and platelet adhesion molecules: novel mechanisms of thrombosis and anti-thrombotic therapies. Thromb J. 14(Suppl. 1), 29 (2016).
MedlineGoogle Scholar
124. Kim CR, Uemura T, Kitagawa S. Inorganic nanoparticles in porous coordination polymers. Chem. Soc. Rev. 45(14), 3828–3845 (2016).
Medline CASGoogle Scholar
125. Malekkhaiat Häffner S, Malmsten M. Membrane interactions and antimicrobial effects of inorganic nanoparticles. Adv. Colloid Interface Sci. 248, 105–128 (2017).
MedlineGoogle Scholar
126. Fernandes LF, Bruch GE, Massensini AR, Frézard F. Recent advances in the therapeutic and diagnostic use of liposomes and carbon nanomaterials in ischemic stroke. Front. Neurosci. 12, 453 (2018).
MedlineGoogle Scholar
127. Vani JR, Mohammadi MT, Foroshani MS, Jafari M. Polyhydroxylated fullerene nanoparticles attenuate brain infarction and oxidative stress in rat model of ischemic stroke. EXCLI J. 15, 378–390 (2016).
MedlineGoogle Scholar
128. Zhao M, Wang C, Xie J, Ji C, Gu Z. Eco-friendly and scalable synthesis of fullerenols with high free radical scavenging ability for skin radioprotection. Small 17(37), e2102035 (2021).
Medline CASGoogle Scholar
129. Chanaday NL, Nosyreva E, Shin OH et al. Presynaptic store-operated Ca²⁺ entry drives excitatory spontaneous neurotransmission and augments endoplasmic reticulum stress. Neuron 109(8), 1314–1332e5 (2021).
Medline CASGoogle Scholar
130. Zhao Y, Shen X, Ma R, Hou Y, Qian Y, Fan C. Biological and biocompatible characteristics of fullerenols nanomaterials for tissue engineering. Histol. Histopathol. 36(7), 725–731 (2021).
Medline CASGoogle Scholar
131. Lee HJ, Park J, Yoon OJ et al. Amine-modified single-walled carbon nanotubes protect neurons from injury in a rat stroke model. Nat. Nanotechnol. 6(2), 121–125 (2011).
Medline CASGoogle Scholar
132. Hassanzadeh P, Arbabi E, Atyabi F, Dinarvand R. Nerve growth factor–carbon nanotube complex exerts prolonged protective effects in an in vitro model of ischemic stroke. Life Sci. 179, 15–22 (2017).
Medline CASGoogle Scholar
133. Künzle M, Mangler J, Lach M, Beck T. Peptide-directed encapsulation of inorganic nanoparticles into protein containers. Nanoscale 10(48), 22917–22926 (2018).
Medline CASGoogle Scholar
134. Gao Y, Chen X, Liu H. A facile approach for synthesis of nano-CeO₂ particles loaded co-polymer matrix and their colossal role for blood–brain barrier permeability in cerebral ischemia. J. Photochem. Photobiol. B 187, 184–189 (2018).
Medline CASGoogle Scholar
135. Taslimifar M, Faltys M, Kurtcuoglu V, Verrey F, Makrides V. Analysis of L-leucine amino acid transporter species activity and gene expression by human blood brain barrier hCMEC/D3 model reveal potential LAT1, LAT4, B⁰AT2 and y⁺LAT1 functional cooperation. J. Cereb. Blood Flow Metab. 42(1), 90–103 (2022).
Medline CASGoogle Scholar
136. Daoud WA, Xin JH, Zhang YH. Surface functionalization of cellulose fibers with titanium dioxide nanoparticles and their combined bactericidal activities. Surface Sci. 599(1–3), 69–75 (2005).
CASGoogle Scholar
137. Kim CK, Kim T, Choi IY et al. Ceria nanoparticles that can protect against ischemic stroke. Angew. Chem. Int. Ed. 51(44), 11039–11043 (2012).
Medline CASGoogle Scholar
138. Estevez AY, Pritchard S, Harper K et al. Neuroprotective mechanisms of cerium oxide nanoparticles in a mouse hippocampal brain slice model of ischemia. Free Radic. Biol. Med. 51(6), 1155–1163 (2011).
Medline CASGoogle Scholar
139. Nelson BC, Johnson ME, Walker ML, Riley KR, Sims CM. Antioxidant cerium oxide nanoparticles in biology and medicine. Antioxidants 5(2), DOI: 10.3390/antiox5020015 (2016).
MedlineGoogle Scholar
