INCLUSION CRITERIA UPDATE OF THE INTRALUMINAL ISCHEMIC MODEL IN RAT FOR PRECLINICAL STUDIES

ABSTRACTA proper occlusion of the medial cerebral artery (MCA) determined by laser Doppler during cerebral ischemia in rat models is an important inclusion criteria in experimental studies. However, a successful occlusion of the artery does not always guarantee a reproducible infarct volume which is critical to validate the efficacy of new protective drugs. In this study, we have compared the variability of infarct size in ischemic animals when the artery occlusion is monitored with laser Doppler alone and in combination with MRI during artery occlusion. Infarct volume determined at 24 hours was compared between animals with laser Doppler monitoring alone and in combination with MR angiography (MRA) and diffusion weighted images (DWI). Twenty-eight animals presented a successful occlusion and reperfusion determined by Doppler monitoring with an infarct size at 24 hours of 16.71±11.58%. However, when artery occlusion and infarct damage were analyzed in these animals by MRA and DWI, 15 animals were excluded and only 13 animals were included based on Doppler and MRI inclusion criteria, with an infarct size of 21.65±6.15% at 24 hours. These results show that laser Doppler monitoring is needed but not enough to guarantee a reproducible infarct volume in rat ischemic model.Summary statementLaser Doppler monitoring in combination with DWI and MR angiography represents a reliable inclusion protocol during ischemic surgery for the analysis of protective drugs in the acute phase of stroke.

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Neuroprotective mechanisms of erythropoietin in a rat stroke model

Translational Neuroscience ◽

10.1515/tnsci-2020-0008 ◽

2020 ◽

Vol 11 (1) ◽

pp. 48-59

Author(s):

Martin Juenemann ◽

Tobias Braun ◽

Nadine Schleicher ◽

Mesut Yeniguen ◽

Patrick Schramm ◽

...

Keyword(s):

Blood Flow ◽

Infarct Size ◽

Cerebral Edema ◽

Infarct Volume ◽

Artery Occlusion ◽

Lesion Volume ◽

Ischemic Lesion ◽

Human Erythropoietin ◽

Male Wistar Rats ◽

Cerebral Artery Occlusion

AbstractObjectiveThis study was designed to investigate the indirect neuroprotective properties of recombinant human erythropoietin (rhEPO) pretreatment in a rat model of transient middle cerebral artery occlusion (MCAO).MethodsOne hundred and ten male Wistar rats were randomly assigned to four groups receiving either 5,000 IU/kg rhEPO intravenously or saline 15 minutes prior to MCAO and bilateral craniectomy or sham craniectomy. Bilateral craniectomy aimed at elimination of the space-consuming effect of postischemic edema. Diagnostic workup included neurological examination, assessment of infarct size and cerebral edema by magnetic resonance imaging, wet–dry technique, and quantification of hemispheric and local cerebral blood flow (CBF) by flat-panel volumetric computed tomography.ResultsIn the absence of craniectomy, EPO pretreatment led to a significant reduction in infarct volume (34.83 ± 9.84% vs. 25.28 ± 7.03%; p = 0.022) and midline shift (0.114 ± 0.023 cm vs. 0.083 ± 0.027 cm; p = 0.013). We observed a significant increase in regional CBF in cortical areas of the ischemic infarct (72.29 ± 24.00% vs. 105.53 ± 33.10%; p = 0.043) but not the whole hemispheres. Infarct size-independent parameters could not demonstrate a statistically significant reduction in cerebral edema with EPO treatment.ConclusionsSingle-dose pretreatment with rhEPO 5,000 IU/kg significantly reduces ischemic lesion volume and increases local CBF in penumbral areas of ischemia 24 h after transient MCAO in rats. Data suggest indirect neuroprotection from edema and the resultant pressure-reducing and blood flow-increasing effects mediated by EPO.

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Association of Infarct Volume Before Hemicraniectomy and Outcome After Malignant Infarction

Neurology ◽

10.1212/wnl.0000000000011987 ◽

2021 ◽

pp. 10.1212/WNL.0000000000011987

Author(s):

Dominik Lehrieder ◽

Katharina Layer ◽

Hans-Peter Müller ◽

Viktoria Rücker ◽

Jan Kassubek ◽

...

