2007 Heart-Brain summit proceedings

Preconditioning paradigms and pathways in the brain

Karl B. Shpargel

Department of Neurosciences, Cleveland Clinic, Cleveland, OH

Walid Jalabi, PhD

Department of Neurosciences, Cleveland Clinic, Cleveland, OH

 

Yongming Jin

Department of Neurosciences, Cleveland Clinic, Cleveland, OH

 

Alisher Dadabayev, MD

Department of Stem Cell Biology and Regenerative Medicine,

Cleveland Clinic, Cleveland, OH

 

Marc S. Penn, MD, PhD

Departments of Cardiovascular Medicine, Biomedical Engineering, and Stem Cell Biology and Regenerative Medicine; and Director, Bakken Heart-Brain Institute, Cleveland Clinic, Cleveland, OH

 

Bruce D. Trapp, PhD

Chairman, Department of Neurosciences, Cleveland Clinic, Cleveland, OH

trappb@ccf.org

ABSTRACT

Preconditioning is a phenomenon in which the brain protects itself against future injury by adapting to low doses of noxious insults. Preconditioning stimuli include ischemia, low doses of endotoxin, hypoxia, hypothermia and hyperthermia, cortical spreading depression, anesthetics, and 3-nitropropionic acid, among others. Understanding of the mechanisms underlying preconditioning has been elusive, but NMDA receptor activation, nitric oxide, inflammatory cytokines, and suppression of the innate immune system appear to have a role. Elucidation of the endogenous cell survival pathways involved in preconditioning has significant clinical implications for preventing neuronal damage in susceptible patients.

CITATIONS

  1. Kunz A, Park L, Abe T, et al.
    Neurovascular protection by ischemic tolerance: role of nitric oxide and reactive oxygen species. J Neurosci 2007; 27:7083–7093.
    http://www.ncbi.nlm.nih.gov/pubmed/17611261

