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October 1996, Vol 53, No. 10 >
Article | October 1996

The Validity of Rodent Brain-Ischemia Models Is Self-evident

Myron D. Ginsberg, MD
Arch Neurol. 1996;53(10):1065-1067. doi:10.1001/archneur.1996.00550100151024
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Comments

The point of contention implicit in the title of this article would, at first glance, appear to have little basis in reality. To challenge the validity of rodent studies of brain ischemia would seem on a par, for example, with questioning whether primate kidney cell cultures are a valid model for cultivating the human poliomyelitis virus.1 A vast body of scientific literature spanning more than 3 decades attests to the utility of the rodent brain in modeling ischemic-anoxic injury.2 Certain truths deserve emphasis here. As discomfiting as this may appear to certain members of our highly evolved species, it is nonetheless firmly established that there is a very high degree of genetic homology between humans and rodents.3 Thus, the use of rodents to study genes, messages, enzymes, second messengers, receptors, and neurotransmitters would be expected to lead to insights more relevant than not to the human brain.

REFERENCES

1 +
Paul JR. A History of Poliomyelitis. New Haven, Conn: Yale University Press.
2 +
Ginsberg MD, Busto R.  Progress review: rodent models of cerebral ischemia . Stroke . 1989;;20:1627-1642.
3 +
Rabin M, Ferguson-Smith A, Hart CP, Ruddle F.  Cognate homeo-box loci mapped on homologous human and mouse chromosomes . Proc Natl Acad Sci USA . 1986;;83:9104-9108.
4 +
Purves MJ. The Physiology of the Cerebral Circulation . Cambridge, England: Cambridge University Press; 1972;:1-420.
5 +
Siesjö BK. Brain Energy Metabolism . Chichester, NY: John Wiley & Sons Inc; 1978;:1-607.
6 +
Siesjö BK.  Cell damage in the brain: a speculative synthesis . J Cereb Blood Flow Metab . 1981;; 1:155-185.
7 +
Sakurada O, Kennedy C, Jehle J, Brown JD, Carbin GL, Sokoloff L.  Measurement of local cerebral blood flow with iodo (14C) antipyrine . Am J Physiol . 1978;;234:H59-H66.
8 +
Sokoloff L, Reivich M, Kennedy C, et al.  The (14C) deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat . J Neurochem . 1977;;28:897-916.
9 +
Zhao W, Ginsberg MD, Smith DW.  Three-dimensional quantitative autoradiography by disparity analysis: theory and application to image-averaging of local cerebral glucose utilization . J Cereb Blood Flow Metab . 1995;;15:552-565.
10 +
Smith CB, Deibler GE, Eng N, Schmidt K, Sokoloff L.  Measurement of local cerebral protein synthesis in vivo: influence of recycling of amino acids derived from protein degradation . Proc Natl Acad Sci USA . 1988;;85:9341-9345.
11 +
Mazziotta JC, Phelps ME.  Positron emission tomography studies of the brain . In: Phelps ME, Mazziotta JC, Schelbert HR, eds. Positron Emission Tomography and Autoradiography: Principles and Applications for the Brain and Heart . New York, NY: Raven Press; 1986;:chap 11.
12 +
Choi DW.  Excitotoxic cell death . J Neurobiol . 1992;; 23:1261-1276.
13 +
Rothman SM, Olney JW.  Glutamate and the pathophysiology of hypoxic-ischemic brain damage . Ann Neurol . 1986;;19:105-111.
14 +
Benveniste H.  The excitotoxin hypothesis in relation to cerebral ischemia . Cerebrovasc Brain Metab Rev . 1991;;3:213-245.
15 +
Siesjö BK, Rengtsson F.  Calcium fluxes, calcium antagonists, and calcium-related pathology in brain ischemia, hypoglycemia, and spreading depression: a unifying hypothesis . J Cereb Blood Flow Metab . 1989;;9:127-140.
16 +
Watson BD, Ginsberg MD.  Ischemic injury in the brain: role of oxygen radical-mediated processes . Ann N Y Acad Sci . 1989;;559:269-281.
17 +
Siesjö BK, Agardh C-D, Bengtsson F.  Free radicals and brain damage . Cerebrovasc Brain Metab Rev . 1989;;1:165-211.
