Recent advances in the development of neuroprotective agents and therapeutic targets in the treatment of cerebral ischemia

European Journal of Medicinal Chemistry

Volumn 162, Issue , 2019, Pages 132-146

  Luo, Yin ^a   Tang, Haishuang ^a   Li, He ^a   Zhao, Rui ^a   Huang, Qinghai ^a   Liu, Jianmin ^a  

^a SECOND MILITARY MEDICAL UNIVERSITY   (China)

Author keywords

Anti apoptotic agent; Anti inflammatory agent; Antioxidant; Calcium channel blocker; Cerebral ischemia; Free radical scavenger; Neuroprotection; NMDA receptor antagonist

Indexed keywords

ANTIINFLAMMATORY AGENT; ANTIOXIDANT; APOPTOSIS INHIBITOR; CALCIUM CHANNEL BLOCKING AGENT; CASPASE 3 INHIBITOR; CHEMOKINE RECEPTOR ANTAGONIST; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE ACTIVATOR; N METHYL DEXTRO ASPARTIC ACID RECEPTOR BLOCKING AGENT; NEUROPROTECTIVE AGENT; NITRIC OXIDE SYNTHASE INHIBITOR; OXIDOREDUCTASE INHIBITOR; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; SCAVENGER;

BRAIN ISCHEMIA; HUMAN; NEUROPATHOLOGY; NONHUMAN; REVIEW; ANIMAL; DRUG EFFECT; MOLECULARLY TARGETED THERAPY; NERVE CELL; PATHOLOGY; PRECLINICAL STUDY;

ANIMALS; BRAIN ISCHEMIA; DRUG EVALUATION, PRECLINICAL; HUMANS; MOLECULAR TARGETED THERAPY; NEURONS; NEUROPROTECTIVE AGENTS;

EID: 85056465193     PISSN: 02235234     EISSN: 17683254     Source Type: Journal    
DOI: 10.1016/j.ejmech.2018.11.014     Document Type: Review

References (158)

1. Benjamin, E.J., Virani, S.S., Callaway, C.W., Chang, A.R., Cheng, S., Chiuve, S.E., Cushman, M., Delling, F.N., Deo, R., de Ferranti, S.D., Heart disease and stroke statistics-2018 update: a report from the American heart association. Circulation, 137, 2018 CIR.0000000000000558.
2. Deb, P., Sharma, S., Hassan, K.M., Pathophysiologic mechanisms of acute ischemic stroke: an overview with emphasis on therapeutic significance beyond thrombolysis. Pathophysiology 17 (2010), 197–218.
3. Liu, R., Yuan, H., Yuan, F., Yang, S.H., Neuroprotection targeting ischemic penumbra and beyond for the treatment of ischemic stroke. Neurol. Res. 34 (2012), 331–337.
4. Schellinger, P.D., Thomalla, G., Fiehler, J., Köhrmann, M., Molina, C.A., Neumann-Haefelin, T., Ribo, M., Singer, O.C., Zaro-Weber, O., Sobesky, J., MRI-based and CT-Based Thrombolytic Therapy in Acute Stroke within and beyond Established Time Windows, an Analysis of 1210 Patients, 38, 2007, 2640–2645.
5. Jung, S., Gralla, J., Fischer, U., Mono, M.L., Weck, A., Lüdi, R., Heldner, M.R., Findling, O., El-Koussy, M., Brekenfeld, C., Schroth, G., Mattle, H.P., Arnold, M., Safety of endovascular treatment beyond the 6-h time window in 205 patients. Eur. J. Neurol. 20 (2013), 865–871.
6. Furuichi, Y., Katsuta, K., Maeda, M., Ueyama, N., Moriguchi, A., Matsuoka, N., Goto, T., Yanagihara, T., Neuroprotective action of tacrolimus (FK506) in focal and global cerebral ischemia in rodents: dose dependency, therapeutic time window and long-term efficacy. Brain Res. 965 (2003), 137–145.
7. Murata, Y., Rosell, A., Scannevin, R.H., Rhodes, K.J., Wang, X., Lo, E.H., Extension of the thrombolytic time window with minocycline in experimental stroke. Stroke 39 (2008), 3372–3377.
8. Yang, Y., Li, Q., Ahmad, F., Shuaib, A., Survival and histological evaluation of therapeutic window of post-ischemia treatment with magnesium sulfate in embolic stroke model of rat. Neurosci. Lett. 285 (2000), 119–122.
9. Doyle, K.P., Simon, R.P., Stenzel-Poore, M.P., Mechanisms of ischemic brain damage. Neuropharmacology 55 (2008), 310–318.
10. Sims, N.R., Muyderman, H., Mitochondria, oxidative metabolism and cell death in stroke. Biochim. Biophys. Acta (BBA) - Mol. Basis Dis. 1802 (2010), 80–91.
11. Liu, X., Ye, R., Yan, T., Yu, S.P., Wei, L., Xu, G., Fan, X., Jiang, Y., Stetler, R.A., Liu, G., Chen, J., Cell based therapies for ischemic stroke: from basic science to bedside. Prog. Neurobiol. 115 (2014), 92–115.
12. Lee, J., Zipfel, G., Choi, D., The changing landscape of ischaemic brain injury mechanisms. Nature 399 (1999), A7–A14.
13. Erecińska, M., Silver, I.A., Tissue oxygen tension and brain sensitivity to hypoxia. Respir. Physiol. 128 (2001), 263–276.
14. Sailaja Rao, P., Kalva, S., Yerramilli, A., Mamidi, S., Free radicals and tissue damage: role of antioxidants. Free Radic. Antioxidants 1 (2011), 2–7.
15. Ishrat, T., Sayeed, I., Atif, F., Hua, F., Stein, D.G., Progesterone and allopregnanolone attenuate blood–brain barrier dysfunction following permanent focal ischemia by regulating the expression of matrix metalloproteinases. Exp. Neurol. 226 (2010), 183–190.
16. Horn, J., Limburg, M., Calcium Antagonists for Ischemic Stroke, a Systematic Review, 32, 2001, 570–576.
17. Godfraind, T., Miller, R., Wibo, M., Calcium antagonism and calcium entry blockade. Pharmacol. Rev. 38 (1986), 321–416.
