The science of cerebral ischemia and the quest for neuroprotection: navigating past failure to future success

A review

Restricted access

Ischemic stroke remains a leading cause of morbidity and death for which few therapeutic options are available. The development of neuroprotective agents, a once promising field of investigation, has failed to translate from bench to bedside successfully. This work reviews the ischemic cascade, agents targeting steps within the cascade, and potential reasons for lack of translation. Additional therapeutic targets are highlighted and areas requiring further investigation are discussed. It is clear that alternative targets need to be pursued, such as the role glia play in neurological injury and recovery, particularly the interactions between neurons, astrocytes, microglia, and the vasculature. Similarly, the biphasic nature of many signaling molecules such as matrix metalloproteinases and high-mobility group box 1 protein must be further investigated to elucidate periods of detrimental versus beneficial activity.

Abbreviations used in this paper:AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; ATP = adenosine 5'-triphosphate; ATPase = adenosine triphosphatase; GABAA = γ-aminobutyric acid-A; MMP = matrix metalloproteinase; MPTP = 1-methyl-4-phenyl-2,5,6-tetrahydropyridine; NADPH = nicotinamide adenine dinucleotide phosphate (reduced form); NMDA = N-methyl-d-aspartate; ROS = reactive oxygen species; SAINT = Stroke Acute Ischemic NXY Treatment; STAIR = Stroke Therapy Academic-Industry Roundtable; tPA = tissue plasminogen activator; VENUS = Very Early Nimodipine Use in Stroke; 5-HT = 5-hydroxytryptamine.

Article Information

Address correspondence to: Charles L. Rosen, M.D., Department of Neurosurgery, West Virginia University School of Medicine, One Medical Center Drive, PO Box 9183 Health Sciences Center, Morgantown, West Virginia 26506-9183. email: crosen@hsc.wvu.edu.

Please include this information when citing this paper: published online January 18, 2012; DOI: 10.3171/2012.11.JNS12408.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    A diagrammatic representation of the ischemic injury cascade from the onset of ischemia to cell death.

  • View in gallery

    A representation of targets pursued for preventing neuronal excitotoxicity, often attributed to excessive glutamate release. These targets include the following: 1) NMDA receptor antagonists; 2) AMPA receptor antagonists; 3) kappa opiate receptor antagonists; 4) GABAA receptor agonists; 5) 5-HT1A receptor agonist; and 6) potassium channel openers.

  • View in gallery

    Schematic showing that ischemia results in increased intracellular calcium levels through not only the NMDA and AMPA receptors but also through a slow Ca++ channel. Increased cytosolic calcium results in activation of endonucleases and phospholipases as well as proteases. The MPTP allows calcium to enter the mitochondria, which causes production of ROS and further damage. Calcium in the mitochondria also causes swelling and eventual rupture, releasing cytochrome c, long known to play a role in apoptosis.

  • View in gallery

    Inflammation has been identified as a promising avenue of therapeutic development. Multiple aspects can be inhibited, including release of inflammatory mediators from microglia, preventing adhesion, and blocking migration of inflammatory cells outside of the vasculature and into the parenchyma. ICAM-1 = intercellular adhesion molecule–1.

  • View in gallery

    The concept of neuroprotection is perhaps misguided; the neurocentric approach has failed to produce effective therapeutic agents. Cerebroprotection is needed, and for that the entire neurovascular unit must be considered. Also, supporting glia play a crucial role in health and disease, necessitating inclusion in therapeutic development.

References

1

Albers GWAtkinson RPKelley RERosenbaum DM: Safety, tolerability, and pharmacokinetics of the N-methyl-D-aspartate antagonist dextrorphan in patients with acute stroke. Stroke 26:2542581995

2

Albers GWGoldstein LBHall DLesko LM: Aptiganel hydrochloride in acute ischemic stroke: a randomized controlled trial. JAMA 286:267326822001

3

Astrup JSymon LBranston NMLassen NA: Cortical evoked potential and extracellular K+ and H+ at critical levels of brain ischemia. Stroke 8:51571977

4

Badan IBuchhold BHamm AGratz MWalker LCPlatt D: Accelerated glial reactivity to stroke in aged rats correlates with reduced functional recovery. J Cereb Blood Flow Metab 23:8458542003