  2. Simon RP, Niiro M, Gwinn R.
    Prior ischemic stress protects against experimental stroke. Neurosci Lett 1993; 163:135–137.
    http://www.ncbi.nlm.nih.gov/pubmed/8309618
  3. Chen J, Simon R. Ischemic tolerance in the brain. Neurology 1997; 48:306–311.
    http://www.ncbi.nlm.nih.gov/pubmed/9040711
  4. Kitagawa K, Matsumoto M, Tagaya M, et al.
    ‘Ischemic tolerance’ phenomenon found in the brain. Brain Res 1990; 528:21–24.
    http://www.ncbi.nlm.nih.gov/pubmed/2245337
  5. Kawahara N, Ruetzler CA, Klatzo I.
    Protective effect of spreading depression against neuronal damage following cardiac arrest cerebral ischaemia. Neurol Res 1995; 17:9–16.
    http://www.ncbi.nlm.nih.gov/pubmed/7746347
  6. Taga K, Patel PM, Drummond JC, Cole DJ, Kelly PJ.
    Transient PRECONDITIONING S80 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 75 • SUPPLEMENT 2 MARCH 2008 neuronal depolarization induces tolerance to subsequent forebrain ischemia in rats. Anesthesiology 1997; 87:918–925.
    http://www.ncbi.nlm.nih.gov/pubmed/9357895
  7. Kobayashi S, Harris VA, Welsh FA.
    Spreading depression induces tolerance of cortical neurons to ischemia in rat brain. J Cereb Blood Flow Metab 1995; 15:721–727.
    http://www.ncbi.nlm.nih.gov/pubmed/7673367
  8. Baughman VL, Hoffman WE, Miletich DJ, Albrecht RF, Thomas C.
    Neurologic outcome in rats following incomplete cerebral ischemia during halothane, isoflurane, or N2O. Anesthesiology 1988; 69:192–198.
    http://www.ncbi.nlm.nih.gov/pubmed/3407968
  9. Kapinya KJ, Lowl D, Futterer C, et al.
    Tolerance against ischemic neuronal injury can be induced by volatile anesthetics and is inducible NO synthase dependent. Stroke 2002; 33:1889–1898.
    http://www.ncbi.nlm.nih.gov/pubmed/12105371
  10. Zheng S, Zuo Z.
    Isoflurane preconditioning induces neuroprotection against ischemia via activation of P38 mitogen-activated protein kinases. Mol Pharmacol 2004; 65:1172–1180.
    http://www.ncbi.nlm.nih.gov/pubmed/15102945
  11. Tasaki K, Ruetzler CA, Ohtsuki T, et al.
    Lipopolysaccharide pre-treatment induces resistance against subsequent focal cerebral ischemic damage in spontaneously hypertensive rats. Brain Res 1997; 748:267–270.
    http://www.ncbi.nlm.nih.gov/pubmed/9067475
  12. Zimmermann C, Ginis I, Furuya K, et al.
    Lipopolysaccharide-induced ischemic tolerance is associated with increased levels of ceramide in brain and in plasma. Brain Res 2001; 895:59–65.
    http://www.ncbi.nlm.nih.gov/pubmed/11259760
  13. Nishio S, Yunoki M, Chen ZF, Anzivino MJ, Lee KS.
    Ischemic tolerance in the rat neocortex following hypothermic preconditioning. J Neurosurg 2000; 93:845–851.
    http://www.ncbi.nlm.nih.gov/pubmed/11059667
  14. Ota A, Ikeda T, Xia XY, Xia YX, Ikenoue T.
    Hypoxic-ischemic tolerance induced by hyperthermic pretreatment in newborn rats. J Soc Gynecol Investig 2000; 7:102–105.
    http://www.ncbi.nlm.nih.gov/pubmed/10785609
  15. Riepe MW, Niemi WN, Megow D, Ludolph AC, Carpenter DO.
    Mitochondrial oxidation in rat hippocampus can be preconditioned by selective chemical inhibition of succinic dehydrogenase. Exp Neurol 1996; 138:15–21.
    http://www.ncbi.nlm.nih.gov/pubmed/8593890
  16. Sugino T, Nozaki K, Takagi Y, Hashimoto N. 3-Nitropropionic acid induces ischemic tolerance in gerbil hippocampus in vivo. Neurosci Lett 1999; 259:9–12.
    http://www.ncbi.nlm.nih.gov/pubmed/10027543
  17. Perez-Pinzon MA, Xu GP, Dietrich WD, Rosenthal M, Sick TJ.
    Rapid preconditioning protects rats against ischemic neuronal damage after 3 but not 7 days of reperfusion following global cerebral ischemia. J Cereb Blood Flow Metab 1997; 17:175–182.
    http://www.ncbi.nlm.nih.gov/pubmed/9040497
  18. Stagliano NE, Perez-Pinzon MA, Moskowitz MA, Huang PL.
    Focal ischemic preconditioning induces rapid tolerance to middle cerebral artery occlusion in mice. J Cereb Blood Flow Metab 1999; 19:757–761.
    http://www.ncbi.nlm.nih.gov/pubmed/10413030
  19. Perez-Pinzon MA, Born JG.