18. Lazarewicz, J.W., Pluta, R., Puka, M., Salinska, E., Diverse mechanisms of neuronal protection by nimodipine in experimental rabbit brain ischemia. Stroke, 21, 1990 IV108-110.
19. Xiao, A.J., Chen, W., Xu, B., Liu, R., Turlova, E., Barszczyk, A., Sun, C.L., Liu, L., Deurloo, M., Wang, G.L., Feng, Z.P., Sun, H.S., Marine compound Xyloketal B reduces neonatal hypoxic-ischemic brain injury. Mar. Drugs 13 (2015), 29–47.
20. Szydlowska, K., Tymianski, M., Calcium, ischemia and excitotoxicity. Cell Calcium 47 (2010), 122–129.
21. Wong, E.H., Kemp, J.A., Priestley, T., Knight, A.R., Woodruff, G.N., Iversen, L.L., The anticonvulsant MK-801 is a potent N-methyl-D-aspartate antagonist. Proc. Natl. Acad. Sci. U. S. A. 83 (1986), 7104–7108.
22. Schurr, A., Neuroprotection against ischemic/hypoxic brain damage: blockers of ionotropic glutamate receptor and voltage sensitive calcium channels. Curr. Drug Targets 5 (2004), 603–618.
23. Yam, P., Dunn, L., Graham, D., Dewar, D., McCulloch, J., NMDA receptor blockade fails to alter axonal injury in focal cerebral ischemia. J. Cerebr. Blood Flow Metabol. 20 (2000), 772–779.
24. Gill, R., Foster, A.C., Woodruff, G.N., MK-801 is neuroprotective in gerbils when administered during the post-ischaemic period. Neuroscience 25 (1988), 847–855.
25. Buchan, A., Pulsinelli, W., Hypothermia but not the N-methyl-D-aspartate antagonist, MK-801, attenuates neuronal damage in gerbils subjected to transient global ischemia. J. Neurosci. 10 (1990), 311–316.
26. Qian, Y., Tang, X., Guan, T., Li, Y., Sun, H., Neuroprotection by combined administration with maslinic acid, a natural product from Olea europaea, and MK-801 in the cerebral ischemia model. Molecules, 21, 2016, E1093.
27. Proescholdt, M., Heimann, A., Kempski, O., Neuroprotection of S(+) ketamine isomer in global forebrain ischemia. Brain Res. 904 (2001), 245–251.
28. Hudetz, J.A., Pagel, P.S., Neuroprotection by ketamine: a review of the experimental and clinical evidence. J. Cardiothorac. Vasc. Anesth. 24 (2010), 131–142.
29. Zhou, Z., Lu, J., Liu, W.W., Manaenko, A., Hou, X., Mei, Q., Huang, J.L., Tang, J., Zhang, J.H., Yao, H., Hu, Q., Advances in stroke pharmacology. Pharmacol. Therapeut. 191 (2018), 23–42.
30. Lai, T.W., Shyu, W.C., Wang, Y.T., Stroke intervention pathways: NMDA receptors and beyond. Trends Mol. Med. 17 (2011), 266–275.
31. Clemmensen, A.E., Kristensen, L.K., Nielsen, C.H., Johansen, F.F., Kjaer, A., T2-weighted magnetic resonance imaging accurately shows treatment response of novel neuroprotective compound, Tat-N-dimer, in ischemic stroke. Circulation, 130, 2014, A15119.
32. Hill, J.W., Thompson, J.F., Carter, M.B., Edwards, B.S., Sklar, L.A., Rosenberg, G.A., Identification of isoxsuprine hydrochloride as a neuroprotectant in ischemic stroke through cell-based high-throughput screening. PLoS One, 9, 2014, e96761.
33. Jang, J.Y., Choi, Y.W., Kim, H.N., Kim, Y.R., Hong, J.W., Bae, D.W., Park, S.J., Shin, H.K., Choi, B.T., Neuroprotective effects of a novel single compound 1-methoxyoctadecan-1-ol isolated from uncaria sinensis in primary cortical neurons and a photothrombotic ischemia model. PLoS One, 9, 2014, e85322.
34. Kucharz, K., Rasmussen, I.S., Bach, A., Stromgaard, K., Lauritzen, M., PSD-95 uncoupling from NMDA receptors by Tat-N-dimer ameliorates neuronal depolarization in cortical spreading depression. J. Cerebr. Blood Flow Metabol. 37 (2017), 1820–1828.
35. Mo, S.F., Liao, G.Y., Yang, J., Wang, M.Y., Hu, Y., Lian, G.N., Kong, L.D., Zhao, Y., Protection of neuronal cells from excitotoxicity by disrupting nNOS-PSD95 interaction with a small molecule SCR-4026. Brain Res. 1648 (2016), 250–256.
36. Morozov, V.A., Korzhevskii, D.E., Tihonov, D.B., Barygin, O.I., Isaeva, A.V., Portsel, M.N., Vlasov, T.D., Neuroprotective activity of creatylglycine ethyl ester fumarate. J. Stroke Cerebrovasc. Dis. 24 (2015), 591–600.
37. Shi, Z., Zhu, L., Li, T., Tang, X., Xiang, Y., Han, X., Xia, L., Zeng, L., Nie, J., Huang, Y., Tsang, C.K., Wang, Y., Lei, Z., Xu, Z., So, K.-f., Ruan, Y., Neuroprotective mechanisms of lycium barbarum polysaccharides against ischemic insults by regulating NR2B and NR2A containing NMDA receptor signaling pathways. Front. Cell. Neurosci., 11, 2017, 288.
38. Wu, S., Yue, Y., Tian, H., Tao, L., Wang, Y., Xiang, J., Wang, S., Ding, H., Tramiprosate protects neurons against ischemic stroke by disrupting the interaction between PSD95 and nNOS. Neuropharmacology 83 (2014), 107–117.
39. Yu, G., Wu, F., Wang, E.S., BQ-869, a novel NMDA receptor antagonist, protects against excitotoxicity and attenuates cerebral ischemic injury in stroke. Int. J. Clin. Exp. Pathol. 8 (2015), 1213–1225.