5

Barber PAZhang JDemchuk AMHill MDBuchan AM: Why are stroke patients excluded from TPA therapy? An analysis of patient eligibility. Neurology 56:101510202001

6

Becker KJ: Anti-leukocyte antibodies: LeukArrest (Hu23F2G) and Enlimomab (R6.5) in acute stroke. Curr Med Res Opin 18:Suppl 2s18s222002

7

Block MLZecca LHong JS: Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8:57692007

8

Bordi FPietra CZiviani LReggiani A: The glycine antagonist GV150526 protects somatosensory evoked potentials and reduces the infarct area in the MCAo model of focal ischemia in the rat. Exp Neurol 145:4254331997

9

Bowes MPRothlein RFagan SCZivin JA: Monoclonal antibodies preventing leukocyte activation reduce experimental neurologic injury and enhance efficacy of thrombolytic therapy. Neurology 45:8158191995

10

Braeuninger SKleinschnitz C: Rodent models of focal cerebral ischemia: procedural pitfalls and translational problems. Exp Transl Stroke Med 1:82009

11

Bredesen DE: Apoptosis: overview and signal transduction pathways. J Neurotrauma 17:8018102000

12

Broughton BRReutens DCSobey CG: Apoptotic mechanisms after cerebral ischemia. Stroke 40:e331e3392009

13

Burns TCSteinberg GK: Stem cells and stroke: opportunities, challenges and strategies. Expert Opin Biol Ther 11:4474612011

14

Candelario-Jalil E: Injury and repair mechanisms in ischemic stroke: considerations for the development of novel neurotherapeutics. Curr Opin Investig Drugs 10:6446542009

15

Carmignoto GGómez-Gonzalo M: The contribution of astrocyte signalling to neurovascular coupling. Brain Res Brain Res Rev 63:1381482010

16

Cheney JAWeisser JDBareyre FMLaurer HLSaatman KERaghupathi R: The maxi-K channel opener BMS-204352 attenuates regional cerebral edema and neurologic motor impairment after experimental brain injury. J Cereb Blood Flow Metab 21:3964032001

17

Clark WMRaps ECTong DCKelly RE: Cervene (Nalmefene) in acute ischemic stroke: final results of a phase III efficacy study. Stroke 31:123412392000

18

Cotrina MLNedergaard M: Astrocytes in the aging brain. J Neurosci Res 67:1102002

19

Davis SMLees KRAlbers GWDiener HCMarkabi SKarlsson G: Selfotel in acute ischemic stroke: possible neurotoxic effects of an NMDA antagonist. Stroke 31:3473542000

20

De Ryck MKeersmaekers RDuytschaever HClaes CClincke GJanssen M: Lubeluzole protects sensorimotor function and reduces infarct size in a photochemical stroke model in rats. J Pharmacol Exp Ther 279:7487581996

21

del Zoppo GJ: The neurovascular unit in the setting of stroke. J Intern Med 267:1561712010

22

Diener HCCortens MFord GGrotta JHacke WKaste M: Lubeluzole in acute ischemic stroke treatment: a double-blind study with an 8-hour inclusion window comparing a 10-mg daily dose of lubeluzole with placebo. Stroke 31:254325512000

23

Diener HCLees KRLyden PGrotta JDavalos ADavis SM: NXY-059 for the treatment of acute stroke: pooled analysis of the SAINT I and II Trials. Stroke 39:175117582008

24

Dinapoli VABenkovic SALi XKelly KAMiller DBRosen CL: Age exaggerates proinflammatory cytokine signaling and truncates signal transducers and activators of transcription 3 signaling following ischemic stroke in the rat. Neuroscience 170:6336442010

25

Du CHu RHsu CYChoi DW: Dextrorphan reduces infarct volume, vascular injury, and brain edema after ischemic brain injury. J Neurotrauma 13:2152221996

26

Durukan AStrbian DTatlisumak T: Rodent models of ischemic stroke: a useful tool for stroke drug development. Curr Pharm Des 14:3593702008