18 +
Ginsberg MD.  Neuroprotection in brain ischemia—an update—parts I and II . Neuroscientist . 1995;;1:95-103, 164-175.
19 +
Buchan AM.  Do NMDA antagonists protect against cerebral ischemia? are clinical trials warranted? Cerebrovasc Brain Metab Rev . 1990;;2:1-26.
20 +
Albers GW.  Potential therapeutic uses of N-methyl-d-aspartate antagonists in cerebral ischemia . Clin Neuropharmacol . 1990;;13:177-197.
21 +
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;;6:225-256.
22 +
Valentino K, Newcomb R, Gadbois T, et al.  A selective N-type calcium channel antagonist protects against neuronal loss after global cerebral ischemia . Proc Natl Acad Sci USA . 1993;;90:7894-7897.
23 +
Busto R, Dietrich WD, Globus MY-T, Valdes I, Scheinberg P, Ginsberg MD.  Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury . J Cereb Blood Flow Metab . 1987;;7:729-738.
24 +
Ginsberg MD, Sternau LL, Globus MY-T, Dietrich WD, Busto R.  Therapeutic modulation of brain temperature: relevance to ischemic brain injury . Cerebrovasc Brain Metab Rev . 1992;;4:189-225.
25 +
Kinouchi H, Epstein CJ, Mizui T, Carlson E, Chen SF, Chan PH.  Attenuation of focal cerebral ischemic injury in transgenic mice overexpressing CuZn superoxide dismutase . Proc Natl Acad Sci USA . 1991;;88:11158-11162.
26 +
Traystman RJ.  The goal of animal welfare, animal 'rights,' and antivivisectionist groups in the United States . J Neurosurg Anesthesiol . 1990;; 2:153-158.
27 +
Ginsberg MD.  The concept of the therapeutic window: a synthesis of critical issues . In: Moskowitz MA, Caplan LR, eds. Cerebrovascular Diseases—Nineteenth Princeton Stroke Conference . Newton, Mass: Butterworth-Heinemann; 1995;: 331-351.
28 +
Ginsberg MD, Pulsinelli WA.  Editorial: The ischemic penumbra, injury thresholds, and the therapeutic window for acute stroke . Ann Neurol . 1994;; 36:553-554.
29 +
Heiss W-D, Rosner G.  Functional recovery of cortical neurons as related to degree and duration of ischemia . Ann Neurol . 1983;;14:294-301.
30 +
Jones TH, Morawetz RB, Crowell RM, et al.  Thresholds of focal cerebral ischemia in awake monkeys . J Neurosurg . 1981;;54:773-782.
31 +
Kaplan B, Brint S, Tanabe J, Jacewicz M, Wang X-J, Pulsinelli W.  Temporal thresholds for neocortical infarction in rats subjected to reversible focal cerebral ischemia . Stroke . 1991;;22:1032-1039.
32 +
Buchan AM, Xue D, Slivka A.  A new model of temporary focal neocortical ischemia in the rat . Stroke . 1992;;23:273-279.
33 +
Wiebers DO, Adams HP Jr, Whisnant JP.  Editorial: Animal models of stroke: are they relevant to human disease? Stroke . 1990;;21:1-3.
34 +
Millikan C.  Animal stroke models . Stroke . 1992;; 23:795-797.
35 +
Coyle P.  Different susceptibilities to cerebral infarction in spontaneously hypertensive (SHR) and normotensive Sprague-Dawley rats . Stroke . 1986;; 17:520-525.
36 +
Baumbach GL, Dobrin PB, Hart MN, Heistad DD.  Mechanics of cerebral arterioles in hypertensive rats . Circ Res . 1988;;62:56-64.
37 +
Armstrong ML, Heistad DD.  Animal models of atherosclerosis . Atherosclerosis . 1990;;85:15-23.
38 +
Huang Z, Huang PL, Panahian N, Dalkara T, Fishman MC, Moskowitz MA.  Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase . Science . 1994;;265:1883-1885.
39 +
Markgraf CG, Kraydieh S, Prado R, Watson BD, Dietrich WD, Ginsberg MD.  Comparative histopathologic consequences of photothrombotic occlusion of the distal middle cerebral artery in Sprague-Dawley and Wistar rats . Stroke . 1993;; 24:286-292.
