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. 2009 Jul 7;25(3):139–152. doi: 10.1007/s12264-009-0104-3

The mechanisms of brain ischemic insult and potential protective interventions

脑缺血的损伤机制及其保护性干预

Zhao-Hui Guo 1, Feng Li 1,✉, Wei-Zhi Wang 1
PMCID: PMC5552559  PMID: 19448688

Abstract

The mechanisms of brain ischemic insult include glutamate excitoxicity, calcium toxicity, free radicals, nitric oxide, inflammatory reactions, as well as dysfunctions of endoplasmic reticulum and mitochondrion. These injury cascades are interconnected in complex ways, thus it is hard to compare their pathogenic importances in ischemia models. And the research in cellular and molecular pathways has spurred the studies in potential neuroprotections mainly in pharmacological fields, such as anti-excitotoxic treatment, calcium-channel antagonism, approaches for inhibition of oxidation, inflammation and apoptosis, etc. Besides, other protective interventions including thrombolysis, arteriogenesis, regeneration therapy, and ischemia preconditioning or postconditioning, are also under investigations. Despite the present difficulties, we are quite optimistic towards future clinical applications of neuroprotective agents, by optimizing experimental approaches and clinical trials.

Key words: brain ischemia, glutamate receptors, calcium toxicity, endoplasmic reticulum stress, neuroprotection

References

  • [1].Ginsberg M.D. Adventures in the pathophysiology of brain ischemia: penumbra, gene expression, neuroprotection: the 2002 Thomas Willis Lecture. Stroke. 2003;34(1):214–223. doi: 10.1161/01.STR.0000048846.09677.62. [DOI] [PubMed] [Google Scholar]
  • [2].Heiss W.D., Kracht L.W., Thiel A., Grond M., Pawlik G. Penumbral probability thresholds of cortical flumazenil binding and blood flow predicting tissue outcome in patients with cerebral ischaemia. Brain. 2001;124(Pt1):20–29. doi: 10.1093/brain/124.1.20. [DOI] [PubMed] [Google Scholar]
  • [3].Hossmann K.A. Pathophysiology and therapy of experimental stroke. Cell Mol Neurobiol. 2006;26(7–8):1057–1083. doi: 10.1007/s10571-006-9008-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [4].Ginsberg M.D. The New Language of Cerebral Ischemia. Am J Neuroradiol. 1997;18(8):1435–1445. [PMC free article] [PubMed] [Google Scholar]
  • [5].Mehta S.L., Manhas N., Raghubir R. Molecular targets in cerebral ischemia for developing novel therapeutics. Brain Res Rev. 2007;54(1):34–66. doi: 10.1016/j.brainresrev.2006.11.003. [DOI] [PubMed] [Google Scholar]
  • [6].Kristián T., Siesjö B.K. Calcium in ischemic cell death. Stroke. 1998;29(3):705–718. doi: 10.1161/01.str.29.3.705. [DOI] [PubMed] [Google Scholar]
  • [7].Chen M., Lu T.J., Chen X.J., Zhou Y., Chen Q., Feng X.Y., et al. Differential roles of NMDA receptor subtypes in ischemic neuronal cell death and ischemic tolerance. Stroke. 2008;39(11):3042–3048. doi: 10.1161/STROKEAHA.108.521898. [DOI] [PubMed] [Google Scholar]
  • [8].Berridge M.J. Cell signalling. A tale of two messengers. Nature. 1993;365(6445):388–389. doi: 10.1038/365388a0. [DOI] [PubMed] [Google Scholar]