27

Enlimomab Acute Stroke Trial Investigators: Use of anti-ICAM-1 therapy in ischemic stroke: results of the Enlimomab Acute Stroke Trial. Neurology 57:142814342001

28

Faden AIShirane RChang LHJames TLLemke MWeinstein PR: Opiate-receptor antagonist improves metabolic recovery and limits neurochemical alterations associated with reperfusion after global brain ischemia in rats. J Pharmacol Exp Ther 255:4514581990

29

Fagan SCCronic LEHess DC: Minocycline development for acute ischemic stroke. Transl Stroke Res 2:2022082011

30

Fisher MFeuerstein GHowells DWHurn PDKent TASavitz SI: Update of the stroke therapy academic industry roundtable preclinical recommendations. Stroke 40:224422502009

31

Fogelholm RErilä TPalomäki HMurros KKaste M: Effect of nimodipine on final infarct volume after acute ischemic stroke. Cerebrovasc Dis 10:1891932000

32

Graham SHChen JSimon RP: A dose-response study of dextrorphan in permanent focal ischemia. Neurosci Lett 160:21231993

33

Guevara RGianotti MOliver JRoca P: Age and sex-related changes in rat brain mitochondrial oxidative status. Exp Gerontol 46:9239282011

34

Hayakawa KMishima KNozako MHazekawa MMishima SFujioka M: Delayed treatment with minocycline ameliorates neurologic impairment through activated microglia expressing a high-mobility group box1-inhibiting mechanism. Stroke 39:9519582008

35

Hayakawa KNakano TIrie KHiguchi SFujioka MOrito K: Inhibition of reactive astrocytes with fluorocitrate retards neurovascular remodeling and recovery after focal cerebral ischemia in mice. J Cereb Blood Flow Metab 30:8718822010

36

Hayakawa KQiu JLo EH: Biphasic actions of HMGB1 signaling in inflammation and recovery after stroke. Ann N Y Acad Sci 1207:50572010

37

Heidenreich PATrogdon JGKhavjou OAButler JDracup KEzekowitz MD: Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association. Circulation 123:9339442011

38

Hellström HOWanhainen AValtysson JPersson LHillered L: Effect of tirilazad mesylate given after permanent middle cerebral artery occlusion in rat. Acta Neurochir (Wien) 129:1881921994

39

Horn Jde Haan RJVermeulen MLimburg M: Very Early Nimodipine Use in Stroke (VENUS): a randomized, double-blind, placebo-controlled trial. Stroke 32:4614652001

40

Hossmann KA: Pathophysiological basis of translational stroke research. Folia Neuropathol 47:2132272009

41

Hossmann KA: Pathophysiology and therapy of experimental stroke. Cell Mol Neurobiol 26:105710832006

42

Huang JUpadhyay UMTamargo RJ: Inflammation in stroke and focal cerebral ischemia. Surg Neurol 66:2322452006

43

Jensen BS: BMS-204352: a potassium channel opener developed for the treatment of stroke. CNS Drug Rev 8:3533602002

44

Jin RYang GLi G: Inflammatory mechanisms in ischemic stroke: role of inflammatory cells. J Leukoc Biol 87:7797892010

45

Jin RYang GLi G: Molecular insights and therapeutic targets for blood-brain barrier disruption in ischemic stroke: critical role of matrix metalloproteinases and tissue-type plasminogen activator. Neurobiol Dis 38:3763852010

46

Johnson EM JrGreenlund LJAkins PTHsu CY: Neuronal apoptosis: current understanding of molecular mechanisms and potential role in ischemic brain injury. J Neurotrauma 12:8438521995

47

Joly LMMucignat VMariani JPlotkine MCharriaut-Marlangue C: Caspase inhibition after neonatal ischemia in the rat brain. J Cereb Blood Flow Metab 24:1241312004

48

Jordán JSegura TBrea DGalindo MFCastillo J: Inflammation as therapeutic objective in stroke. Curr Pharm Des 14:354935642008

49

Kelly KALi XTan ZVanGilder RLRosen CLHuber JD: NOX2 inhibition with apocynin worsens stroke outcome in aged rats. Brain Res 1292:1651722009

