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Incomplete Assessment of Experimental Cytoprotectants in Rodent Ischemia Studies

Published online by Cambridge University Press:  02 December 2014

Suzanne B. DeBow
Affiliation:
Department of Psychology and Center for Neuroscience, University of Alberta, Edmonton, Alberta, Canada
Darren L. Clark
Affiliation:
Department of Psychology and Center for Neuroscience, University of Alberta, Edmonton, Alberta, Canada
Crystal L. MacLellan
Affiliation:
Department of Psychology and Center for Neuroscience, University of Alberta, Edmonton, Alberta, Canada
Frederick Colbourne
Affiliation:
Department of Psychology and Center for Neuroscience, University of Alberta, Edmonton, Alberta, Canada
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Abstract

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Background:

Inadequate preclinical testing (e.g., rodent studies) has been partly blamed for the failure of many cytoprotectants to effectively treat stroke in humans. For example, some drugs went to clinical trial without rigorous functional and histological assessment over long survival times. In this study, we characterized recent experimental practices in rodent cytoprotection experiments to determine whether the limitations of early studies have been rectified.

Methods:

We identified 138 rodent cytoprotection studies published in several leading journals (Journal of Neuroscience, Stroke, Journal of Cerebral Blood Flow and Metabolism and Experimental Neurology) for 2000 - 2002 and compared these to those published in 1990. From each study we determined the ischemia model, age and sex of the animal, the histological and functional endpoints used, and the methodology used to assess intra- and postischemic temperature.

Results:

Ninety-eight percent of recent studies used young adult rodents and most used males. Most studies (60%) did not assess functional outcome and survival times were often ≤ 48 hr (66%) for focal ischemia and ≤ 7 days (80%) for global ischemia. Over 60% of the experiments relied solely upon rectal temperature during ischemia and only 32.6% of ischemia studies measured temperature after surgery. The 1990 data were similar.

Conclusion:

Many investigators ignore the need to assess long-term functional and histological outcome and do not accurately represent clinical conditions of ischemia (e.g., use of aged animals). In addition, intra- and postischemic temperature measurement and control is frequently neglected or inadequately performed. Further clinical failures are likely.

Résumé:

RÉSUMÉ: Introduction:

Une évaluation préclinique inadéquate (i.e. études chez les rongeurs) semble en partie responsable de l'inefficacité de plusieurs cytoprotecteurs pour traiter l'accident vasculaire cérébral chez l'humain. À titre d'exemple, certains médicaments ont atteint la phase des essais thérapeutiques sans évaluation fonctionnelle et histologique rigoureuse à long terme. Dans cette étude, nous décrivons les pratiques expérimentales actuelles au cours d'évaluations de cytoprotection chez les rongeurs pour déterminer si les lacunes des études antérieures ont été corrigées.

Méthodes:

Nous avons identifié 138 études de cytoprotection chez des rongeurs publiées dans plusieurs journaux prestigieux (Journal of Neuroscience, Stroke, Journal of Cerebral Blood Flow and Metabolism et Experimental Neurology) de 2000 à 2002 et nous les avons comparées à celles publiées en 1990. Pour chaque étude, nous avons examiné le modèle d'ischémie, l'âge et le sexe des animaux, les critères d'évaluation histologiques et fonctionnels et la méthodologie utilisée pour évaluer la température infra et postischémie.

Résultats:

Quatre-vingt-dix pour cent des études portaient sur de jeunes rongeurs adultes et la plupart étaient des mâles. La plupart des études (60%) n'évaluaient pas l'issue fonctionnelle et le temps de survie était souvent de £ 48 heures (66%) pour l'ischémie focale et de £ 7 jours (80%) pour l'ischémie globale. Plus de 60% des études étaient basées uniquement sur la température rectale pendant l'ischémie et seulement 32.6% des études mesuraient la température après la chirurgie. Les données de 1990 étaient semblables.