  • [9].Paschen W. Disturbances of calcium homeostasis within the endoplasmic reticulum may contribute to the development of ischemic-cell damage. Med Hypotheses. 1996;47(4):283–288. doi: 10.1016/S0306-9877(96)90068-7. [DOI] [PubMed] [Google Scholar]
  • [10].Sugimoto K., Iadecola C. Delayed effect of administration of COX-2 inhibitor in mice with acute cerebral ischemia. Brain Res. 2003;960(1–2):273–276. doi: 10.1016/S0006-8993(02)03805-2. [DOI] [PubMed] [Google Scholar]
  • [11].Iadecola C., Niwa K., Nogawa S., Zhao X., Nagayama M., Araki E., et al. Reduced susceptibility to ischemic brain injury and N-methyl-d-aspartate-mediated neurotoxicity in cyclooxygenase-2-deficient mice. Proc Natl Acad Sci USA. 2001;98(3):1294–1299. doi: 10.1073/pnas.98.3.1294. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [12].Xu X., Kim J.A., Zuo Z. Isoflurane preconditioning reduces mouse microglial activation and injury induced by lipopolysaccharide and interferon-gamma. Neuroscience. 2008;154(3):1002–1008. doi: 10.1016/j.neuroscience.2008.04.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [13].Tikka T.M., Koistinaho J.E. Minocycline provides neuroprotection against N-methyl-D-aspartate neurotoxicity by inhibiting microglia. J Immunol. 2001;166(12):7527–7533. doi: 10.4049/jimmunol.166.12.7527. [DOI] [PubMed] [Google Scholar]
  • [14].Swanson R.A., Ying W., Kauppinen T.M. Astrocyte influences on ischemic neuronal death. Curr Mol Med. 2004;4(2):193–205. doi: 10.2174/1566524043479185. [DOI] [PubMed] [Google Scholar]
  • [15].Paschen W., Mengesdorf T. Endoplasmic reticulum stress response and neurodegeneration. Cell Calcium. 2005;38(3–4):409–415. doi: 10.1016/j.ceca.2005.06.019. [DOI] [PubMed] [Google Scholar]
  • [16].Garaschuk O., Yaari Y., Konnerth A. Release and sequestration of calcium by ryanodine-sensitive stores in rat hippocampal neurones. J Physiol. 1997;502(Pt1):13–30. doi: 10.1111/j.1469-7793.1997.013bl.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [17].Verkhratsky A. Physiology and pathophysiology of the calcium store in the endoplasmic reticulum of neurons. Physiol Rev. 2005;85(1):201–279. doi: 10.1152/physrev.00004.2004. [DOI] [PubMed] [Google Scholar]
  • [18].Kaufman R.J. Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev. 1999;13(10):1211–1233. doi: 10.1101/gad.13.10.1211. [DOI] [PubMed] [Google Scholar]
  • [19].Paschen W., Mengesdorf T. Cellular abnormalities linked to endoplasmic reticulum dysfunction in cerebrovascular disease—therapeutic potential. Pharmacol Ther. 2005;108(3):362–375. doi: 10.1016/j.pharmthera.2005.05.008. [DOI] [PubMed] [Google Scholar]
  • [20].Harding H.P., Zhang Y., Ron D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature. 1999;397(6716):271–274. doi: 10.1038/16729. [DOI] [PubMed] [Google Scholar]
  • [21].Shen X., Ellis R.E., Lee K., Liu C.Y., Yang K., Solomon A., et al. Complementary signaling pathways regulate the unfolded protein response and are required for C. elegans development. Cell. 2001;107(7):893–903. doi: 10.1016/S0092-8674(01)00612-2. [DOI] [PubMed] [Google Scholar]
  • [22].Yoshida H., Matsui T., Yamamoto A., Okada T., Mori K. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell. 2001;107(7):881–891. doi: 10.1016/S0092-8674(01)00611-0. [DOI] [PubMed] [Google Scholar]