140. Teleanu DM, Chircov C, Grumezescu AM, Volceanov A, Teleanu RI. Impact of nanoparticles on brain health: an up to date overview. J. Clin. Med. 7(12), DOI: 10.3390/jcm7120490 (2018).
MedlineGoogle Scholar
141. Cui J, Chen X, Zhai X et al. Inhalation of water electrolysis-derived hydrogen ameliorates cerebral ischemia–reperfusion injury in rats – a possible new hydrogen resource for clinical use. Neuroscience 335, 232–241 (2016).
Medline CASGoogle Scholar
142. Xie K, Wang Y, Yin L et al. Hydrogen gas alleviates sepsis-induced brain injury by improving mitochondrial biogenesis through the activation of PGC-α in mice. Shock 55(1), 100–109 (2021).
Medline CASGoogle Scholar
143. Li Z, Chen K, Shao Q et al. Nanoparticulate MgH₂ ameliorates anxiety/depression-like behaviors in a mouse model of multiple sclerosis by regulating microglial polarization and oxidative stress. Neuroinflammation 20(1), 16 (2023).
MedlineGoogle Scholar
144. Cruz CCR, Da Silva NP, Castilho AV et al. Synthesis, characterization and photothermal analysis of nanostructured hydrides of Pd and PdCeO₂. Sci. Rep. 10(1), 17561 (2020).
Medline CASGoogle Scholar
145. Zhang D, Liu L, Wang J et al. Drug-loaded PEG-PLGA nanoparticles for cancer treatment. Front. Pharmacol. 13, 990505 (2022).
Medline CASGoogle Scholar
146. Pastorino L, Dellacasa E, Petrini P, Monticelli O. Stereocomplex poly(lactic acid) nanocoated chitosan microparticles for the sustained release of hydrophilic drugs. Mater. Sci. Eng. C 76, 1129–1135 (2017).
Medline CASGoogle Scholar
147. Azadmanesh J, Borgstahl GEO. A review of the catalytic mechanism of human manganese superoxide dismutase. Antioxidants 7(2), DOI: 10.3390/antiox7020025 (2018).
MedlineGoogle Scholar
148. Zhao H, Zhang R, Yan X, Fan K. Superoxide dismutase nanozymes: an emerging star for anti-oxidation. J. Mater. Chem. B 9(35), 6939–6957 (2021).
Medline CASGoogle Scholar
149. Reddy MK, Labhasetwar V. Nanoparticle-mediated delivery of superoxide dismutase to the brain: an effective strategy to reduce ischemia–reperfusion injury. FASEB J. 23(5), 1384–1395 (2009).
Medline CASGoogle Scholar
150. Petro M, Jaffer H, Yang J, Kabu S, Morris VB, Labhasetwar V. Tissue plasminogen activator followed by antioxidant-loaded nanoparticle delivery promotes activation/mobilization of progenitor cells in infarcted rat brain. Biomaterials 81, 169–180 (2016).
Medline CASGoogle Scholar
151. Chen J, Cheng D, Li J et al. Influence of lipid composition on the phase transition temperature of liposomes composed of both DPPC and HSPC. Drug Dev. Ind. Pharm. 39(2), 197–204 (2013).
Medline CASGoogle Scholar
152. Mitragotri S, Burke PA, Langer R. Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies. Nat. Rev. Drug Discov. 13(9), 655–672 (2014).
Medline CASGoogle Scholar
153. Andonova V, Peneva P. Characterization methods for solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC). Curr. Pharm. Des. doi:10.2174/1381612823666171115105721 (2017) (Epub ahead of print).
MedlineGoogle Scholar
154. Partoazar A, Nasoohi S, Rezayat SM et al. Nanoliposome containing cyclosporine A reduced neuroinflammation responses and improved neurological activities in cerebral ischemia/reperfusion in rat. Fundam. Clin. Pharmacol. 31(2), 185–193 (2017).
Medline CASGoogle Scholar
155. Smoleński M, Karolewicz B, Gołkowska AM, Nartowski KP, Małolepsza-Jarmołowska K. Emulsion-based multicompartment vaginal drug carriers: from nanoemulsions to nanoemulgels. Int. J. Mol. Sci. 22(12), DOI: 10.3390/ijms22126455 (2021).
Google Scholar
156. Elzayat A, Adam-Cervera I, Álvarez-Bermúdez O, Muñoz-Espí R. Nanoemulsions for synthesis of biomedical nanocarriers. Colloids Surf. B 203, 111764 (2021).
Medline CASGoogle Scholar