50

Kristián TSiesjö BK: Calcium in ischemic cell death. Stroke 29:7057181998

51

Kunz ADirnagl UMergenthaler P: Acute pathophysiological processes after ischaemic and traumatic brain injury. Best Pract Res Clin Anaesthesiol 24:4955092010

52

Labiche LAGrotta JC: Clinical trials for cytoprotection in stroke. NeuroRx 1:46702004

53

Lacy CRSuh DCBueno MKostis JB: Delay in presentation and evaluation for acute stroke: Stroke Time Registry for Outcomes Knowledge and Epidemiology (S.T.R.O.K.E.). Stroke 32:63692001

54

Lampl YBoaz MGilad RLorberboym MDabby RRapoport A: Minocycline treatment in acute stroke: an open-label, evaluator-blinded study. Neurology 69:140414102007

55

Lees KRAsplund KCarolei ADavis SMDiener HCKaste M: Glycine antagonist (gavestinel) in neuroprotection (GAIN International) in patients with acute stroke: a randomised controlled trial. Lancet 355:194919542000

56

Liu FYuan RBenashski SEMcCullough LD: Changes in experimental stroke outcome across the life span. J Cereb Blood Flow Metab 29:7928022009

57

Liu SZhen GMeloni BPCampbell KWinn HR: Rodent stroke model guidelines for preclinical stroke trials (1st edition). J Exp Stroke Transl Med 2:2272009

58

Lo EH: Experimental models, neurovascular mechanisms and translational issues in stroke research. Br J Pharmacol 153:Suppl 1S396S4052008

59

Lo EH: A new penumbra: transitioning from injury into repair after stroke. Nat Med 14:4975002008

60

Lo EHDalkara TMoskowitz MA: Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci 4:3994152003

61

Lyden PShuaib ANg KLevin KAtkinson RPRajput A: Clomethiazole Acute Stroke Study in ischemic stroke (CLASS-I): final results. Stroke 33:1221282002

62

Macleod MRO'Collins THorky LLHowells DWDonnan GA: Systematic review and metaanalysis of the efficacy of FK506 in experimental stroke. J Cereb Blood Flow Metab 25:7137212005

63

MacManus JPBuchan AM: Apoptosis after experimental stroke: fact or fashion?. J Neurotrauma 17:8999142000

64

Madden KPClark WMZivin JA: Delayed therapy of experimental ischemia with competitive N-methyl-D-aspartate antagonists in rabbits. Stroke 24:106810711993

65

Maeda MFuruichi YNoto TMatsuoka NMutoh SYoneda Y: Tacrolimus (FK506) suppresses rt-PA-induced hemorrhagic transformation in a rat thrombotic ischemia stroke model. Brain Res 1254:991082009

66

Marshall JWCross AJRidley RM: Functional benefit from clomethiazole treatment after focal cerebral ischemia in a nonhuman primate species. Exp Neurol 156:1211291999

67

Mauler FHorváth E: Neuroprotective efficacy of repinotan HCl, a 5-HT1A receptor agonist, in animal models of stroke and traumatic brain injury. J Cereb Blood Flow Metab 25:4514592005

68

McCullough LDAlkayed NJTraystman RJWilliams MJHurn PD: Postischemic estrogen reduces hypoperfusion and secondary ischemia after experimental stroke. Stroke 32:7968022001

69

Meadows MEFisher MMinematsu K: Delayed treatment with a noncompetitive nmda antagonist, CNS-1102, reduces infarct size in rats. Cerebrovasc Dis 4:26311994

70

Meden POvergaard KPedersen HBoysen G: Effect of early treatment with tirilazad (u74006f) combined with delayed thrombolytic therapy in rat embolic stroke. Cerebrovasc Dis 6:1411481996

71

Mizoguchi HLeitermann RJNarita MNagase HSuzuki TTseng LF: Region-dependent G-protein activation by kappa-opioid receptor agonists in the mouse brain. Neurosci Lett 356:1451472004

72

Muir KW: Magnesium in stroke treatment. Postgrad Med J 78:6416452002

73

Nakamura HStrong AJDohmen CSakowitz OWVollmar SSué M: Spreading depolarizations cycle around and enlarge focal ischaemic brain lesions. Brain 133:199420062010