  • [23].Calfon M., Zeng H., Urano F., Till J.H., Hubbard S.R., Harding H.P., et al. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature. 2002;415(6867):92–96. doi: 10.1038/415092a. [DOI] [PubMed] [Google Scholar]
  • [24].Harding H.P., Novoa I., Zhang Y., Zeng H., Wek R., Schapira M., et al. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell. 2000;6(5):1099–1108. doi: 10.1016/S1097-2765(00)00108-8. [DOI] [PubMed] [Google Scholar]
  • [25].Harding H.P., Zhang Y., Zeng H., Novoa I., Lu P.D., Calfon M., et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell. 2003;11(3):619–633. doi: 10.1016/S1097-2765(03)00105-9. [DOI] [PubMed] [Google Scholar]
  • [26].Novoa I., Zeng H., Harding H.P., Ron D. Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha. J Cell Biol. 2001;153(5):1011–1022. doi: 10.1083/jcb.153.5.1011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [27].Luo S., Baumeister P., Yang S., Abcouwer S.F., Lee A.S. Induction of Grp78/BiP by translational block: activation of the Grp78 promoter by ATF4 through and upstream ATF/CRE site independent of the endoplasmic reticulum stress elements. J Biol Chem. 2003;278(39):37375–37385. doi: 10.1074/jbc.M303619200. [DOI] [PubMed] [Google Scholar]
  • [28].Averous J., Bruhat A., Jousse C., Carraro V., Thiel G., Fafournoux P. Induction of CHOP expression by amino acid limitation requires both ATF4 expression and ATF2 phosphorylation. J Biol Chem. 2004;279(7):5288–5297. doi: 10.1074/jbc.M311862200. [DOI] [PubMed] [Google Scholar]
  • [29].Ma Y., Hendershot L.M. Herp is dually regulated by both the endoplasmic reticulum stress-specific branch of the unfolded protein response and a branch that is shared with other cellular stress pathways. J Biol Chem. 2004;279(14):13792–13799. doi: 10.1074/jbc.M313724200. [DOI] [PubMed] [Google Scholar]
  • [30].Oyadomari S., Mori M. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ. 2004;11(4):381–389. doi: 10.1038/sj.cdd.4401373. [DOI] [PubMed] [Google Scholar]
  • [31].Nakagawa T., Zhu H., Morishima N., Li E., Xu J., Yankner B.A., et al. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature. 2000;403(6765):98–103. doi: 10.1038/47513. [DOI] [PubMed] [Google Scholar]
  • [32].Häcki J., Egger L., Monney L., Conus S., Rossé T., Fellay I., et al. Apoptotic crosstalk between the endoplasmic reticulum and mitochondria controlled by Bcl-2. Oncogene. 2000;19(19):2286–2295. doi: 10.1038/sj.onc.1203592. [DOI] [PubMed] [Google Scholar]
  • [33].Boya P., Cohen I., Zamzami N., Vieira H.L., Kroemer G. Endoplasmic reticulum stress-induced cell death requires mitochondrial membrane permeabilization. Cell Death Differ. 2002;9(4):465–467. doi: 10.1038/sj.cdd.4401006. [DOI] [PubMed] [Google Scholar]
  • [34].Germain M., Mathai J.P., Shore G.C. BH-3-only BIK functions at the endoplasmic reticulum to stimulate cytochrome c release from mitochondria. J Biol Chem. 2002;277(20):18053–18060. doi: 10.1074/jbc.M201235200. [DOI] [PubMed] [Google Scholar]
  • [35].Hori O., Ichinoda F., Tamatani T., Yamaguchi A., Sato N., Ozawa K., et al. Transmission of cell stress from endoplasmic reticulum to mitochondria: enhanced expression of Lon protease. J Cell Biol. 2002;157(7):1151–1160. doi: 10.1083/jcb.200108103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [36].Lipton P. Ischemic cell death in brain neurons. Physiol Rev. 1999;79(4):1431–1568. doi: 10.1152/physrev.1999.79.4.1431. [DOI] [PubMed] [Google Scholar]