    Rapid preconditioning neuroprotection following anoxia in hippocampal slices: role of the K+ ATP channel and protein kinase C. Neuroscience 1999; 89:453–459.
    http://www.ncbi.nlm.nih.gov/pubmed/10077327
  20. Kariko K, Weissman D, Welsh FA.
    Inhibition of toll-like receptor and cytokine signaling—a unifying theme in ischemic tolerance. J Cereb Blood Flow Metab 2004; 24:1288–1304.
    http://www.ncbi.nlm.nih.gov/pubmed/15545925
  21. Hoyte LC, Papadakis M, Barber PA, Buchan AM.
    Improved regional cerebral blood flow is important for the protection seen in a mouse model of late phase ischemic preconditioning. Brain Res 2006; 1121:231–237.
    http://www.ncbi.nlm.nih.gov/pubmed/17010948
  22. Nakase H, Heimann A, Uranishi R, Riepe MW, Kempski O.
    Early-onset tolerance in rat global cerebral ischemia induced by a mitochondrial inhibitor. Neurosci Lett 2000; 290:105–108.
    http://www.ncbi.nlm.nih.gov/pubmed/10936688
  23. Meller R, Cameron JA, Torrey DJ, et al.
    Rapid degradation of Bim by the ubiquitin-proteasome pathway mediates short-term ischemic tolerance in cultured neurons. J Biol Chem 2006; 281:7429–7436.
    http://www.ncbi.nlm.nih.gov/pubmed/16431916
  24. Kirino T.
    Ischemic tolerance. J Cereb Blood Flow Metab 2002; 22:1283–1296.
    http://www.ncbi.nlm.nih.gov/pubmed/12439285
  25. Stenzel-Poore MP, Stevens SL, Xiong Z, et al.
    Effect of ischaemic preconditioning on genomic response to cerebral ischaemia: similarity to neuroprotective strategies in hibernation and hypoxia-tolerant states. Lancet 2003; 362:1028–1037.
    http://www.ncbi.nlm.nih.gov/pubmed/14522533
  26. Murry CE, Jennings RB, Reimer KA.
    Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 1986; 74:1124–1136.
    http://www.ncbi.nlm.nih.gov/pubmed/3769170
  27. Kitagawa K, Matsumoto M, Kuwabara K, et al.
    ‘Ischemic tolerance’ phenomenon detected in various brain regions. Brain Res 1991; 561:203–211.
    http://www.ncbi.nlm.nih.gov/pubmed/1802339
  28. Roach GW, Kanchuger M, Mangano CM, et al.
    Adverse cerebral outcomes after coronary bypass surgery. Multicenter Study of Perioperative Ischemia Research Group and the Ischemia Research and Education Foundation Investigators. N Engl J Med 1996; 335:1857–1863.
    http://www.ncbi.nlm.nih.gov/pubmed/8948560
  29. Newman MF, Kirchner JL, Phillips-Bute B, et al.
    Longitudinal assessment of neurocognitive function after coronary-artery bypass surgery. N Engl J Med 2001; 344:395–402.
    http://www.ncbi.nlm.nih.gov/pubmed/11172175
  30. Corbett D, Crooks P.
    Ischemic preconditioning: a long term survival study using behavioural and histological endpoints. Brain Res 1997; 760:129–136.
    http://www.ncbi.nlm.nih.gov/pubmed/9237527
  31. Barone FC, White RF, Spera PA, et al.
    Ischemic preconditioning and brain tolerance: temporal histological and functional outcomes, protein synthesis requirement, and interleukin-1 receptor antagonist and early gene expression. Stroke 1998; 29:1937–1950.
    http://www.ncbi.nlm.nih.gov/pubmed/9731622
  32. Wu C, Zhan RZ, Qi S, et al.
    A forebrain ischemic preconditioning model established in C57Black/Crj6 mice. J Neurosci Methods 2001; 107:101–106.
    http://www.ncbi.nlm.nih.gov/pubmed/11389947
  33. Dawson DA, Furuya K, Gotoh J, et al.
    Cerebrovascular hemodynamics and ischemic tolerance: lipopolysaccharide-induced resistance to focal cerebral ischemia is not due to changes in severity of the initial ischemic insult, but is associated with preservation of microvascular perfusion. J Cereb Blood Flow Metab 1999; 19:616–623.
    http://www.ncbi.nlm.nih.gov/pubmed/10366191
  34. Ahmed SH, He YY, Nassief A, et al.
    Effects of lipopolysaccharide priming on acute ischemic brain injury. Stroke 2000; 31:193–199.
    http://www.ncbi.nlm.nih.gov/pubmed/10625737
  35. Rosenzweig HL, Lessov NS, Henshall DC, et al.
    Endotoxin preconditioning prevents cellular inflammatory response during ischemic neuroprotection in mice. Stroke 2004; 35:2576–2581.
    http://www.ncbi.nlm.nih.gov/pubmed/15375302