40 +
Yao H, Ginsberg MD, Watson BD, et al.  Failure of MK-801 to reduce infarct volume in thrombotic middle cerebral artery occlusion in rats . Stroke . 1993;;24:864-871.
41 +
Helfaer MA, Kirsch JR, Traystman RJ.  Anesthetic modulation of cerebral hemodynamic and evoked responses to transient middle cerebral artery occlusion in cats . Stroke . 1990;;21:795-800.
42 +
Mohamed AA, Gotoh O, Graham DI, et al.  Effect of pretreatment with the calcium antagonist nimodipine on local cerebral blood flow and histopathology after middle cerebral artery occlusion . Ann Neurol . 1985;;18:705-711.
43 +
Gotoh O, Mohamed AA, McCulloch J, Graham DI, Harper AM, Teasdale GM.  Nimodipine and the haemodynamic and histopathological consequences of middle cerebral artery occlusion in the rat . J Cereb Blood Flow Metab . 1986;;6:321-331.
44 +
Germano IM, Bartkowski HM, Cassel ME, Pitts LH.  The therapeutic value of nimodipine in experimental focal cerebral ischemia: neurological outcome and histopathological findings . J Neurosurg . 1987;;67:81-87.
45 +
Gelmers HJ, Gorier K, de Weerdt CJ, Wiezer HJA.  A controlled trial of nimodipine in acute ischemic stroke . N Engl J Med . 1988;;318:203-207.
46 +
American Nimodipine Study.  Clinical trial of nimodipine in acute ischemic stroke . Stroke . 1992;; 23:3-8.
47 +
 Major ongoing stroke trials . Stroke . 1994;;25:541-545.
48 +
The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group.  Tissue plasminogen activator for acute ischemic stroke . N Engl J Med . 1995;;333:1581-1587.
49 +
Ringelstein EB, Biniek R, Weiller C, Ammeling B, Nolte PN, Thron A.  Type and extent of hemispheric brain infarctions and clinical outcome in early and delayed middle cerebral artery recanalization . Neurology . 1992;;42:289-298.
50 +
Pulsinelli WA, Buchan A.  The utility of animal ischemia models in predicting pharmacotherapeutic response in the clinical setting . In: Ginsberg MD, Dietrich WD, eds. Cerebrovascular Diseases—Sixteenth Research (Princeton) Conference . New York, NY: Raven Press; 1989;: 87-91.
51 +
Hsu CY.  Criteria for valid preclinical trials using animal stroke models . Stroke . 1993;;24:633-636.
52 +
Zivin JA, Grotta JC.  Editorial: Animal stroke models: they are relevant to human disease . Stroke . 1990;;21:981-983.

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1 +
Paul JR. A History of Poliomyelitis. New Haven, Conn: Yale University Press.
2 +
Ginsberg MD, Busto R.  Progress review: rodent models of cerebral ischemia . Stroke . 1989;;20:1627-1642.
3 +
Rabin M, Ferguson-Smith A, Hart CP, Ruddle F.  Cognate homeo-box loci mapped on homologous human and mouse chromosomes . Proc Natl Acad Sci USA . 1986;;83:9104-9108.
4 +
Purves MJ. The Physiology of the Cerebral Circulation . Cambridge, England: Cambridge University Press; 1972;:1-420.
5 +
Siesjö BK. Brain Energy Metabolism . Chichester, NY: John Wiley & Sons Inc; 1978;:1-607.
6 +
Siesjö BK.  Cell damage in the brain: a speculative synthesis . J Cereb Blood Flow Metab . 1981;; 1:155-185.
7 +
Sakurada O, Kennedy C, Jehle J, Brown JD, Carbin GL, Sokoloff L.  Measurement of local cerebral blood flow with iodo (14C) antipyrine . Am J Physiol . 1978;;234:H59-H66.
8 +
Sokoloff L, Reivich M, Kennedy C, et al.  The (14C) deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat . J Neurochem . 1977;;28:897-916.
9 +
Zhao W, Ginsberg MD, Smith DW.  Three-dimensional quantitative autoradiography by disparity analysis: theory and application to image-averaging of local cerebral glucose utilization . J Cereb Blood Flow Metab . 1995;;15:552-565.