  • [37].Bursch W., Ellinger A., Kienzl H., Török L., Pandey S., Sikorska M., et al. Active cell death induced by the anti-estrogens tamoxifen and ICI 164 384 in human mammary carcinoma cells (MCF-7) in culture: the role of autophagy. Carcinogenesis. 1996;17(8):1595–1607. doi: 10.1093/carcin/17.8.1595. [DOI] [PubMed] [Google Scholar]
  • [38].Maiese K., Boniece I.R., Skurat K., Wagner J.A. Protein kinases modulate the sensitivity of hippocampal neurons to nitric oxide toxicity and anoxia. J Neurosci Res. 1993;36(1):77–87. doi: 10.1002/jnr.490360109. [DOI] [PubMed] [Google Scholar]
  • [39].Bano D., Nicotera P. Ca2+ signals and neuronal death in brain ischemia. Stroke. 2007;38(2Suppl):674–676. doi: 10.1161/01.STR.0000256294.46009.29. [DOI] [PubMed] [Google Scholar]
  • [40].Qin A.P., Zhang H.L., Qin Z.H. Mechanisms of lysosomal proteases participating in cerebral ischemia-induced neuronal death. Neurosci Bull. 2008;24(2):117–123. doi: 10.1007/s12264-008-0117-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [41].Busch H.J., Buschmann I.R., Mies G., Bode C., Hossmann K.A. Arteriogenesis in hypoperfused rat brain. J Cereb Blood Flow Metab. 2003;23(5):621–628. doi: 10.1097/01.WCB.0000057741.00152.E4. [DOI] [PubMed] [Google Scholar]
  • [42].Buschmann I.R., Busch H.J., Mies G., Hossmann K.A. Therapeutic induction of arteriogenesis in hypoperfused rat brain via granulocyte-macrophage colony-stimulating factor. Circulation. 2003;108(5):610–615. doi: 10.1161/01.CIR.0000074209.17561.99. [DOI] [PubMed] [Google Scholar]
  • [43].Busch H.J., Buschmann I., Schneeloch E., Bode C., Mies G., Hossmann K.A. Therapeutically induced arteriogenesis in the brain. A new approach for the prevention of cerebral ischemia with vascular stenosis. Nervenarzt. 2006;77(2):215–220. doi: 10.1007/s00115-005-1988-4. [DOI] [PubMed] [Google Scholar]
  • [44].Lees K.R. Cerestat and other NMDA antagonists in ischemic stroke. Neurology. 1997;49(5Suppl4):S66–69. doi: 10.1212/wnl.49.5_suppl_4.s66. [DOI] [PubMed] [Google Scholar]
  • [45].Muir K.W., Lees K.R. Clinical experience with excitatory amino acid antagonist drugs. Stroke. 1995;26(3):503–513. doi: 10.1161/01.str.26.3.503. [DOI] [PubMed] [Google Scholar]
  • [46].Schachter S.C., Tarsy D. Remacemide: current status and clinical applications. Expert Opin Investig Drugs. 2000;9(4):871–883. doi: 10.1517/13543784.9.4.871. [DOI] [PubMed] [Google Scholar]
  • [47].Kato T. Role of magnesium ions on the regulation of NMDA receptor—a pharmacopathology of memantine. Clin Calcium. 2004;14(8):76–80. [PubMed] [Google Scholar]
  • [48].Sun A., Cheng J. Novel targets for therapeutic intervention against ischemic brain injury. Clin Neuropharmacol. 1999;22(3):164–171. [PubMed] [Google Scholar]
  • [49].Gill R. The pharmacology of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainate antagonists and their role in cerebral ischaemia. Cerebrovasc Brain Metab Rev. 1994;6(3):225–256. [PubMed] [Google Scholar]