  36. Furuya K, Zhu L, Kawahara N, et al.
    Differences in infarct evolution between lipopolysaccharide-induced tolerant and nontolerant conditions to focal cerebral ischemia. J Neurosurg 2005; 103:715–723.
    http://www.ncbi.nlm.nih.gov/pubmed/16266055
  37. Bernaudin M, Nedelec AS, Divoux D, et al.
    Normobaric hypoxia induces tolerance to focal permanent cerebral ischemia in association with an increased expression of hypoxia-inducible factor-1 and its target genes, erythropoietin and VEGF, in the adult mouse brain. J Cereb Blood Flow Metab 2002; 22:393–403.
    http://www.ncbi.nlm.nih.gov/pubmed/11919510
  38. Kulinskii VI, Minakina LN, Gavrilina TV.
    Neuroprotective effect of hypoxic preconditioning: phenomenon and mechanisms. Bull Exp Biol Med 2002; 133:202–204.
    http://www.ncbi.nlm.nih.gov/pubmed/12428296
  39. Miller BA, Perez RS, Shah AR, et al.
    Cerebral protection by hypoxic preconditioning in a murine model of focal ischemia-reperfusion. Neuroreport 2001; 12:1663–1669.
    http://www.ncbi.nlm.nih.gov/pubmed/11409736
  40. Prass K, Scharff A, Ruscher K, et al.
    Hypoxia-induced stroke tolerance in the mouse is mediated by erythropoietin. Stroke 2003; 34:1981–1986.
    http://www.ncbi.nlm.nih.gov/pubmed/12829864
  41. Liu J, Ginis I, Spatz M, Hallenbeck JM.
    Hypoxic preconditioning protects cultured neurons against hypoxic stress via TNF-alpha and ceramide. Am J Physiol Cell Physiol 2000; 278:C144–C153.
    http://www.ncbi.nlm.nih.gov/pubmed/10644522
  42. Kuroiwa T, Yamada I, Endo S, Hakamata Y, Ito U.
    3-Nitropropionic acid preconditioning ameliorates delayed neurological deterioration and infarction after transient focal cerebral ischemia in gerbils. Neurosci Lett 2000; 283:145–148.
    http://www.ncbi.nlm.nih.gov/pubmed/10739896
  43. Horiguchi T, Kis B, Rajapakse N, Shimizu K, Busija DW.
    Opening of mitochondrial ATP-sensitive potassium channels is a trigger of 3-nitropropionic acid-induced tolerance to transient focal cerebral ischemia in rats. Stroke 2003; 34:1015–1020.
    http://www.ncbi.nlm.nih.gov/pubmed/12649508
  44. Aketa S, Nakase H, Kamada Y, Hiramatsu K, Sakaki T.
    Chemical preconditioning with 3-nitropropionic acid in gerbil hippocampal slices: therapeutic window and the participation of adenosine receptor. Exp Neurol 2000; 166:385–391.
    http://www.ncbi.nlm.nih.gov/pubmed/11085903
  45. Nishio S, Chen ZF, Yunoki M, et al.
    Hypothermia-induced ischemic tolerance. Ann N Y Acad Sci 1999; 890:26–41.
    http://www.ncbi.nlm.nih.gov/pubmed/10668411
  46. Yunoki M, Nishio S, Ukita N, Anzivino MJ, Lee KS.
    Hypothermic preconditioning induces rapid tolerance to focal ischemic injury in the rat. Exp Neurol 2003; 181:291–300.
    http://www.ncbi.nlm.nih.gov/pubmed/12782001
  47. Kawahara N, Ruetzler CA, Mies G, Klatzo I.
    Cortical spreading depression increases protein synthesis and upregulates basic fibroblast growth factor. Exp Neurol 1999; 158:27–36.
    http://www.ncbi.nlm.nih.gov/pubmed/10448415
  48. Yanamoto H, Hashimoto N, Nagata I, Kikuchi H.
    Infarct tolerance against temporary focal ischemia following spreading depression in rat brain. Brain Res 1998; 784:239–249.
    http://www.ncbi.nlm.nih.gov/pubmed/9518633
  49. McAuliffe JJ, Joseph B, Vorhees CV.
    Isoflurane-delayed preconditioning reduces immediate mortality and improves striatal function in adult mice after neonatal hypoxia-ischemia. Anesth Analg 2007; CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 75 • SUPPLEMENT 2 MARCH 2008 S81
    SHPARGEL AND COLLEAGUES
    104:1066–1077.
    http://www.ncbi.nlm.nih.gov/pubmed/17456654
  50. Grabb MC, Choi DW.
    Ischemic tolerance in murine cortical cell culture: critical role for NMDA receptors. J Neurosci 1999; 19:1657–1662.
    http://www.ncbi.nlm.nih.gov/pubmed/10024352
  51. Kato H, Liu Y, Araki T, Kogure K.
    MK-801, but not anisomycin, inhibits the induction of tolerance to ischemia in the gerbil hippocampus. Neurosci Lett 1992; 139:118–121.
    http://www.ncbi.nlm.nih.gov/pubmed/1407677