Keyword(s):

Infarct Size ◽

Middle Cerebral Artery ◽

Cerebral Artery ◽

Randomized Trials ◽

Infarct Volume ◽

Unfavorable Outcome ◽

Inclusion Criteria ◽

Younger Patients ◽

Malignant Infarction ◽

The Impact

ObjectiveTo determine the impact of infarct volume before hemicraniectomy in malignant middle cerebral artery infarction (MMI) as an independent predictor for patient selection and outcome prediction, we retrospectively analyzed data of 140 patients from a prospective multi-center study.MethodsPatients from the DESTINY-Registry that underwent hemicraniectomy after ischemic infarction of >50% of the middle cerebral artery territory were included. Functional outcome according to the modified Rankin Scale (mRS) was assessed at 12 months. Unfavorable outcome was defined as mRS 4-6. Infarct size was quantified semi-automatically from computed tomography or magnetic resonance imaging before hemicraniectomy. Subgroup analyses in patients fulfilling inclusion criteria of randomized trials in younger patients (age≤60y) were predefined.ResultsAmong 140 patients with complete datasets (34% female, mean (SD) age 54 (11) years), 105 (75%) had an unfavorable outcome (mRS > 3). Mean (SD) infarct volume was 238 (63) ml. Multivariable logistic regression identified age (OR 1.08 per 1 year increase; 95%-CI 1.02-1.13; p=0.004), infarct size (OR 1.27 per 10ml increase; 95%-CI 1.12-1.44; p<0.001) and NIHSS (OR 1.10; 95%-CI 1.01-1.20; p=0.030) before hemicraniectomy as independent predictors for unfavorable outcome. Findings were reproduced in patients fulfilling inclusion criteria of randomized trials in younger patients. Infarct volume thresholds for prediction of unfavorable outcome with high specificity (94% in overall cohort and 92% in younger patients) were more than 258 ml before hemicraniectomy.ConclusionOutcome in MMI strongly depends on age and infarct size before hemicraniectomy. Standardized volumetry may be helpful in the process of decision making concerning hemicraniectomy.

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Intraventricular Brain-Derived Neurotrophic Factor Reduces Infarct Size after Focal Cerebral Ischemia in Rats

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-199705000-00003 ◽

1997 ◽

Vol 17 (5) ◽

pp. 500-506 ◽

Cited By ~ 253

Author(s):

Wolf-R. Schäbitz ◽

Stefan Schwab ◽

Matthias Spranger ◽

Werner Hacke

Keyword(s):

Cerebral Ischemia ◽

Infarct Size ◽

Middle Cerebral Artery ◽

Middle Cerebral Artery Occlusion ◽

Neurotrophic Factor ◽

Cortical Neurons ◽

Focal Cerebral Ischemia ◽

Infarct Volume ◽

Artery Occlusion ◽

Cerebral Artery Occlusion

Brain-derived neurotrophic factor (BDNF), acting through the high-affinity receptor tyrosine kinase (TrkB), is widely distributed throughout the central nervous system and displays in vitro trophic effects on a wide range of neuronal cells, including hippocampal, cerebellar, and cortical neurons. In vivo, BDNF rescues motorneurons, hippocampal, and substantia nigral dopaminergic cells from traumatic and toxic brain injury. After transient middle cerebral artery occlusion (MCAO), upregulation of BDNF-mRNA in cortical neurons suggests that BDNF potentially plays a neuroprotective role in focal cerebral ischemia. In the current study, BDNF (2.1 μg/d) in vehicle or vehicle alone (controls) was delivered intraventricularly for 8 days, beginning 24 hours before permanent middle cerebral artery occlusion by intraluminal suture in Wistar rats (n = 13 per group). There were no differences in physiological variables recorded during surgery for the two groups. Neurological deficit (0 to 4 scale), which was assessed on a daily basis, improved in BDNF-treated animals compared with controls ( P < 0.05; analysis of variance and Scheffe's test). There were no significant differences in weight in BDNF-treated animals and controls during the experiment. After elective killing on day 7 after MCAO, brains underwent 2,3,5-triphenyltetrazolium chloride staining for calculation of the infarct volume and for histology (hematoxylin and eosin and glial fibrillary acid protein). The mean total infarct volume was 83.1 ± 27.1 mm3 in BDNF-treated animals and 139.2 ± 56.4 mm3 in controls (mean ± SD; P < 0.01, unpaired, two-tailed t-test). The cortical infarct volume was 10.8 ± 7.1 mm3 in BDNF-treated animals and 37.9 ± 19.8 mm3 in controls (mean ± SD; P < 0.05; unpaired, two-tailed t-test), whereas ischemic lesion volume in caudoputaminal infarction was not significantly different. These results show that pretreatment with intraventricular BDNF reduces infarct size after focal cerebral ischemia in rats and support the hypothesis of a neuroprotective role for BDNF in stoke.