40. Joza, N., Susin, S.A., Daugas, E., Stanford, W.L., Cho, S.K., Li, C.Y.J., Sasaki, T., Elia, A.J., Cheng, H.Y.M., Ravagnan, L., Ferri, K.F., Zamzami, N., Wakeham, A., Hakem, R., Yoshida, H., Kong, Y.Y., Mak, T.W., Zúñiga-Pflücker, J.C., Kroemer, G., Penninger, J.M., Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death. Nature 410 (2001), 549–554.
41. Ouyang, Y.B., Giffard, R.G., Cellular neuroprotective mechanisms in cerebral ischemia: Bcl-2 family proteins and protection of mitochondrial function. Cell Calcium 36 (2004), 303–311.
42. Yang, J., Liu, X., Bhalla, K., Kim, C.N., Ibrado, A.M., Cai, J., Peng, T.I., Jones, D.P., Wang, X., Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science 275 (1997), 1129–1132.
43. Bu, Q., Liu, X., Zhu, Y., Liu, Y., Wang, Y., w007B protects brain against ischemia-reperfusion injury in rats through inhibiting inflammation, apoptosis and autophagy. Brain Res. 1558 (2014), 100–108.
44. Gong, J., Sun, F., Li, Y., Zhou, X., Duan, Z., Duan, F., Zhao, L., Chen, H., Qi, S., Shen, J., Momordica charantia polysaccharides could protect against cerebral ischemia/reperfusion injury through inhibiting oxidative stress mediated c-Jun N-terminal kinase 3 signaling pathway. Neuropharmacology 91 (2015), 123–134.
45. Li, H., Liu, X., Zhu, Y., Liu, Y., Wang, Y., Magnolol derivative 002C-3 protects brain against ischemia-reperfusion injury via inhibiting apoptosis and autophagy. Neurosci. Lett. 588 (2015), 178–183.
46. Li, K., Ding, D., Zhang, M., Neuroprotection of osthole against cerebral ischemia/reperfusion injury through an anti-apoptotic pathway in rats. Biol. Pharmaceut. Bull. 39 (2016), 336–342.
47. Lin, C.M., Lin, Y.T., Lin, R.D., Huang, W.J., Lee, M.H., Neurocytoprotective effects of aliphatic hydroxamates from lovastatin, a secondary metabolite from monascus-fermented red mold rice, in 6-hydroxydopamine (6-OHDA)-treated nerve growth factor (NGF)-differentiated PC12 Cells. ACS Chem. Neurosci. 6 (2015), 716–724.
48. Marutani, E., Yamada, M., Tokuda, K., Shirozu, K., Hanaoka, K., Kaneki, M., Ichinose, F., Thiosulfate: a Carrier molecule of the protective effects of hydrogen sulfide against neuronal ischemia. Circulation, 130, 2014 e002125.
49. Wang, C.P., Li, G.C., Shi, Y.W., Zhang, X.C., Li, J.L., Wang, Z.W., Ding, F., Liang, X.M., Neuroprotective effect of schizandrin A on oxygen and glucose deprivation/reperfusion-induced cell injury in primary culture of rat cortical neurons. J. Physiol. Biochem. 70 (2014), 735–747.
50. Wang, C.P., Shi, Y.W., Tang, M., Zhang, X.C., Gu, Y., Liang, X.M., Wang, Z.W., Ding, F., Isoquercetin ameliorates cerebral impairment in focal ischemia through anti-oxidative, anti-inflammatory, and anti-apoptotic effects in primary culture of rat hippocampal neurons and hippocampal CA1 region of rats. Mol. Neurobiol. 54 (2017), 2126–2142.
51. Wang, H., Huang, S., Yan, K., Fang, X., Abussaud, A., Martinez, A., Sun, H.S., Feng, Z.P., Tideglusib, a chemical inhibitor of GSK3 beta, attenuates hypoxic-ischemic brain injury in neonatal mice. Biochim. Biophys. Acta Gen. Subj. 1860 (2016), 2076–2085.
52. Yang, C.H., Yen, T.L., Hsu, C.Y., Thomas, P.A., Sheu, J.R., Jayakumar, T., Multi-targeting andrographolide, a novel NF-κB inhibitor, as a potential therapeutic agent for stroke. Int. J. Mol. Sci., 18, 2017, E1638.
53. Yang, Y., Gao, K., Hu, Z., Li, W., Davies, H., Ling, S., Rudd, J.A., Fang, M., Autophagy upregulation and apoptosis downregulation in DAHP and triptolide treated cerebral ischemia. Mediat. Inflamm., 2015, 2015, 120198.
54. Zhong, Y., Xu, Y., Zhang, A.X., Li, X.F., Xu, Z.Y., Li, P., Wu, B., Synthesis and biological evaluation of aryloxyacetamide derivatives as neuroprotective agents. Bioorg. Med. Chem. Lett 26 (2016), 2526–2530.
55. Ji, H., Wang, D., Hu, J., Sun, M., Li, G., Li, Z., Wu, D., Liu, G., Chen, N., IMM-H004, a novel courmarin derivative, protects against oxygen-and glucose-deprivation/restoration-induced apoptosis in PC12 cells. Eur. J. Pharmacol. 723 (2014), 259–266.
56. Chu, S.F., Zhang, Z., Zhang, W., Zhang, M.J., Gao, Y., Han, N., Zuo, W., Huang, H.Y., Chen, N.H., Upregulating the expression of survivin-HBXIP complex contributes to the protective role of IMM-H004 in transient global cerebral ischemia/reperfusion. Mol. Neurobiol. 54 (2017), 524–540.
57. Joseph, J., Mecca, A., Regenhardt, R., Bennion, D., Rodríguez, V., Desland, F., Patel, N., Pioquinto, D., Unger, T., Katovich, M., Steckelings, U., Sumners, C., The angiotensin type 2 receptor agonist Compound 21 elicits cerebroprotection in endothelin-1 induced ischemic stroke. Neuropharmacology 81 (2014), 134–141.
58. Min, L., Mogi, M., Tsukuda, K., Jing, F., Ohshima, K., Nakaoka, H., Kan-No, H., Wang, X., Chisaka, T., Bai, H., Iwanami, J., Horiuchi, M., Direct stimulation of angiotensin II type 2 receptor initiated after stroke ameliorates ischemic brain damage. Am. J. Hypertens. 27 (2014), 1036–1044.