Conclusions:

Plusieurs chercheurs ignorent l'importance d'évaluer les résultats fonctionnels et histologiques à long terme et ne reproduisent pas avec exactitude les conditions cliniques de l'ischémie (i.e., utilisation d'animaux âgés). De plus, la mesure et le contrôle de la température infra et postischémie sont souvent négligés ou faits de façon inadéquate. D'autres échecs cliniques sont à prévoir.

Type
Experimental Neurosciences
Copyright
Copyright © The Canadian Journal of Neurological 2003

References

1. Gladstone, DJ, Black, SE Hakim AM. Toward wisdom from failure:lessons from neuroprotective stroke trials and new therapeutic directions. Stroke 2002;33:21232136.CrossRefGoogle ScholarPubMed
2. Corbett, D, Nurse, S. The problem of assessing effective neuroprotection in experimental cerebral ischemia. Prog Neurobiol 1998;54:531548.CrossRefGoogle ScholarPubMed
3. Stroke Therapy Academic Industry Roundtable (STAIR). Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke 1999;30:27522758.CrossRefGoogle ScholarPubMed
4. DeGraba, TJ, Pettigrew, LC. Why do neuroprotective drugs work in animals but not humans? Neurol Clin 2000;18:475493.CrossRefGoogle Scholar
5. Garcia, JH, Yoshida, Y, Chen, H, et al. Progression from ischemic injury to infarct following middle cerebral artery occlusion in the rat. Am J Physiol 1993;142:623635.Google ScholarPubMed
6. Kirino, T. Delayed neuronal death in the gerbil hippocampus following ischemia. Brain Res 1982;239:5769.CrossRefGoogle ScholarPubMed
7. Pulsinelli, WA, Brierley, JB, Plum, F. Temporal profile of neuronal damage in a model of transient forebrain ischemia. Ann Neurol 1982;11:491498.CrossRefGoogle Scholar
8. Colbourne, F, Li, H, Buchan, AM. Continuing postischemic neuronal death in CA1 : influence of ischemia duration and cytoprotective doses of NBQX and SNX-111 in rats. Stroke 1999;30:662668.CrossRefGoogle ScholarPubMed
9. Garcia, JH, Liu, K-F, Ye, Z-R, Gutierrez, JA. Incomplete infarct and delayed neuronal death after transient middle cerebral artery occlusion in rats. Stroke 1997;28:23032310.CrossRefGoogle ScholarPubMed
10. Du, C, Hu, R, Csernansky CA, Hsu CY, Choi DW. Very delayed infarction after mild focal cerebral ischemia: a role for apoptosis? J Cereb Blood Flow Metab 1996;16:195201.CrossRefGoogle ScholarPubMed
11. Dietrich, WD, Busto, R, Alonso, O, Globus, MY-T, Ginsberg, MD. Intra-ischemic but not postischemic brain hypothermia protects chronically following global forebrain ischemia in rats. J Cereb Blood Flow Metab 1993;13:541549.CrossRefGoogle Scholar
12. Colbourne, F, Corbett, D. Delayed postischemic hypothermia: a six month survival study using behavioural and histological assessments of neuroprotection. J Neurosci 1995;15:72507260.Google ScholarPubMed
13. Valtysson, J, Hillered, L, Andine, P, Hagberg, H, Persson, L. Neuropathological endpoints in experimental stroke pharmacotherapy: the importance of both early and late evaluation. Acta Neurochir (Wien) 1994;129:5863.CrossRefGoogle ScholarPubMed
14. Wang, F, Corbett, D, Osuga, H, et al. Inhibition of cyclin-dependent kinases improves CA1 neuronal survival and behavioural performance after global ischemia in the rat. J Cereb Blood Flow Metab 2002;22:171182.CrossRefGoogle ScholarPubMed