  • [50].Hampson A.J., Grimaldi M., Axelrod J., Wink D. Cannabidiol and (−)Delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci USA. 1998;95(14):8268–8273. doi: 10.1073/pnas.95.14.8268. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [51].Zhang Y., Deng P., Ruan Y., Xu Z.C. Dopamine D1-like receptors depress excitatory synaptic transmissions in striatal neurons after transient forebrain ischemia. Stroke. 2008;39(8):2370–2376. doi: 10.1161/STROKEAHA.107.506824. [DOI] [PubMed] [Google Scholar]
  • [52].O’Neill M.J., Hicks C.A., Ward M.A., Cardwell G.P., Reymann J.M., Allain H., et al. Dopamine D2 receptor agonists protect against ischaemia-induced hippocampal neurodegeneration in global cerebral ischaemia. Eur J Pharmacol. 1998;352(1):37–46. doi: 10.1016/S0014-2999(98)00333-1. [DOI] [PubMed] [Google Scholar]
  • [53].Kuhmonen J., Pokorný J., Miettinen R., Haapalinna A., Jolkkonen J., Riekkinen P., Sr, et al. Neuroprotective effects of dexmedetomidine in the gerbil hippocampus after transient global ischemia. Anesthesiology. 1997;87(2):371–377. doi: 10.1097/00000542-199708000-00025. [DOI] [PubMed] [Google Scholar]
  • [54].Marcoli M., Cervetto C., Castagnetta M., Sbaffi P., Maura G. 5-HT control of ischemia-evoked glutamate efflux from human cerebrocortical slices. Neurochem Int. 2004;45(5):687–691. doi: 10.1016/j.neuint.2004.03.004. [DOI] [PubMed] [Google Scholar]
  • [55].Zhou C., Li C., Yu H.M., Zhang F., Han D., Zhang G.Y. Neuroprotection of gamma-aminobutyric acid receptor agonists via enhancing neuronal nitric oxide synthase (Ser847) phosphorylation through increased neuronal nitric oxide synthase and PSD95 interaction and inhibited protein phosphatase activity in cerebral ischemia. J Neurosci Res. 2008;86(13):2973–2983. doi: 10.1002/jnr.21728. [DOI] [PubMed] [Google Scholar]
  • [56].Zhang D.J., Xu G.R., Li Z.Y., Li Y.Z., Xu L.X., Lu F.Y., et al. The effects of Shuxuetong on the pathology of cerebral ischemia-reperfusion injury and GABA and TNF-alpha expression in gerbil models. Neurosci Bull. 2006;22(1):41–46. [PubMed] [Google Scholar]
  • [57].Stone T.W. Purines and neuroprotection. Adv Exp Med Biol. 2002;513:249–280. doi: 10.1007/978-1-4615-0123-7_9. [DOI] [PubMed] [Google Scholar]
  • [58].Schurr A. Neuroprotection against ischemic/hypoxic brain damage: blockers of ionotropic glutamate receptor and voltage sensitive calcium channels. Curr Drug Targets. 2004;5(7):603–618. doi: 10.2174/1389450043345209. [DOI] [PubMed] [Google Scholar]
  • [59].Yenari M.A., Palmer J.T., Sun G.H., de Crespigny A., Mosely M.E., Steinberg G.K. Time-course and treatment response with SNX-111, an N-type calcium channel blocker, in a rodent model of focal cerebral ischemia using diffusion-weighted MRI. Brain Res. 1996;739(1–2):36–45. doi: 10.1016/S0006-8993(96)00808-6. [DOI] [PubMed] [Google Scholar]
  • [60].Campbell C.A., Mackay K.B., Patel S., King P.D., Stretton J.L., Hadingham S.J., et al. Effects of isradipine, an L-type calcium channel blocker on permanent and transient focal cerebral ischemia in spontaneously hypertensive rats. Exp Neurol. 1997;148(1):45–50. doi: 10.1006/exnr.1997.6611. [DOI] [PubMed] [Google Scholar]