10 +
Smith CB, Deibler GE, Eng N, Schmidt K, Sokoloff L.  Measurement of local cerebral protein synthesis in vivo: influence of recycling of amino acids derived from protein degradation . Proc Natl Acad Sci USA . 1988;;85:9341-9345.
11 +
Mazziotta JC, Phelps ME.  Positron emission tomography studies of the brain . In: Phelps ME, Mazziotta JC, Schelbert HR, eds. Positron Emission Tomography and Autoradiography: Principles and Applications for the Brain and Heart . New York, NY: Raven Press; 1986;:chap 11.
12 +
Choi DW.  Excitotoxic cell death . J Neurobiol . 1992;; 23:1261-1276.
13 +
Rothman SM, Olney JW.  Glutamate and the pathophysiology of hypoxic-ischemic brain damage . Ann Neurol . 1986;;19:105-111.
14 +
Benveniste H.  The excitotoxin hypothesis in relation to cerebral ischemia . Cerebrovasc Brain Metab Rev . 1991;;3:213-245.
15 +
Siesjö BK, Rengtsson F.  Calcium fluxes, calcium antagonists, and calcium-related pathology in brain ischemia, hypoglycemia, and spreading depression: a unifying hypothesis . J Cereb Blood Flow Metab . 1989;;9:127-140.
16 +
Watson BD, Ginsberg MD.  Ischemic injury in the brain: role of oxygen radical-mediated processes . Ann N Y Acad Sci . 1989;;559:269-281.
17 +
Siesjö BK, Agardh C-D, Bengtsson F.  Free radicals and brain damage . Cerebrovasc Brain Metab Rev . 1989;;1:165-211.
18 +
Ginsberg MD.  Neuroprotection in brain ischemia—an update—parts I and II . Neuroscientist . 1995;;1:95-103, 164-175.
19 +
Buchan AM.  Do NMDA antagonists protect against cerebral ischemia? are clinical trials warranted? Cerebrovasc Brain Metab Rev . 1990;;2:1-26.
20 +
Albers GW.  Potential therapeutic uses of N-methyl-d-aspartate antagonists in cerebral ischemia . Clin Neuropharmacol . 1990;;13:177-197.
21 +
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;;6:225-256.
22 +
Valentino K, Newcomb R, Gadbois T, et al.  A selective N-type calcium channel antagonist protects against neuronal loss after global cerebral ischemia . Proc Natl Acad Sci USA . 1993;;90:7894-7897.
23 +
Busto R, Dietrich WD, Globus MY-T, Valdes I, Scheinberg P, Ginsberg MD.  Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury . J Cereb Blood Flow Metab . 1987;;7:729-738.
24 +
Ginsberg MD, Sternau LL, Globus MY-T, Dietrich WD, Busto R.  Therapeutic modulation of brain temperature: relevance to ischemic brain injury . Cerebrovasc Brain Metab Rev . 1992;;4:189-225.
25 +
Kinouchi H, Epstein CJ, Mizui T, Carlson E, Chen SF, Chan PH.  Attenuation of focal cerebral ischemic injury in transgenic mice overexpressing CuZn superoxide dismutase . Proc Natl Acad Sci USA . 1991;;88:11158-11162.
26 +
Traystman RJ.  The goal of animal welfare, animal 'rights,' and antivivisectionist groups in the United States . J Neurosurg Anesthesiol . 1990;; 2:153-158.
27 +
Ginsberg MD.  The concept of the therapeutic window: a synthesis of critical issues . In: Moskowitz MA, Caplan LR, eds. Cerebrovascular Diseases—Nineteenth Princeton Stroke Conference . Newton, Mass: Butterworth-Heinemann; 1995;: 331-351.
28 +
Ginsberg MD, Pulsinelli WA.  Editorial: The ischemic penumbra, injury thresholds, and the therapeutic window for acute stroke . Ann Neurol . 1994;; 36:553-554.
29 +
Heiss W-D, Rosner G.  Functional recovery of cortical neurons as related to degree and duration of ischemia . Ann Neurol . 1983;;14:294-301.
30 +
Jones TH, Morawetz RB, Crowell RM, et al.  Thresholds of focal cerebral ischemia in awake monkeys . J Neurosurg . 1981;;54:773-782.