15. Wahl, F, Allix, M, Plotkine, M, Boulu, RG. Neurological and behavioural outcomes of focal cerebral ischemia in rats. Stroke 1992;23:267272.CrossRefGoogle ScholarPubMed
16. Cregan, EF, Peeling, J, Corbett, D, et al. [(s)-alpha-phenyl-2-pyridine- ethanamine dihyrdochloride], a low affinity uncompetitive N-methly-D-aspartic acid antagonist, is effective in rodent models of global and focal ischemia. J Pharm Exp Therap 1997;283:14121424.Google Scholar
17. Whishaw, IQ. Loss of the innate cortical engram for action patterns used in skilled reaching and the development of behavioural compensation following motor cortex lesions in the rat. Neuropharmacology 2000;39:788805.CrossRefGoogle ScholarPubMed
18. Duverger, D, MacKenzie, ET. The quantification of cerebral infarction following focal ischemia in the rat: influence of strain, arterial pressure, blood glucose concentration, and age. J Cereb Blood Flow Metab 1988;8:449461.CrossRefGoogle Scholar
19. Futrell, N, Garcia, J, Peterson, E. Embolic stroke in aged rats. Stroke 1991;22:15821591.CrossRefGoogle ScholarPubMed
20. Sutherland, GR, Dix, GA, Auer, RN. Effect of age in rodent models of focal and forebrain ischemia. Stroke 1996;27:16631667.CrossRefGoogle ScholarPubMed
21. Roof, RL, Hall, ED. Gender differences in acute CNS trauma and stroke: neuroprotective effects of estrogen and progesterone. J Neurotrauma 2000;17:367388.CrossRefGoogle ScholarPubMed
22. Dietrich, WD, Busto, R, Globus, MYT, Ginsberg, MD. Brain damage and temperature: cellular and molecular mechanisms. Adv Neurol 1996;71:177194.Google ScholarPubMed
23. Colbourne, F, Sutherland, G, Corbett, D. Postischemic hypothermia: a critical appraisal with implications for clinical treatment. Mol Neurobiol 1997;14:171201.CrossRefGoogle ScholarPubMed
24. Busto, R, Dietrich, W, Globus, M-T, et al. Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury. J Cereb Blood Flow Metab 1987;7:729738.CrossRefGoogle ScholarPubMed
25. Colbourne, F, Nurse, SM, Corbett, D. Temperature changes associated with forebrain ischemia in the gerbil. Brain Res 1993;602:264267.CrossRefGoogle ScholarPubMed
26. Minamisawa, H, Mellergard, P, Smith, ML, et al. Preservation of brain temperature during ischemia in rats. Stroke 1990;21:758764.CrossRefGoogle ScholarPubMed
27. Baena, RC, Busto, R, Dietrich, WD, Globus, MY, Ginsberg, MD. Hyperthermia delayed by 24 hours aggravates neuronal damage in rat hippocampus following global ischemia. Neurology 1997;48:768773.CrossRefGoogle ScholarPubMed
28. Coimbra, C, Boris-Möller, F, Drake, M, Wieloch, T. Diminished neuronal damage in the rat brain by late treatment with the antipyretic drug dipyrone or cooling following cerebral ischemia. Acta Neuropathol 1996;92:447453.CrossRefGoogle ScholarPubMed
29. Kim, Y, Busto, R, Dietrich, WD, et al. Delayed postischemic hyperthermia in awake rats worsens the histopathological outcome of transient focal cerebral ischemia. Stroke 1996;27:22742281.CrossRefGoogle ScholarPubMed
30. Memezawa, H, Zhao, Q, Smith, ML, Siesjo, BK. Hyperthermia nullifies the ameliorating effect of dizocilpine maleate (MK-801) in focal cerebral ischemia. Brain Res 1995;670:4852.CrossRefGoogle Scholar
31. Reglodi, D, Somogyvari-Vigh, A, Maderdrut, JL, Vigh, S, Arimura, A. Postischemic spontaneous hyperthermia and its effects in middle cerebral artery occlusion in the rat. Exp Neurol 2000;163:399407.CrossRefGoogle ScholarPubMed