  52. Kasischke K, Ludolph AC, Riepe MW.
    NMDA-antagonists reverse increased hypoxic tolerance by preceding chemical hypoxia. Neurosci Lett 1996; 214:175–178.
    http://www.ncbi.nlm.nih.gov/pubmed/8878112
  53. Blondeau N, Widmann C, Lazdunski M, Heurteaux C.
    Activation of the nuclear factor-_B is a key event in brain tolerance. J Neurosci 2001; 21:4668–4677.
    http://www.ncbi.nlm.nih.gov/pubmed/11425894
  54. Soriano FX, Papadia S, Hofmann F, et al.
    Preconditioning doses of NMDA promote neuroprotection by enhancing neuronal excitability. J Neurosci 2006; 26:4509–4518.
    http://www.ncbi.nlm.nih.gov/pubmed/16641230
  55. Douen AG, Akiyama K, Hogan MJ, et al.
    Preconditioning with cortical spreading depression decreases intraischemic cerebral glutamate levels and down-regulates excitatory amino acid transporters EAAT1 and EAAT2 from rat cerebal cortex plasma membranes. J Neurochem 2000; 75:812–818.
    http://www.ncbi.nlm.nih.gov/pubmed/10899959
  56. Atochin DN, Clark J, Demchenko IT, Moskowitz MA, Huang PL.
    Rapid cerebral ischemic preconditioning in mice deficient in endothelial and neuronal nitric oxide synthases. Stroke 2003; 34:1299–1303.
    http://www.ncbi.nlm.nih.gov/pubmed/12677017
  57. Cho S, Park EM, Zhou P, et al.
    Obligatory role of inducible nitric oxide synthase in ischemic preconditioning. J Cereb Blood Flow Metab 2005; 25:493–501.
    http://www.ncbi.nlm.nih.gov/pubmed/15689953
  58. Yamada T, Kawahara K, Kosugi T, Tanaka M.
    Nitric oxide produced during sublethal ischemia is crucial for the preconditioninginduced down-regulation of glutamate transporter GLT-1 in neuron/ astrocyte co-cultures. Neurochem Res 2006; 31:49–56.
    http://www.ncbi.nlm.nih.gov/pubmed/16474996
  59. Gonzalez-Zulueta M, Feldman AB, Klesse LJ, et al.
    Requirement for nitric oxide activation of p21ras/extracellular regulated kinase in neuronal ischemic preconditioning. Proc Natl Acad Sci U S A 2000; 97:436–441.
    http://www.ncbi.nlm.nih.gov/pubmed/10618436
  60. Kurkinen K, Keinanen R, Li W, Koistinaho J.
    Preconditioning with spreading depression activates specifically protein kinase C_. Neuroreport 2001; 12:269–273.
    http://www.ncbi.nlm.nih.gov/pubmed/11209933
  61. Shamloo M, Rytter A, Wieloch T.
    Activation of the extracellular signal-regulated protein kinase cascade in the hippocampal CA1 region in a rat model of global cerebral ischemic preconditioning. Neuroscience 1999; 93:81–88.
    http://www.ncbi.nlm.nih.gov/pubmed/10430472
  62. Zhao L, Nowak TS Jr.
    CBF changes associated with focal ischemic preconditioning in the spontaneously hypertensive rat. J Cereb Blood Flow Metab 2006; 26:1128–1140.
    http://www.ncbi.nlm.nih.gov/pubmed/16407854
  63. Nakamura H, Katsumata T, Nishiyama Y, et al.
    Effect of ischemic preconditioning on cerebral blood flow after subsequent lethal ischemia in gerbils. Life Sci 2006; 78:1713–1719.
    http://www.ncbi.nlm.nih.gov/pubmed/16253278
  64. Bastide M, Gele P, Petrault O, et al.
    Delayed cerebrovascular protective effect of lipopolysaccharide in parallel to brain ischemic tolerance. J Cereb Blood Flow Metab 2003; 23:399–405.
    http://www.ncbi.nlm.nih.gov/pubmed/12679716
  65. Qin L, Wu X, Block ML, et al.
    Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 2007; 55:453–462.