59. Alhusban, A., Fouda, A.Y., Pillai, B., Ishrat, T., Soliman, S., Fagan, S.C., Compound 21 is pro-angiogenic in the brain and results in sustained recovery after ischemic stroke. J. Hypertens. 33 (2015), 170–180.
60. Fouda, A.Y., Pillai, B., Dhandapani, K.M., Ergul, A., Fagan, S.C., Role of interleukin-10 in the neuroprotective effect of the Angiotensin Type 2 Receptor agonist, compound 21, after ischemia/reperfusion injury. Eur. J. Pharmacol. 799 (2017), 128–134.
61. Bennion, D.M., Isenberg, J.D., Harmel, A.T., DeMars, K., Dang, A.N., Jones, C.H., Pignataro, M.E., Graham, J.T., Steckelings, U.M., Alexander, J.C., Febo, M., Krause, E.G., de Kloet, A.D., Candelario-Jalil, E., Sumners, C., Post-stroke angiotensin II type 2 receptor activation provides long-term neuro-protection in aged rats. PLoS One, 12, 2017 e0180738.
62. Bennion, D.M., Jones, C.H., Dang, A.N., Isenberg, J., Graham, J.T., Lindblad, L., Domenig, O., Waters, M.F., Poglitsch, M., Sumners, C., Steckelings, U.M., Protective effects of the angiotensin II AT(2) receptor agonist compound 21 in ischemic stroke: a nose-to-brain delivery approach. Clin. Sci. 132 (2018), 581–593.
63. Yang, Y., Zhang, X.J., Li, L.T., Cui, H.Y., Zhang, C., Zhu, C.H., Miao, J.Y., Apelin-13 protects against apoptosis by activating AMP-activated protein kinase pathway in ischemia stroke. Peptides 75 (2016), 96–100.
64. Wang, M., Zhang, Y., Feng, L., Zheng, J., Fan, S., Liu, J., Yang, N., Liu, Y., Zuo, P., Compound porcine cerebroside and ganglioside injection attenuates cerebral ischemiar-perfusion injury in rats by targeting multiple cellular processes. Neuropsychiatric Dis. Treat. 13 (2017), 927–935.
65. Ma, Y., Li, Y., Zhang, C., Zhou, X., Wu, Y., Neuroprotective effect of 4-methylcyclopentadecanone on focal cerebral ischemia/reperfusion injury in rats. J. Pharmacol. Sci. 125 (2014), 320–328.
66. Kihara, T., Shimohama, S., Sawada, H., Honda, K., Nakamizo, T., Kanki, R., Yamashita, H., Akaike, A., Protective effect of dopamine D2 agonists in cortical neurons via the phosphatidylinositol 3 kinase cascade. J. Neurosci. Res. 70 (2002), 274–282.
67. Chen, S.D., Yang, D.I., Lin, T.K., Shaw, F.Z., Liou, C.W., Chuang, Y.C., Roles of oxidative stress, apoptosis, PGC-1α and mitochondrial biogenesis in cerebral ischemia. Int. J. Mol. Sci., 12, 2011, 7199.
68. Seth, L., Oxidative stress in brain ischemia. Brain Pathol. 9 (1999), 119–131.
69. Saito, A., Maier, C.M., Narasimhan, P., Nishi, T., Song, Y.S., Yu, F., Liu, J., Lee, Y.S., Nito, C., Kamada, H., Dodd, R.L., Hsieh, L.B., Hassid, B., Kim, E.E., González, M., Chan, P.H., Oxidative stress and neuronal death/survival signaling in cerebral ischemia. Mol. Neurobiol. 31 (2005), 105–116.
70. Allen, C.L., Bayraktutan, U., Oxidative stress and its role in the pathogenesis of ischaemic stroke. Int. J. Stroke 4 (2010), 461–470.
71. Floyd, R.A., Role of oxygen free radicals in carcinogenesis and brain ischemia. Faseb. J. 4 (1990), 2587–2597.
72. Blomgren, K., Hagberg, H., Free radicals, mitochondria, and hypoxia-ischemia in the developing brain. Free Radic. Biol. Med. 40 (2006), 388–397.
73. Dempsey, Robert J., Roy, Mark W., Meyer, Kathleen, Cowen, David E., Tai, Hsin-Hsiung, Development of cyclooxygenase and lipoxygenase metabolites of arachidonic acid after transient cerebral ischemia. J. Neurosurg. 64 (1986), 118–124.
74. Shah, Z., Li, R., Ahmad, A., Kensler, T., Yamamoto, M., Biswal, S., Doré, S., The flavanol (-)-epicatechin prevents stroke damage through the Nrf2/HO1 pathway. J. Cerebr. Blood Flow Metabol. 30 (2010), 1951–1961.
75. Alfieri, A., Srivastava, S., Siow, R., Cash, D., Modo, M., Duchen, M., Fraser, P., Williams, S., Mann, G., Sulforaphane preconditioning of the Nrf2/HO-1 defense pathway protects the cerebral vasculature against blood-brain barrier disruption and neurological deficits in stroke. Free Radic. Biol. Med. 65 (2013), 1012–1022.
76. Guo, C., Wang, S., Duan, J., Jia, N., Zhu, Y., Ding, Y., Guan, Y., Wei, G., Yin, Y., Xi, M., Wen, A., Protocatechualdehyde protects against cerebral ischemia-reperfusion-induced oxidative injury via protein kinase C epsilon/Nrf2/HO-1 pathway. Mol. Neurobiol. 54 (2017), 833–845.
77. Ashabi, G., Khalaj, L., Khodagholi, F., Goudarzvand, M., Sarkaki, A., Pre-treatment with metformin activates Nrf2 antioxidant pathways and inhibits inflammatory responses through induction of AMPK after transient global cerebral ischemia. Metab. Brain Dis. 30 (2015), 747–754.
78. Guo, H., Kong, S., Chen, W., Dai, Z., Lin, T., Su, J., Li, S., Xie, Q., Su, Z., Xu, Y., Lai, X., Apigenin mediated protection of OGD-evoked neuron-like injury in differentiated PC12 cells. Neurochem. Res. 39 (2014), 2197–2210.