32. Zhao, Q, Memezawa, H, Smith, ML, Siesjo, BK. Hyperthermia complicates middle cerebral artery occlusion induced by an intraluminal filament. Brain Res 1994;649:253259.CrossRefGoogle ScholarPubMed
33. Colbourne, F, Corbett, D. Delayed and prolonged postischemic hypothermia is neuroprotective in the gerbil. Brain Res 1994;654:265267.CrossRefGoogle Scholar
34. Hickey, RW, Ferimer, H, Alexander, HL, et al. Delayed, spontaneous hypothermia reduces neuronal damage after asphyxial cardiac arrest in rats. Crit Care Med 2000;28:35113516.CrossRefGoogle ScholarPubMed
35. Colbourne, F, Corbett, D, Zhao, Z, Yang, J, Buchan, AM. Prolonged postischemic hypothermia: a long-term outcome study in the rat middle cerebral artery occlusion model. J Cereb Blood Flow Metab 2000;20:17021708.CrossRefGoogle ScholarPubMed
36. Corbett, D, Hamilton, M, Colbourne, F. Persistent neuroprotection with prolonged postischemic hypothermia in adult rats subjected to transient middle cerebral artery occlusion. Exp Neurology 2000;163:200206.CrossRefGoogle ScholarPubMed
37. Maier, CM, Sun, GH, Kunis, D, Yenari, MA, Steinberg, GK. Delayed induction and long-term effects of mild hypothermia in a focal model of transient cerebral ischemia: neurological outcome and infarct size. J Neurosurg 2001;94:9096.CrossRefGoogle Scholar
38. Coimbra, C, Wieloch, T. Moderate hypothermia mitigates neuronal damage in the rat brain when initiated several hours following transient cerebral ischemia. Acta Neuropathol 1994;87:325331.CrossRefGoogle ScholarPubMed
39. Colbourne, F, Sutherland, GR, Auer, RN. Electron microscopic evidence against apoptosis as the mechanism of neuronal death in global ischemia. J Neurosci 1999;19:42004210.Google ScholarPubMed
40. Corbett, D, Evans, S, Thomas, C, Wang, D, Jonas, R. MK-801 reduces cerebral ischemic injury by inducing hypothermia. Brain Res 1990;514:300304.CrossRefGoogle Scholar
41. Buchan, AM, 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 1990;10:311316.Google ScholarPubMed
42. Nurse, S, Corbett, D. Neuroprotection after several days of mild, drug-induced hypothermia. J Cereb Blood Flow Metab 1996;16:474480.CrossRefGoogle ScholarPubMed
43. DeBow, S, Colbourne, F. Brain temperature measurement in awake and freely moving rodents. Methods 2003;30:167171.CrossRefGoogle ScholarPubMed
44. Colbourne, F, Li, H, Buchan, AM. Indefatigable CA1 sector neuroprotection with mild hypothermia induced 6 hours after severe forebrain ischemia in rats. J Cereb Blood Flow Metab 1999;19:742749.CrossRefGoogle ScholarPubMed
45. Corbett, D, McKay, K, Wight, V, Granter-Button, S. Effects of different postischemic temperature regulation regimens on focal ischemic outcome in the mouse. Soc Neurosci Abst 2002;28:abst.# 491.411.Google Scholar
46. Colbourne, F, Sutherland, GR, Auer, RN. An automated system for regulating brain temperature in awake and freely moving rodents. J Neurosci Meth 1996;67:185190.CrossRefGoogle ScholarPubMed
47. Clark, DL, DeBow, SB, Iseke, MD, Colbourne, F. Stress induced fever after postischemic rectal temperature measurements in the gerbil. Can J Physiol Pharmacol 2003:in press.CrossRefGoogle ScholarPubMed
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