74

Nakanishi HWu Z: Microglia-aging: roles of microglial lysosome- and mitochondria-derived reactive oxygen species in brain aging. Behav Brain Res 201:172009

75

Nakase TMaeda TYoshida YNagata K: Ischemia alters the expression of connexins in the aged human brain. J Biomed Biotechnol 2009:1479462009

76

North American Glycine Antagonist in Neuroprotection (GAIN) Investigators: Phase II studies of the glycine antagonist GV150526 in acute stroke: the North American experience. Stroke 31:3583652000

77

Nuttall MELee DMcLaughlin BErhardt JA: Selective inhibitors of apoptotic caspases: implications for novel therapeutic strategies. Drug Discov Today 6:85912001

78

O'Collins VEMacleod MRDonnan GAHorky LLvan der Worp BHHowells DW: 1,026 experimental treatments in acute stroke. Ann Neurol 59:4674772006

79

Orset CHaelewyn BVivien KVivien DYoung ARRodent models of thromboembolic stroke. Dirnagl U: Rodent Models of Stroke New YorkSpringer2010. 47:5570

80

Pettigrew LCKasner SEAlbers GWGorman MGrotta JCSherman DG: Safety and tolerability of arundic acid in acute ischemic stroke. J Neurol Sci 251:50562006

81

Pilegaard KLadefoged O: Total number of astrocytes in the molecular layer of the dentate gyrus of rats at different ages. Anal Quant Cytol Histol 18:2792851996

82

Popa-Wagner ACarmichael STKokaia ZKessler CWalker LC: The response of the aged brain to stroke: too much, too soon?. Curr Neurovasc Res 4:2162272007

83

Robertson GSCrocker SJNicholson DWSchulz JB: Neuroprotection by the inhibition of apoptosis. Brain Pathol 10:2832922000

84

Roda JMCarceller FDíez-Tejedor EAvendaño C: Reduction of infarct size by intra-arterial nimodipine administered at reperfusion in a rat model of partially reversible brain focal ischemia. Stroke 26:188818921995

85

Rosen CLDinapoli VANagamine TCrocco T: Influence of age on stroke outcome following transient focal ischemia. J Neurosurg 103:6876942005

86

Rossi DJBrady JDMohr C: Astrocyte metabolism and signaling during brain ischemia. Nat Neurosci 10:137713862007

87

Saver JLKidwell CEckstein MStarkman S: Prehospital neuroprotective therapy for acute stroke: results of the Field Administration of Stroke Therapy-Magnesium (FASTMAG) pilot trial. Stroke 35:e106e1082004

88

Savitz SI: A critical appraisal of the NXY-059 neuroprotection studies for acute stroke: a need for more rigorous testing of neuroprotective agents in animal models of stroke. Exp Neurol 205:20252007

89

Semkova IWolz PKrieglstein J: Neuroprotective effect of 5-HT1A receptor agonist, Bay X 3702, demonstrated in vitro and in vivo. Eur J Pharmacol 359:2512601998

90

Shuaib AHussain MS: The past and future of neuroprotection in cerebral ischaemic stroke. Eur Neurol 59:4142008

91

Shuaib AIjaz SKanthan R: Clomethiazole protects the brain in transient forebrain ischemia when used up to 4 h after the insult. Neurosci Lett 197:1091121995

92

Shuaib ALees KRLyden PGrotta JDavalos ADavis SM: NXY-059 for the treatment of acute ischemic stroke. N Engl J Med 357:5625712007

93

Siesjö BK: Pathophysiology and treatment of focal cerebral ischemia. Part I: Pathophysiology. J Neurosurg 77:1691841992

94

Smith WS: Pathophysiology of focal cerebral ischemia: a therapeutic perspective. J Vasc Interv Radiol 15:S3S122004

95

Sorbera LACastaner JCastaner RM: Arundic acid. Drugs Future 29:4414492004

96

Stankowski JNGupta R: Therapeutic targets for neuroprotection in acute ischemic stroke: lost in translation?. Antioxid Redox Signal 14:184118512011