  • [61].Xiong Z.G., Zhu X.M., Chu X.P., Minami M., Hey J., Wei W.L., et al. Neuroprotection in ischemia: blocking calcium-permeable acid-sensing ion channels. Cell. 2004;118(6):687–698. doi: 10.1016/j.cell.2004.08.026. [DOI] [PubMed] [Google Scholar]
  • [62].Zhang H., Song L.C., Liu Y.Y., Ma Y., Lu Y.L. Pinacidil reduces neuronal apoptosis following cerebral ischemia-reperfusion in rats through both mitochondrial and death-receptor signal pathways. Neurosci Bull. 2007;23(3):145–150. doi: 10.1007/s12264-007-0021-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [63].Sharma S.S., Gupta S. Neuroprotective effect of MnTMPyP, a superoxide dismutase/catalase mimetic in global cerebral ischemia is mediated through reduction of oxidative stress and DNA fragmentation. Eur J Pharmacol. 2007;561(1–3):72–79. doi: 10.1016/j.ejphar.2006.12.039. [DOI] [PubMed] [Google Scholar]
  • [64].Park C.K., Hall E.D. Dose-response analysis of the effect of 21-aminosteroid tirilazad mesylate (U-74006F) upon neurological outcome and ischemic brain damage in permanent focal cerebral ischemia. Brain Res. 1994;645(1–2):157–163. doi: 10.1016/0006-8993(94)91649-7. [DOI] [PubMed] [Google Scholar]
  • [65].Villa R.F., Gorini A. Pharmacology of lazaroids and brain energy metabolism: a review. Pharmacol Rev. 1997;49(1):99–136. [PubMed] [Google Scholar]
  • [66].Yoshida H., Yanai H., Namiki Y., Fukatsu-Sasaki K., Furutani N., Tada N. Neuroprotective effects of edaravone: a novel free radical scavenger in cerebrovascular injury. CNS Drug Rev. 2006;12(1):9–20. doi: 10.1111/j.1527-3458.2006.00009.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [67].MacGregor D.G., Avshalumov M.V., Rice M.E. Brain edema induced by in vitro ischemia: causal factors and neuroprotection. J Neurochem. 2003;85(6):1402–1411. doi: 10.1046/j.1471-4159.2003.01772.x. [DOI] [PubMed] [Google Scholar]
  • [68].Lapchak P.A., Araujo D.M., Song D., Wei J., Zivin J.A. Neuroprotective effects of the spin trap agent disodium-[(tert-butylimino)methyl] benzene-1,3-disulfonate N-oxide (generic NXY-059) in a rabbit small clot embolic stroke model: combination studies with the thrombolytic tissue plasminogen activator. Stroke. 2002;33(5):1411–1415. doi: 10.1161/01.STR.0000015346.00054.8B. [DOI] [PubMed] [Google Scholar]
  • [69].Vaughan C.J., Delanty N. Neuroprotective properties of statins in cerebral ischemia and stroke. Stroke. 1999;30(9):1969–1973. doi: 10.1161/01.str.30.9.1969. [DOI] [PubMed] [Google Scholar]
  • [70].Cai Z.Y., Yan Y., Sun S.Q., Zhang J., Huang L.G., Yan N., et al. Minocycline attenuates cognitive impairment and restrains oxidative stress in the hippocampus of rats with chronic cerebral hypoperfusion. Neurosci Bull. 2008;24(5):305–313. doi: 10.1007/s12264-008-0324-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [71].Bartus R.T., Baker K.L., Heiser A.D., Sawyer S.D., Dean R.L., Elliott P.J., et al. Postischemic administration of AK275, a calpain inhibitor, provides substantial protection against focal ischemic brain damage. J Cereb Blood Flow Metab. 1994;14(4):537–544. doi: 10.1038/jcbfm.1994.67. [DOI] [PubMed] [Google Scholar]
  • [72].Liao S.L., Chen W.Y., Raung S.L., Chen C.J. Neuroprotection of naloxone against ischemic injury in rats: role of mu receptor antagonism. Neurosci Lett. 2003;345(3):169–172. doi: 10.1016/S0304-3940(03)00540-8. [DOI] [PubMed] [Google Scholar]