157. Singh Y, Meher JG, Raval K et al. Nanoemulsion: concepts, development and applications in drug delivery. J. Control. Rel. 252, 28–49 (2017).
Medline CASGoogle Scholar
158. Burger C, Shahzad Y, Brummer A, Gerber M, Du Plessis J. Traversing the skin barrier with nano-emulsions. Curr. Drug Deliv. 4(4), 458–472 (2017).
Google Scholar
159. Yadav S, Gandham SK, Panicucci R, Amiji MM. Intranasal brain delivery of cationic nanoemulsion-encapsulated TNF-α siRNA in prevention of experimental neuroinflammation. Nanomedicine 2(4), 987–1002 (2016).
Google Scholar
160. Azambuja JH, Schuh RS, Michels LR et al. Nasal administration of cationic nanoemulsions as CD73-siRNA delivery system for glioblastoma treatment: a new therapeutical approach. Mol. Neurobiol. 57(2), 635–649 (2020).
Medline CASGoogle Scholar
161. Ghosh B, Biswas S. Polymeric micelles in cancer therapy: state of the art. J. Control. Rel. 332, 127–147 (2021).
Medline CASGoogle Scholar
162. Kotta S, Aldawsari HM, Badr-Eldin SM, Nair AB, Yt K. Progress in polymeric micelles for drug delivery applications. Pharmaceutics 14(8), DOI: 10.3390/pharmaceutics14081636 (2022).
Google Scholar
163. Jin GW, Rejinold NS, Choy JH. Multifunctional polymeric micelles for cancer therapy. Polymers 14(22), DOI: 10.3390/polym14224839 (2022).
Google Scholar
164. Okamura K, Tsubokawa T, Johshita H, Miyazaki H, Shiokawa Y. Edaravone, a free radical scavenger, attenuates cerebral infarction and hemorrhagic infarction in rats with hyperglycemia. Neurol. Res. 36(1), 65–69 (2014).
Medline CASGoogle Scholar
165. Higashi Y. Edaravone for the treatment of acute cerebral infarction: role of endothelium-derived nitric oxide and oxidative stress. Expert Opin. Pharmacother. 10(2), 323–331 (2009).
Medline CASGoogle Scholar
166. Le Guyader G, Do B, Rietveld IB et al. Mixed polymeric micelles for rapamycin skin delivery. Pharmaceutics 14(3), DOI: 10.3390/pharmaceutics14030569 (2022).
Google Scholar
167. Shin YB, Choi JY, Shin DH, Lee JW. Anticancer evaluation of methoxy poly(ethylene glycol)-b-poly(caprolactone) polymeric micelles encapsulating fenbendazole and rapamycin in ovarian cancer. Int. J. Nanomed. 8, 2209–2223 (2023).
Google Scholar
168. Jelonek K, Li S, Kaczmarczyk B et al. Multidrug PLA-PEG filomicelles for concurrent delivery of anticancer drugs – the influence of drug–drug and drug–polymer interactions on drug loading and release properties. Int. J. Pharm. 510(1), 365–374 (2016).
Medline CASGoogle Scholar
169. Cheng CC, Liang MC, Liao ZS, Huang JJ, Lee DJ. Self-assembled supramolecular nanogels as a safe and effective drug delivery vector for cancer therapy. Macromol. Biosci. 17(5), DOI: 10.1002/mabi.201600370 (2017). • Introduces how nanomedicines can play a role in the treatment of cancer, which is a hot topic in nanomedicine research.
Google Scholar
170. Mura P. Advantages of the combined use of cyclodextrins and nanocarriers in drug delivery: a review. Int. J. Pharm. 579, 119181 (2020).
Medline CASGoogle Scholar
171. Luo T, Wang J, Hao S et al. Brain drug delivery systems for the stroke intervention and recovery. Curr. Pharm. Des. 23(15), 2258–2267 (2017).
Medline CASGoogle Scholar

Vol. 19, No. 9

Supplemental Materials

Metrics

Downloaded 52 times

History

Received 17 September 2023

Accepted 25 January 2024

Published online 6 March 2024

Published in print April 2024

Information

Keywords

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/nnm-2023-0266

Financial disclosure

The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

PDF download

Advances in nanomedicines: a promising therapeutic strategy for ischemic cerebral stroke treatment

Abstract

References