79. Huang, L., Wang, J., Chen, L., Zhu, M., Wu, S., Chu, S., Zheng, Y., Fan, Z., Zhang, J., Li, W., Chen, D., Yang, X., Wang, S., Qiu, P., Wu, J., Design, synthesis, and evaluation of NDGA analogues as potential anti-ischemic stroke agents. Eur. J. Med. Chem. 143 (2018), 1165–1173.
80. Shi, H., Jing, X., Wei, X., Perez, R.G., Ren, M., Zhang, X., Lou, H., S-allyl cysteine activates the Nrf2-dependent antioxidant response and protects neurons against ischemic injury in vitro and in vivo. J. Neurochem. 133 (2015), 298–308.
81. Xu, X.H., Li, G.L., Wang, B.A., Qin, Y., Bai, S.R., Rong, J., Deng, T., Li, Q., Diallyl trisufide protects against oxygen glucose deprivation -induced apoptosis by scavenging free radicals via the PI3K/Akt -mediated Nrf2/HO-1 signaling pathway in B35 neural cells. Brain Res. 1614 (2015), 38–50.
82. Ding, Y., Chen, M., Wang, M., Li, Y., Wen, A., Posttreatment with 11-Keto-beta-Boswellic acid ameliorates cerebral ischemia-reperfusion injury: Nrf2/HO-1 pathway as a potential mechanism. Mol. Neurobiol. 52 (2015), 1430–1439.
83. Mullonkal, C.J., Toledo-Pereyra, L.H., Akt in ischemia and reperfusion. J. Invest. Surg. 20 (2007), 195–203.
84. Chen, H., Tan, G., Cao, J., Zhang, G., Yi, P., Yu, P., Sun, Y., Zhang, Z., Wang, Y., Design, synthesis, and biological evaluation of novel tetramethylpyrazine derivatives as potential neuroprotective agents. Chem. Pharmaceut. Bull. 65 (2017), 56–65.
85. Egea, J., Parada, E., Gomez-Rangel, V., Buendia, I., Negredo, P., Montell, E., Ruhi, R., Verges, J., Roda, J.M., Garcia, A.G., Lopez, M.G., Small synthetic hyaluronan disaccharides afford neuroprotection in brain ischemia-related models. Neuroscience 265 (2014), 313–322.
86. Zhu, Y., Hoell, P., Ahlemeyer, B., Sure, U., Bertalanffy, H., Krieglstein, J., Implication of PTEN in production of reactive oxygen species and neuronal death in in vitro models of stroke and Parkinson's disease. Neurochem. Int. 50 (2007), 507–516.
87. Mao, L.L., Hao, D.L., Mao, X.W., Xu, Y.F., Huang, T.T., Wu, B.N., Wang, L.H., Neuroprotective effects of bisperoxovanadium on cerebral ischemia by inflammation inhibition. Neurosci. Lett. 602 (2015), 120–125.
88. Puneet, K., Harikesh, K., Anil, K., Protective effect of sesamol against 3-nitropropionic acid-induced cognitive dysfunction and altered glutathione redox balance in rats. Basic Clin. Pharmacol. Toxicol. 107 (2010), 577–582.
89. Hassanzadeh, P., Atyabi, F., Dinarvand, R., Dehpour, A.R., Azhdarzadeh, M., Dinarvand, M., Application of nanostructured lipid carriers: the prolonged protective effects for sesamol in in vitro and in vivo models of ischemic stroke via activation of PI3K signalling pathway. Daru, 25, 2017, 25.
90. Hassanzadeh, P., Arbabi, E., Atyabi, F., Dinarvand, R., Ferulic acid-loaded nanostructured lipid carriers: a promising nanoformulation against the ischemic neural injuries. Life Sci. 193 (2018), 64–76.
91. Kim, J.Y., Park, J., Lee, J.E., Yenari, M.A., NOX inhibitors-a promising avenue for ischemic stroke. Exp. Neurobiol. 26 (2017), 195–205.
92. Chen, W., Guo, Y., Yang, W., Zheng, P., Zeng, J., Tong, W., Protective effect of ginsenoside Rb1 on integrity of blood-brain barrier following cerebral ischemia. Exp. Brain Res. 233 (2015), 2823–2831.
93. Wang, Y., Jia, J., Ao, G., Hu, L., Liu, H., Xiao, Y., Du, H., Alkayed, N.J., Liu, C.F., Cheng, J., Hydrogen sulfide protects blood-brain barrier integrity following cerebral ischemia. J. Neurochem. 129 (2014), 827–838.
94. Wang, Z., Zhou, Z., Wei, X., Wang, M., Wang, B.O., Zhang, Y., He, X., Sun, Y., Wang, X., Sun, M., Zhang, Y., Gong, X., Yi, F., Therapeutic potential of novel twin compounds containing tetramethylpyrazine and carnitine substructures in experimental ischemic stroke. Oxid. Med. Cell. Longev., 2017, 7191856.
95. Murakami, A., Ohigashi, H., Targeting NOX, INOS and COX-2 in inflammatory cells: chemoprevention using food phytochemicals. Int. J. Canc. 121 (2007), 2357–2363.
96. Förstermann, U., Sessa, W.C., Nitric oxide synthases: regulation and function. Eur. Heart J. 33 (2012), 829–837 837a-837d.
97. Mahmood, Q., Wang, G.F., Wu, G., Wang, H., Zhou, C.X., Yang, H.Y., Liu, Z.R., Han, F., Zhao, K., Salvianolic acid A inhibits calpain activation and eNOS uncoupling during focal cerebral ischemia in mice. Phytomedicine 25 (2017), 8–14.
98. Sheu, J.R., Chen, Z.C., Jayakumar, T., Chou, D.S., Yen, T.L., Lee, H.N., Pan, S.H., Hsia, C.H., Yang, C.H., Hsieh, C.Y., A novel indication of platonin, a therapeutic immunomodulating medicine, on neuroprotection against ischemic stroke in mice. Sci. Rep., 7, 2017, 42277.
99. Zang, Y., Song, X., Li, C., Ma, J., Chu, S., Liu, D., Ren, Q., Li, Y., Chen, N., Zhang, D., Pyrano 3,2-a carbazole alkaloids as effective agents against ischemic stroke in vitro and in vivo. Eur. J. Med. Chem. 143 (2018), 438–448.