    http://www.ncbi.nlm.nih.gov/pubmed/17203472
  66. Eising GP, Mao L, Schmid-Schonbein GW, Engler RL, Ross J.
    Effects of induced tolerance to bacterial lipopolysaccharide on myocardial infarct size in rats. Cardiovasc Res 1996; 31:73–81.
    http://www.ncbi.nlm.nih.gov/pubmed/8849591
  67. Zacharowski K, Otto M, Hafner G, et al.
    Endotoxin induces a second window of protection in the rat heart as determined by using pnitro- blue tetrazolium staining, cardiac troponin T release, and histology. Arterioscler Thromb Vasc Biol 1999; 19:2276–2280.
    http://www.ncbi.nlm.nih.gov/pubmed/10479673
  68. Colletti LM, Remick DG, Campbell DA Jr.
    LPS pretreatment protects from hepatic ischemia/reperfusion. J Surg Res 1994; 57:337–343.
    http://www.ncbi.nlm.nih.gov/pubmed/8072280
  69. Fernandez ED, Flohe S, Siemers F, et al.
    Endotoxin tolerance protects against local hepatic ischemia/reperfusion injury in the rat. J Endotoxin Res 2000; 6:321–328.
    http://www.ncbi.nlm.nih.gov/pubmed/11521053
  70. Heemann U, Szabo A, Hamar P, et al.
    Lipopolysaccharide pretreatment protects from renal ischemia/reperfusion injury: possible connection to an interleukin-6-dependent pathway. Am J Pathol 2000; 156:287–293.
    http://www.ncbi.nlm.nih.gov/pubmed/10623677
  71. Obermaier R, Drognitz O, Grub A, et al.
    Endotoxin preconditioning in pancreatic ischemia/reperfusion injury. Pancreas 2003; 27:e51–e56.
    http://www.ncbi.nlm.nih.gov/pubmed/14508141
  72. Rosenzweig HL, Minami M, Lessov NS, et al.
    Endotoxin preconditioning protects against the cytotoxic effects of TNF_ after stroke: a novel role for TNF_ in LPS-ischemic tolerance. J Cereb Blood Flow Metab 2007; 27:1663–1674.
    http://www.ncbi.nlm.nih.gov/pubmed/17327883
  73. Barone FC, Arvin B, White RF, et al.
    Tumor necrosis factor-alpha. A mediator of focal ischemic brain injury. Stroke 1997; 28:1233–1244.
    http://www.ncbi.nlm.nih.gov/pubmed/9183357
  74. Nawashiro H, Tasaki K, Ruetzler CA, Hallenbeck JM.
    TNFalpha pretreatment induces protective effects against focal cerebral ischemia in mice. J Cereb Blood Flow Metab 1997; 17:483–490.
    http://www.ncbi.nlm.nih.gov/pubmed/9183285
  75. Furuya K, Ginis I, Takeda H, et al.
    Cell permeable exogenous ceramide reduces infarct size in spontaneously hypertensive rats supporting in vitro studies that have implicated ceramide in induction of tolerance to ischemia. J Cereb Blood Flow Metab 2001; 21:226–232.
    http://www.ncbi.nlm.nih.gov/pubmed/11295877
  76. Loddick SA, Turnbull AV, Rothwell NJ.
    Cerebral interleukin-6 is neuroprotective during permanent focal cerebral ischemia in the rat. J Cereb Blood Flow Metab 1998; 18:176–179.
    http://www.ncbi.nlm.nih.gov/pubmed/9469160
  77. Ohtsuki T, Ruetzler CA, Tasaki K, Hallenbeck JM.
    Interleukin-1 mediates induction of tolerance to global ischemia in gerbil hippocampal CA1 neurons. J Cereb Blood Flow Metab 1996; 16:1137–1142.
    http://www.ncbi.nlm.nih.gov/pubmed/8898685
  78. Bruce AJ, Boling W, Kindy MS, et al.
    Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors. Nat Med 1996; 2:788–794.
    http://www.ncbi.nlm.nih.gov/pubmed/8673925
  79. Gary DS, Bruce-Keller AJ, Kindy MS, Mattson MP.