  • [73].Yenari M.A., Kunis D., Sun G.H., Onley D., Watson L., Turner S., et al. Hu23F2G, an antibody recognizing the leukocyte CD11/CD18 integrin, reduces injury in a rabbit model of transient focal cerebral ischemia. Exp Neurol. 1998;153(2):223–233. doi: 10.1006/exnr.1998.6876. [DOI] [PubMed] [Google Scholar]
  • [74].Morales J.R., Ballesteros I., Deniz J.M., Hurtado O., Vivancos J., Nombela F., et al. Activation of liver X receptors promotes neuroprotection and reduces brain inflammation in experimental stroke. Circulation. 2008;118(14):1450–1459. doi: 10.1161/CIRCULATIONAHA.108.782300. [DOI] [PubMed] [Google Scholar]
  • [75].Szydlowska K., Zawadzka M., Kaminska B. Neuroprotectant FK506 inhibits glutamate-induced apoptosis of astrocytes in vitro and in vivo. J Neurochem. 2006;99(3):965–975. doi: 10.1111/j.1471-4159.2006.04136.x. [DOI] [PubMed] [Google Scholar]
  • [76].Ebisu T., Mori Y., Katsuta K., Fujikawa A., Matsuoka N., Aoki I., et al. Neuroprotective effects of an immunosuppressant agent on diffusion/perfusion mismatch in transient focal ischemia. Magn Reson Med. 2004;51(6):1173–1180. doi: 10.1002/mrm.20087. [DOI] [PubMed] [Google Scholar]
  • [77].Uchino H., Morota S., Takahashi T., Ikeda Y., Kudo Y., Ishii N., et al. A novel neuroprotective compound FR901459 with dual inhibition of calcineurin and cyclophilins. Acta Neurochir Suppl. 2006;96:157–162. doi: 10.1007/3-211-30714-1_35. [DOI] [PubMed] [Google Scholar]
  • [78].Kaminska B., Gaweda-Walerych K., Zawadzka M. Molecular mechanisms of neuroprotective action of immunosuppressants—facts and hypotheses. J Cell Mol Med. 2004;8(1):45–58. doi: 10.1111/j.1582-4934.2004.tb00259.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [79].Pedata F., Gianfriddo M., Turchi D., Melani A. The protective effect of adenosine A2A receptor antagonism in cerebral ischemia. Neurol Res. 2005;27(2):169–174. doi: 10.1179/016164105X21913. [DOI] [PubMed] [Google Scholar]
  • [80].Brambilla R., Cottini L., Fumagalli M., Ceruti S., Abbracchio M.P. Blockade of A2A adenosine receptors prevents basic fibroblast growth factor-induced reactive astrogliosis in rat striatal primary astrocytes. Glia. 2003;43(2):190–194. doi: 10.1002/glia.10243. [DOI] [PubMed] [Google Scholar]
  • [81].Han B.H., Holtzman D.M. BDNF protects the neonatal brain from hypoxic-ischemic injury in vivo via the ERK pathway. J Neurosci. 2000;20(15):5775–5781. doi: 10.1523/JNEUROSCI.20-15-05775.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [82].Robertson G.S., Crocker S.J., Nicholson D.W., Schulz J.B. Neuroprotection by the inhibition of apoptosis. Brain Pathol. 2000;10(2):283–292. doi: 10.1111/j.1750-3639.2000.tb00262.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [83].Hoffman G.E., Merchenthaler I., Zup S.L. Neuroprotection by ovarian hormones in animal models of neurological disease. Endocrine. 2006;29(2):217–231. doi: 10.1385/ENDO:29:2:217. [DOI] [PubMed] [Google Scholar]