100. Chen, H., Yoshioka, H., Kim, G.S., Jung, J.E., Okami, N., Sakata, H., Maier, C.M., Narasimhan, P., Goeders, C.E., Chan, P.H., Oxidative stress in ischemic brain damage: mechanisms of cell death and potential molecular targets for neuroprotection. Antioxidants Redox Signal. 14 (2011), 1505–1517.
101. Ahmad, N., Ahmad, R., Alam, M.A., Samim, M., Iqbal, Z., Ahmad, F.J., Quantification and evaluation of thymoquinone loaded mucoadhesive nanoemulsion for treatment of cerebral ischemia. Int. J. Biol. Macromol. 88 (2016), 320–332.
102. Ayuso, M.I., Martinez-Alonso, E., Chioua, M., Escobar-Peso, A., Gonzalo-Gobernado, R., Montaner, J., Marco-Contelles, J., Alcazar, A., Quinolinyl nitrone RP19 induces neuroprotection after transient brain ischemia. ACS Chem. Neurosci. 8 (2017), 2202–2213.
103. Fluri, F., Gruenstein, D., Cam, E., Ungethuem, U., Hatz, F., Schaefer, J., Samnick, S., Israel, I., Kleinschnitz, C., Orts-Gil, G., Moch, H., Zeis, T., Schaeren-Wiemers, N., Seeberger, P., Fullerenols and glucosamine fullerenes reduce infarct volume and cerebral inflammation after ischemic stroke in normotensive and hypertensive rats. Exp. Neurol. 265 (2015), 142–151.
104. Lan, Z., Xu, X., Xu, W., Li, J., Liang, Z., Zhang, X., Lei, M., Zhao, C., Discovery of 3-n-butyl-2,3-dihydro-1H-isoindol-1-one as a potential anti-ischemic stroke agent. Drug Des. Dev. Ther. 9 (2015), 3377–3391.
105. Sheng, X., Hua, K., Yang, C., Wang, X., Ji, H., Xu, J., Huang, Z., Zhang, Y., Novel hybrids of 3-n-butylphthalide and edaravone: design, synthesis and evaluations as potential anti-ischemic stroke agents. Bioorg. Med. Chem. Lett 25 (2015), 3535–3540.
106. Thi Thuy Hong, D., Chami, B., McMahon, A.C., Fong, G.M., Dennis, J.M., Freedman, S.B., Witting, P.K., Pre-treatment with the synthetic antioxidant T-butyl bisphenol protects cerebral tissues from experimental ischemia reperfusion injury. J. Neurochem. 130 (2014), 733–747.
107. Al-Majed, A.A., Al-Omar, F.A., Nagi, M.N., Neuroprotective effects of thymoquinone against transient forebrain ischemia in the rat hippocampus. Eur. J. Pharmacol. 543 (2006), 40–47.
108. Hosseinzadeh, H., Parvardeh, S., Asl, M.N., Sadeghnia, H.R., Ziaee, T., Effect of thymoquinone and Nigella sativa seeds oil on lipid peroxidation level during global cerebral ischemia-reperfusion injury in rat hippocampus. Phytomedicine 14 (2007), 621–627.
109. Li, L., Zhang, B., Tao, Y., Wang, Y., Wei, H., Zhao, J., Huang, R., Pei, Z., DL-3-n-butylphthalide protects endothelial cells against oxidative/nitrosative stress, mitochondrial damage and subsequent cell death after oxygen glucose deprivation in vitro. Brain Res. 1290 (2009), 91–101.
110. So-Young, H., Joo-Hyun, S., Ji-Sun, H., Song-Yi, K., Jin-A, S., Eok-Soo, O., Seikwan, O., Jung-Bin, K., Ja-Kyung, L., Inn-Oc, H., Glucosamine exerts a neuroprotective effect via suppression of inflammation in rat brain ischemia/reperfusion injury. Glia 58 (2010), 1881–1892.
111. Lin, A.M.Y., Fang, S.F., Lin, S.Z., Chou, C.K., Luh, T.Y., Ho, L.T., Local carboxyfullerene protects cortical infarction in rat brain. Neurosci. Res. 43 (2002), 317–321.
112. Rong, J., Guojun, Y., Guohong, L., Inflammatory mechanisms in ischemic stroke: role of inflammatory cells. J. Leukoc. Biol. 87 (2010), 779–789.
113. Wang, Q., Tang, X.N., Yenari, M.A., The inflammatory response in stroke. J. Neuroimmunol. 184 (2007), 53–68.
114. Lee, J.M., Grabb, M.C., Zipfel, G.J., Choi, D.W., Brain tissue responses to ischemia. J. Clin. Invest. 106 (2000), 723–731.
115. Huang, J., Upadhyay, U.M., Tamargo, R.J., Inflammation in stroke and focal cerebral ischemia. Surg. Neurol. 66 (2006), 232–245.
116. Chodobski, A., Zink, B.J., Szmydynger-Chodobska, J., Blood-brain barrier pathophysiology in traumatic brain injury. Transl. Stroke Res. 2 (2011), 492–516.
117. Ghosh, N., Ghosh, R., Bhat, Z.A., Mandal, V., Bachar, S.C., Nima, N.D., Sunday, O.O., Mandal, S.C., Advances in herbal medicine for treatment of ischemic brain injury. Nat. Prod. Commun. 9 (2014), 1045–1055.
118. Bai, S., Hu, Z., Yang, Y., Yin, Y., Li, W., Wu, L., Fang, M., Anti-inflammatory and Neuroprotective Effects of Triptolide via the Nf-kappa b Signaling Pathway in a Rat Mcao Model, Anatomical Record-advances in Integrative Anatomy and Evolutionary Biology, 299, 2016, 256–266.
119. Cheng, C.Y., Lee, Y.C., Anti-inflammatory effects of traditional Chinese medicines against ischemic injury in in vivo models of cerebral ischemia. Evid. base Compl. Alternative Med., 2016, 5739434.