    Ischemic and excitotoxic brain injury is enhanced in mice lacking the p55 tumor necrosis factor receptor. J Cereb Blood Flow Metab 1998; 18:1283–1287.
    http://www.ncbi.nlm.nih.gov/pubmed/9850139
  80. Spera PA, Ellison JA, Feuerstein GZ, Barone FC.
    IL-10 reduces rat brain injury following focal stroke. Neurosci Lett 1998; 251:189–192.
    http://www.ncbi.nlm.nih.gov/pubmed/9726375
  81. Fan H, Cook JA.
    Molecular mechanisms of endotoxin tolerance. J Endotoxin Res 2004; 10:71–84.
    http://www.ncbi.nlm.nih.gov/pubmed/15119998
  82. Garcia JH, Liu KF, Relton JK.
    Interleukin-1 receptor antagonist decreases the number of necrotic neurons in rats with middle cerebral artery occlusion. Am J Pathol 1995; 147:1477–1486.
    http://www.ncbi.nlm.nih.gov/pubmed/7485410
  83. Relton JK, Martin D, Thompson RC, Russell DA.
    Peripheral administration of interleukin-1 receptor antagonist inhibits brain damage after focal cerebral ischemia in the rat. Exp Neurol 1996; 138:206–213.
    http://www.ncbi.nlm.nih.gov/pubmed/8620919
  84. Raghavendra RV, Bowen KK, Dhodda VK, et al.
    Gene expression analysis of spontaneously hypertensive rat cerebral cortex following transient focal cerebral ischemia. J Neurochem 2002; 83:1072–1086.
    http://www.ncbi.nlm.nih.gov/pubmed/12437578
  85. Victor NA, Wanderi EW, Gamboa J, et al.
    Altered PPAR_ expression and activation after transient focal ischemia in rats. Eur J Neurosci 2006; 24:1653–1663.
    http://www.ncbi.nlm.nih.gov/pubmed/17004929
  86. Zhao Y, Patzer A, Gohlke P, et al.
    The intracerebral application of the PPAR_-ligand pioglitazone confers neuroprotection against focal ischaemia in the rat brain. Eur J Neurosci 2005; 22:278–282.
    http://www.ncbi.nlm.nih.gov/pubmed/16029218
  87. Shioda N, Ishigami T, Han F, et al.
    Activation of phosphatidylinositol 3-kinase/protein kinase B pathway by a vanadyl compound mediates its neuroprotective effect in mouse brain ischemia. Neuroscience 2007; 148:221–229.
    http://www.ncbi.nlm.nih.gov/pubmed/17629407
  88. Mabuchi T, Kitagawa K, Ohtsuki T, et al.
    Contribution of microglia/ macrophages to expansion of infarction and response of oligodendrocytes after focal cerebral ischemia in rats. Stroke 2000; 31:1735–1743.
    http://www.ncbi.nlm.nih.gov/pubmed/10884481
  89. Lai AY, Todd KG.
    Microglia in cerebral ischemia: molecular actions and interactions. Can J Physiol Pharmacol 2006; 84:49–59.
    http://www.ncbi.nlm.nih.gov/pubmed/16845890
  90. Yrjanheikki J, Keinanen R, Pellikka M, Hokfelt T, Koistinaho J.
    Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc Natl Acad Sci U S A 1998; 95:15769–15774.
    http://www.ncbi.nlm.nih.gov/pubmed/9861045
  91. Denes A, Vidyasagar R, Feng J, et al.
    Proliferating resident microglia after focal cerebral ischaemia in mice. J Cereb Blood Flow Metab 2007; 27:1941–1953.
    http://www.ncbi.nlm.nih.gov/pubmed/17440490
  92. Streit WJ.
    Microglia as neuroprotective, immunocompetent cells of the CNS. Glia 2002; 40:133–139.
    http://www.ncbi.nlm.nih.gov/pubmed/12379901
  93. Lalancette-Hebert M, Gowing G, Simard A, Weng YC, Kriz J.
    Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. J Neurosci 2007; 27:2596–2605.
    http://www.ncbi.nlm.nih.gov/pubmed/17344397

 

Society for Heart-Brain Medicine | 216.636.2424 | © Copyright 2008 Sitemap