  • [84].Kotani Y., Shimazawa M., Yoshimura S., Iwama T., Hara H. The experimental and clinical pharmacology of propofol, an anesthetic agent with neuroprotective properties. CNS Neurosci Ther. 2008;14(2):95–106. doi: 10.1111/j.1527-3458.2008.00043.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [85].Luo Y., Ma D., Ieong E., Sanders R.D., Yu B., Hossain M., et al. Xenon and sevoflurane protect against brain injury in a neonatal asphyxia model. Anesthesiology. 2008;109(5):782–789. doi: 10.1097/ALN.0b013e3181895f88. [DOI] [PubMed] [Google Scholar]
  • [86].Schmid-Elsaesser R., Hungerhuber E., Zausinger S., Baethmann A., Reulen H.J. Combination drug therapy and mild hypothermia: a promising treatment strategy for reversible, focal cerebral ischemia. Stroke. 1999;30(9):1891–1899. doi: 10.1161/01.str.30.9.1891. [DOI] [PubMed] [Google Scholar]
  • [87].Wang X.S., Ruan X.Z., Wang W. Protective Effect of Ginkgo Biloba Extract on Brain Injury Induced by Ischemia/Reperfusion in Rats. J Huazhong Univ Sci Tech[Health Sci] 2003;32(5):500–502. [Google Scholar]
  • [88].Hu X.S., Zhou D., Zhou D.M. Protective effects of PTS on cerebral ischemia—reperfusion injury in rat. J Apoplexy and Nervous Disease. 2004;21(4):354–356. [Google Scholar]
  • [89].Wu H.Q., Chang M.Z., Zhang G.L., Zhao Y.X. The mechanism of protective effects of puerarin on learning-memory disorder after global cerebral ischemic reperfusive injury in rats. J Apoplexy and Nervous Disease. 2004;21(4):350–353. [Google Scholar]
  • [90].Kirino T. Ischemic tolerance. J Cereb Blood Flow Metab. 2002;22(11):1283–1296. doi: 10.1097/00004647-200211000-00001. [DOI] [PubMed] [Google Scholar]
  • [91].Stagliano N.E., Pérez-Pinzón M.A., Moskowitz M.A., Huang P.L. Focal ischemic preconditioning induces rapid tolerance to middle cerebral artery occlusion in mice. J Cereb Blood Flow Metab. 1999;19(7):757–761. doi: 10.1097/00004647-199907000-00005. [DOI] [PubMed] [Google Scholar]
  • [92].Dirnagl U., Simon R.P., Hallenbeck J.M. Ischemic tolerance and endogenous neuroprotection. Trends Neurosci. 2003;26(5):248–254. doi: 10.1016/S0166-2236(03)00071-7. [DOI] [PubMed] [Google Scholar]
  • [93].Ge P.F., Luo T.F., Zhang J.Z., Chen D.W., Luan Y.X., Fu S.L. Ischemic preconditioning induces chaperone hsp70 expression and inhibits protein aggregation in the CA1 neurons of rats. Neurosci Bull. 2008;24(5):288–296. doi: 10.1007/s12264-008-0623-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [94].Obrenovitch T.P. Molecular physiology of preconditioning-induced brain tolerance to ischemia. Physiol Rev. 2008;88(1):211–247. doi: 10.1152/physrev.00039.2006. [DOI] [PubMed] [Google Scholar]
  • [95].Xing B., Chen H., Zhang M., Zhao D., Jiang R., Liu X., et al. Ischemic postconditioning inhibits apoptosis after focal cerebral ischemia/reperfusion injury in the rat. Stroke. 2008;39(8):2362–2369. doi: 10.1161/STROKEAHA.107.507939. [DOI] [PubMed] [Google Scholar]
  • [96].Wang J.Y., Shen J., Gao Q., Ye Z.G., Yang S.Y., Liang H.W., et al. Ischemic postconditioning protects against global cerebral ischemia/reperfusion-induced injury in rats. Stroke. 2008;39(3):983–990. doi: 10.1161/STROKEAHA.107.499079. [DOI] [PubMed] [Google Scholar]
  • [97].Faden A.I., Stoica B. Neuroprotection: challenges and opportunities. Arch Neurol. 2007;64(6):794–800. doi: 10.1001/archneur.64.6.794. [DOI] [PubMed] [Google Scholar]

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