120. Galuppo, M., Giacoppo, S., Iori, R., De Nicola, G.R., Milardi, D., Bramanti, P., Mazzon, E., 4(Alpha-l-rhamnosyloxy)-benzyl isothiocyanate, a bioactive phytochemical that defends cerebral tissue and prevents severe damage induced by focal ischemia/reperfusion. J. Biol. Regul. Homeost. Agents 29 (2015), 343–356.
121. Kang, B.K., Kim, M.K., Kim, S.Y., Lee, S.J., Choi, Y.W., Choi, B.T., Shin, H.K., Anti-neuroinflammatory effects of uncaria sinensis in lps-stimulated bv2 microglia cells and focal cerebral ischemic mice. Am. J. Chin. Med. 43 (2015), 1099–1115.
122. Pan, N., Lu, L.Y., Li, M., Wang, G.H., Sun, F.Y., Sun, H.S., Wen, X.J., Cheng, J.D., Chen, J.W., Pang, J.Y., Liu, J., Guan, Y.Y., Zhao, L.Y., Chen, W.L., Wang, G.L., Xyloketal B alleviates cerebral infarction and neurologic deficits in a mouse stroke model by suppressing the ROS/TLR4/NF-kappa B inflammatory signaling pathway. Acta Pharmacol. Sin. 38 (2017), 1236–1247.
123. Park, S.I., Lee, J.H., Chung, Y.A., Park, M.S., Sunwoo, H., Lee, K.S., Sunwoo, Y.Y., The neuroprotective effect of a traditional herbal (kyung-ok-ko) on transient middle cerebral artery occlusion-Induced ischemic rat brain. Int. J. Imag. Syst. Technol. 25 (2015), 131–138.
124. Xu, S., Zhong, A., Ma, H., Li, D., Hu, Y., Xu, Y., Zhang, J., Neuroprotective effect of salvianolic acid B against cerebral ischemic injury in rats via the CD40/NF-kappa B pathway associated with suppression of platelets activation and neuroinflammation. Brain Res. 1661 (2017), 37–48.
125. Ma, L., Pan, X., Zhou, F., Liu, K., Wang, L., Hyperforin protects against acute cerebral ischemic injury through inhibition of interleukin-17A-mediated microglial activation. Brain Res. 1678 (2018), 254–261.
126. Hao, M., Li, X., Feng, J., Pan, N., Triptolide protects against ischemic stroke in rats. Inflammation 38 (2015), 1617–1623.
127. Lin, Y., Zhang, J., Fu, J., Chen, F., Wang, J., Wu, Z., Yuan, S., Hyperforin attenuates brain damage induced by transient middle cerebral artery occlusion (MCAO) in rats via inhibition of TRPC6 channels degradation. J. Cerebr. Blood Flow Metabol. 33 (2013), 253–262.
128. Hakimizadeh, E., Shamsizadeh, A., Roohbakhsh, A., Arababadi, M.K., Hajizadeh, M.R., Shariati, M., Rahmani, M.R., Allahtavakoli, M., Inhibition of transient receptor potential vanilloid-1 confers neuroprotection, reduces tumor necrosis factor-alpha, and increases IL-10 in a rat stroke model. Fund. Clin. Pharmacol. 31 (2017), 420–428.
129. Kim, S.W., Lee, H.K., Kim, I.D., Lee, H., Luo, L., Park, J.Y., Yoon, S.H., Lee, J.K., Robust neuroprotective effects of 2-((2-oxopropanoyl)oxy)-4-(trifluoromethyl)benzoic acid (OPTBA), a HTB/pyruvate ester, in the postischemic rat brain. Sci. Rep., 6, 2016, 31843.
130. Wang, P., He, Y., Li, D., Han, R., Liu, G., Kong, D., Hao, J., Class I PI3K inhibitor ZSTK474 mediates a shift in microglial/macrophage phenotype and inhibits inflammatory response in mice with cerebral ischemia/reperfusion injury. J. Neuroinflammation, 13, 2016, 192.
131. Kocsis, K., Frank, R., Szabo, J., Knapp, L., Kis, Z., Farkas, T., Vecsei, L., Toldi, J., Acetyl-l-carnitine restores synaptic transmission and enhances the inducibility of stable ltp after oxygen-glucose deprivation. Neuroscience 332 (2016), 203–211.
132. Fernández, d.A.A., Cavalcanti, F., Miralles, A., Bayón, Y., Alonso, A., Merlos, M., Garcíarafanell, J., Forn, J., Inhibition of cyclooxygenase-2 expression by 4-trifluoromethyl derivatives of salicylate, triflusal, and its deacetylated metabolite, 2-hydroxy-4-trifluoromethylbenzoic acid. Mol. Pharmacol. 55 (1999), 753–760.
133. Wang, Q., Van, H.M., Tang, X.N., Lee, H., Zheng, Z., Swanson, R.A., Yenari, M.A., Pyruvate protects against experimental stroke via an anti-inflammatory mechanism. Neurobiol. Dis. 36 (2009), 223–231.
134. Ashabi, G., Khodagholi, F., Khalaj, L., Goudarzvand, M., Nasiri, M., Activation of AMP-activated protein kinase by metformin protects against global cerebral ischemia in male rats: interference of AMPK/PGC-1 alpha pathway. Metab. Brain Dis. 29 (2014), 47–58.
135. Bai, A., Ma, A., Yong, M., Weiss, C., Ma, Y., Guan, Q., Bernstein, C., Peng, Z., AMPK agonist downregulates innate and adaptive immune responses in TNBS-induced murine acute and relapsing colitis. Biochem. Pharmacol. 80 (2010), 1708–1717.
136. Wang, Y., Ruan, W., Mi, J., Xu, J., Wang, H., Cao, Z., Saavedra, J.M., Zhang, L., Lin, H., Pang, T., Balasubramide derivative 3C modulates microglia activation via CaMKK beta-dependent AMPK/PGC-1 alpha pathway in neuroinflammatory conditions. Brain Behav. Immun. 67 (2018), 101–117.
137. Qiu, J., Wang, M., Zhang, J., Cai, Q., Lu, D., Li, Y., Dong, Y., Zhao, T., Chen, H., The neuroprotection of Sinomenine against ischemic stroke in mice by suppressing NLRP3 inflammasome via AMPK signaling. Int. Immunopharm. 40 (2016), 492–500.