97

Starkov AAChinopoulos CFiskum G: Mitochondrial calcium and oxidative stress as mediators of ischemic brain injury. Cell Calcium 36:2572642004

98

Stroke Therapy Academic Industry Roundtable (STAIR): Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke 30:275227581999

99

Suzuki MSasamata MMiyata K: Neuroprotective effects of YM872 coadministered with t-PA in a rat embolic stroke model. Brain Res 959:1691722003

100

Switzer JAHess DCErgul AWaller JLMachado LSPortik-Dobos V: Matrix metalloproteinase-9 in an exploratory trial of intravenous minocycline for acute ischemic stroke. Stroke 42:263326352011

101

Takamatsu HTsukada HNoda AKakiuchi TNishiyama SNishimura S: FK506 attenuates early ischemic neuronal death in a monkey model of stroke. J Nucl Med 42:183318402001

102

Takano TOberheim NCotrina MLNedergaard M: Astrocytes and ischemic injury. Stroke 40:3 SupplS8S122009

103

Tateishi NMori TKagamiishi YSatoh SKatsube NMorikawa E: Astrocytic activation and delayed infarct expansion after permanent focal ischemia in rats. Part II: suppression of astrocytic activation by a novel agent (R)-(-) -2-propyloctanoic acid (ONO-2506) leads to mitigation of delayed infarct expansion and early improvement of neurologic deficits. J Cereb Blood Flow Metab 22:7237342002

104

Teal PDavis SHacke WKaste MLyden PDFierus M: A randomized, double-blind, placebo-controlled trial to evaluate the efficacy, safety, tolerability, and pharmacokinetic/pharmacodynamic effects of a targeted exposure of intravenous repinotan in patients with acute ischemic stroke: modified Randomized Exposure Controlled Trial (mRECT). Stroke 40:351835252009

105

Tirilazad International Steering Committee: Tirilazad mesylate in acute ischemic stroke: a systematic review. Stroke 31:225722652000. (Erratum in Stroke 32:279 2001)

106

Toung TJTraystman RJHurn PD: Estrogen-mediated neuroprotection after experimental stroke in male rats. Stroke 29:166616701998

107

Tripathy DYin XSanchez ALuo JMartinez JGrammas P: Cerebrovascular expression of proteins related to inflammation, oxidative stress and neurotoxicity is altered with aging. J Neuroinflammation 7:632010

108

Vibulsresth SDietrich WDBusto RGinsberg MD: Failure of nimodipine to prevent ischemic neuronal damage in rats. Stroke 18:2102161987

109

Viscoli CMBrass LMKernan WNSarrel PMSuissa SHorwitz RI: A clinical trial of estrogen-replacement therapy after ischemic stroke. N Engl J Med 345:124312492001

110

Wang QTang XNYenari MA: The inflammatory response in stroke. J Neuroimmunol 184:53682007

111

Wang XHan WDu XZhu CCarlsson YMallard C: Neuroprotective effect of Bax-inhibiting peptide on neonatal brain injury. Stroke 41:205020552010

112

Weiser T: AMPA receptor antagonists for the treatment of stroke. Curr Drug Targets CNS Neurol Disord 4:1531592005

113

Yang YLi QAhmad FShuaib A: Survival and histological evaluation of therapeutic window of post-ischemia treatment with magnesium sulfate in embolic stroke model of rat. Neurosci Lett 285:1191222000

114

Yenari MAKunis DSun GHOnley DWatson LTurner S: Hu23F2G, an antibody recognizing the leukocyte CD11/CD18 integrin, reduces injury in a rabbit model of transient focal cerebral ischemia. Exp Neurol 153:2232331998

115

Zipfel GJBabcock DJLee JMChoi DW: Neuronal apoptosis after CNS injury: the roles of glutamate and calcium. J Neurotrauma 17:8578692000

116

Zonta MAngulo MCGobbo SRosengarten BHossmann KAPozzan T: Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nat Neurosci 6:43502003

TrendMD

Cited By

Metrics

Metrics

All Time Past Year Past 30 Days
Abstract Views 111 111 36
Full Text Views 144 144 12
PDF Downloads 71 71 5
EPUB Downloads 0 0 0

PubMed

Google Scholar