31 +
Kaplan B, Brint S, Tanabe J, Jacewicz M, Wang X-J, Pulsinelli W.  Temporal thresholds for neocortical infarction in rats subjected to reversible focal cerebral ischemia . Stroke . 1991;;22:1032-1039.
32 +
Buchan AM, Xue D, Slivka A.  A new model of temporary focal neocortical ischemia in the rat . Stroke . 1992;;23:273-279.
33 +
Wiebers DO, Adams HP Jr, Whisnant JP.  Editorial: Animal models of stroke: are they relevant to human disease? Stroke . 1990;;21:1-3.
34 +
Millikan C.  Animal stroke models . Stroke . 1992;; 23:795-797.
35 +
Coyle P.  Different susceptibilities to cerebral infarction in spontaneously hypertensive (SHR) and normotensive Sprague-Dawley rats . Stroke . 1986;; 17:520-525.
36 +
Baumbach GL, Dobrin PB, Hart MN, Heistad DD.  Mechanics of cerebral arterioles in hypertensive rats . Circ Res . 1988;;62:56-64.
37 +
Armstrong ML, Heistad DD.  Animal models of atherosclerosis . Atherosclerosis . 1990;;85:15-23.
38 +
Huang Z, Huang PL, Panahian N, Dalkara T, Fishman MC, Moskowitz MA.  Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase . Science . 1994;;265:1883-1885.
39 +
Markgraf CG, Kraydieh S, Prado R, Watson BD, Dietrich WD, Ginsberg MD.  Comparative histopathologic consequences of photothrombotic occlusion of the distal middle cerebral artery in Sprague-Dawley and Wistar rats . Stroke . 1993;; 24:286-292.
40 +
Yao H, Ginsberg MD, Watson BD, et al.  Failure of MK-801 to reduce infarct volume in thrombotic middle cerebral artery occlusion in rats . Stroke . 1993;;24:864-871.
41 +
Helfaer MA, Kirsch JR, Traystman RJ.  Anesthetic modulation of cerebral hemodynamic and evoked responses to transient middle cerebral artery occlusion in cats . Stroke . 1990;;21:795-800.
42 +
Mohamed AA, Gotoh O, Graham DI, et al.  Effect of pretreatment with the calcium antagonist nimodipine on local cerebral blood flow and histopathology after middle cerebral artery occlusion . Ann Neurol . 1985;;18:705-711.
43 +
Gotoh O, Mohamed AA, McCulloch J, Graham DI, Harper AM, Teasdale GM.  Nimodipine and the haemodynamic and histopathological consequences of middle cerebral artery occlusion in the rat . J Cereb Blood Flow Metab . 1986;;6:321-331.
44 +
Germano IM, Bartkowski HM, Cassel ME, Pitts LH.  The therapeutic value of nimodipine in experimental focal cerebral ischemia: neurological outcome and histopathological findings . J Neurosurg . 1987;;67:81-87.
45 +
Gelmers HJ, Gorier K, de Weerdt CJ, Wiezer HJA.  A controlled trial of nimodipine in acute ischemic stroke . N Engl J Med . 1988;;318:203-207.
46 +
American Nimodipine Study.  Clinical trial of nimodipine in acute ischemic stroke . Stroke . 1992;; 23:3-8.
47 +
 Major ongoing stroke trials . Stroke . 1994;;25:541-545.
48 +
The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group.  Tissue plasminogen activator for acute ischemic stroke . N Engl J Med . 1995;;333:1581-1587.
49 +
Ringelstein EB, Biniek R, Weiller C, Ammeling B, Nolte PN, Thron A.  Type and extent of hemispheric brain infarctions and clinical outcome in early and delayed middle cerebral artery recanalization . Neurology . 1992;;42:289-298.
50 +
Pulsinelli WA, Buchan A.  The utility of animal ischemia models in predicting pharmacotherapeutic response in the clinical setting . In: Ginsberg MD, Dietrich WD, eds. Cerebrovascular Diseases—Sixteenth Research (Princeton) Conference . New York, NY: Raven Press; 1989;: 87-91.
51 +
Hsu CY.  Criteria for valid preclinical trials using animal stroke models . Stroke . 1993;;24:633-636.
52 +
Zivin JA, Grotta JC.  Editorial: Animal stroke models: they are relevant to human disease . Stroke . 1990;;21:981-983.

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