138. Andrade, C., A critical examination of studies on curcumin for depression. J. Clin. Psychiatr., 75, 2014 e1110-1112.
139. Li, Y., Li, J., Li, S., Li, Y., Wang, X., Liu, B., Fu, Q., Ma, S., Curcumin attenuates glutamate neurotoxicity in the hippocampus by suppression of ER stress-associated TXNIP/NLRP3 inflammasome activation in a manner dependent on AMPK. Toxicol. Appl. Pharmacol. 286 (2015), 53–63.
140. Lin, T.Y., Lu, C.W., Huang, S.K., Wang, S.J., Curcumin inhibits glutamate release from rat prefrontal nerve endings by affecting vesicle mobilization. Int. J. Mol. Sci., 13, 2012, 9097.
141. Ruscher, K., Kuric, E., Liu, Y., Walter, H., Issazadeh-Navikas, S., Englund, E., Wieloch, T., Inhibition of CXCL12 signaling attenuates the postischemic immune response and improves functional recovery after stroke. J. Cerebr. Blood Flow Metabol. 33 (2013), 1225–1234.
142. Walter, H.L., van der Maten, G., Antunes, A.R., Wieloch, T., Ruscher, K., Treatment with AMD3100 attenuates the microglial response and improves outcome after experimental stroke. J. Neuroinflammation, 12, 2015, 24.
143. Wu, K.J., Yu, S.J., Shia, K.S., Wu, C.H., Song, J.S., Kuan, H.H., Yeh, K.C., Chen, C.T., Bae, E., Wang, Y., A novel CXCR4 antagonist CX549 induces neuroprotection in stroke brain. Cell Transplant. 26 (2017), 571–583.
144. Li, Y., Guan, Y., Wang, Y., Yu, C.L., Zhai, F.G., Guan, L.X., Neuroprotective effect of the Ginsenoside Rg1 on cerebral ischemic injury in vivo and in vitro is mediated by ppar gamma-regulated antioxidative and anti-inflammatory pathways. Evid. base Compl. Alternative Med., 2017, 7842082.
145. Qiu, J., Yan, Z., Tao, K., Li, Y., Li, Y., Li, J., Dong, Y., Feng, D., Chen, H., Sinomenine activates astrocytic dopamine D2 receptors and alleviates neuroinflammatory injury via the CRYAB/STAT3 pathway after ischemic stroke in mice. J. Neuroinflammation, 13, 2016, 263.
146. Guan, Y.Z., Jin, X.D., Guan, L.X., Yan, H.C., Wang, P., Gong, Z., Li, S.J., Cao, X., Xing, Y.L., Gao, T.M., Nicotine inhibits microglial proliferation and is neuroprotective in global ischemia rats. Mol. Neurobiol. 51 (2015), 1480–1488.
147. Karsy, M., Brock, A., Guan, J., Taussky, P., Kalani, M., Park, M., Neuroprotective strategies and the underlying molecular basis of cerebrovascular stroke. Neurosurg. Focus, 42, 2017, E3.
148. Tetsumori, Y., Yukihiko, K., Katsuhiro, T., Takashi, U., Junkoh, Y., Tohru, Y., Eiki, K., Inhibition of ischaemic hippocampal neuronal death in primates with cathepsin B inhibitor CA-074: a novel strategy for neuroprotection based on “calpain-cathepsin hypothesis. Eur. J. Neurosci. 10 (1998), 1723–1733.
149. Ehrenreich, H., Aust, C., Krampe, H., Jahn, H., Jacob, S., Herrmann, M., Sirén, A.L., Erythropoietin: novel approaches to neuroprotection in human brain disease. Metab. Brain Dis. 19 (2004), 195–206.
150. Sutherland, B.A., Minnerup, J., Balami, J.S., Arba, F., Buchan, A.M., Kleinschnitz, C., Neuroprotection for ischaemic stroke: translation from the bench to the bedside. Int. J. Stroke 7 (2012), 407–418.
151. Weng, Y.C., Kriz, J., Differential neuroprotective effects of a minocycline-based drug cocktail in transient and permanent focal cerebral ischemia. Exp. Neurol. 204 (2007), 433–442.
152. Lapchak, P.A., De Taboada, L., Transcranial near infrared laser treatment (NILT) increases cortical adenosine-5'-triphosphate (ATP) content following embolic strokes in rabbits. Brain Res. 1306 (2010), 100–105.
153. Yanamoto, H., Nagata, I., Niitsu, Y., Zhang, Z., Xue, J.H., Sakai, N., Kikuchi, H., Prolonged mild hypothermia therapy protects the brain against permanent focal ischemia. Stroke 32 (2001), 232–239.
154. van der Worp, H.B., Macleod, M.R., Kollmar, R., Therapeutic hypothermia for acute ischemic stroke: ready to start large randomized trials?. J. Cerebr. Blood Flow Metabol. 30 (2010), 1079–1093.
155. Abe, K., Yamashita, T., Takizawa, S., Kuroda, S., Kinouchi, H., Kawahara, N., Stem cell therapy for cerebral ischemia: from basic science to clinical applications. J. Cerebr. Blood Flow Metabol. 32 (2012), 1317–1331.
156. Wakabayashi, K., Nagai, A., Sheikh, A.M., Shiota, Y., Narantuya, D., Watanabe, T., Masuda, J., Kobayashi, S., Kim, S.U., Yamaguchi, S., Transplantation of human mesenchymal stem cells promotes functional improvement and increased expression of neurotrophic factors in a rat focal cerebral ischemia model. J. Neurosci. Res. 88 (2010), 1017–1025.
157. Wei, L., Fraser, J.L., Lu, Z.Y., Hu, X., Yu, S.P., Transplantation of hypoxia preconditioned bone marrow mesenchymal stem cells enhances angiogenesis and neurogenesis after cerebral ischemia in rats. Neurobiol. Dis. 46 (2012), 635–645.
158. Webb, R.L., Kaiser, E.E., Jurgielewicz, B.J., Spellicy, S., Scoville, S.L., Thompson, T.A., Swetenburg, R.L., Hess, D.C., West, F.D., Stice, S.L., Human neural stem cell extracellular vesicles improve recovery in a porcine model of ischemic stroke. Stroke 49 (2018), 1248–1256.