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Abstract W MP81: Excess Salt Increases Infarct Size Produced by Photothrombotic Middle Cerebral Artery Occlusion Without Increasing Blood Pressure in Spontaneously Hypertensive Rats

Stroke ◽

10.1161/str.45.suppl_1.wmp81 ◽

2014 ◽

Vol 45 (suppl_1) ◽

Author(s):

Hiroshi Yao ◽

Toru Nabika

Keyword(s):

Infarct Size ◽

Brain Tissue ◽

Infarct Volume ◽

Artery Occlusion ◽

Control Group ◽

Salt Loading ◽

Ischemic Brain ◽

Spontaneously Hypertensive ◽

Ischemic Brain Tissue ◽

Cerebral Artery Occlusion

Background and Purpose: Cerebral circulation is known to be vulnerable to excess salt (e.g., impaired vasodilation, increased oxidative stress, accelerated spontaneous stroke, and enhanced blood-brain barrier [BBB] disruption). To our knowledge, however, no study has investigated the effects of excess salt on focal ischemic injury. Methods: After 14 days of salt loading or water, spontaneously hypertensive rats (SHR, Izumo strain, n=43) or normotensive Wistar-Kyoto rats (WKY, n=11) were subjected to photothrombotic middle cerebral artery occlusion (MCAO), and infarct volume was determined at 48 h after MCAO. Brain albumin and hemoglobin contents, as indices of BBB disruption, were determined with SELDI-TOF-MS in ischemic brain tissue. Effects of excess salt on the lower limits of cerebral blood flow (CBF) autoregulation were also determined. Results: Two-way analysis of variance confirmed a significant effect of saline on the volumes of drinking in SHR (p=0.000). Resting mean arterial blood pressure (BP) in SHR was 137±15 (S.D.) mmHg and 141±7 mmHg in the salt loading and control groups, respectively. After MCAO, regional CBF, determined with two ways of laser-Doppler flowmetry (one-point measurement or manual scanning), was more steeply decreased in the salt-loaded group than in the control group. In SHR, infarct volume in the salt-loaded group was 112±27 mm3, which was significantly larger than 77±12 mm3 in the control group (p=0.002), while albumin and hemoglobin levels in discrete brain regions were not different between the groups. In WKY, salt loading did not significantly increase infarct size. CBF response to hemorrhagic hypotension (i.e., autoregulation) was not affected by excess salt. Conclusions: We demonstrated that excess salt increased infarct size produced by photothrombotic MCAO without increasing BP in SHR but not in WKY. Excess salt did not deteriorate both vasogenic edema and hemorrhagic transformation of ischemic brain tissue after MCAO. The detrimental effects of excess salt were considered to be the result of compromised CBF in the ischemic brain tissue supplied by collateral circulation. A future study will investigate the mechanisms underlying the salt sensitivity to focal brain ischemia independent of BP changes.

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Effect of 20-HETE Inhibition on Infarct Volume and Cerebral Blood Flow after Transient Middle Cerebral Artery Occlusion

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2008.156 ◽

2008 ◽

Vol 29 (3) ◽

pp. 629-639 ◽

Cited By ~ 63

Author(s):

Marija Renic ◽

Judith A Klaus ◽

Tomohiro Omura ◽

Naoya Kawashima ◽

Michihito Onishi ◽

...

Keyword(s):

At Risk ◽

Blood Flow ◽

Cerebral Blood Flow ◽

Infarct Size ◽

Middle Cerebral Artery ◽

Cerebral Artery ◽

Infarct Volume ◽

Dienoic Acid ◽

Artery Occlusion ◽

Area At Risk

This study examined the effects of an inhibitor of 20-hydroxyeicosatetraenoic acid (20-HETE) synthesis, N-(3-chloro-4-morpholin-4-yl)phenyl- N'-hydroxyimido formamide (TS-011), on infarct volume, volume at risk, cerebral blood flow (CBF), and levels of cytochrome P450 (CYP450) eicosanoids in the brain after transient occlusion of the middle cerebral artery (t-MCAO) in rats. TS-011 (0.1 mg/kg, iv) reduced cortical infarct volume by approximately 70% and total infarct volume by 55%. TS-011 had no effect on the volume at risk or CBF during or up to 30 mins after the ischemic period. TS-011 reduced the delayed fall in CBF seen 2 h after reperfusion. The levels of CYP450 eicosanoids were similar in the ischemic and contralateral hemispheres after t-MCAO. TS-011 reduced 20-HETE levels in cerebral tissue by 80% but had no effect on the levels of EETs. Administration of another 20-HETE inhibitor, HET0016 (0.01 to 1.0 mg/kg, iv) or a 20-HETE antagonist 20-hydroxyeicosa-6( Z),15( Z)-dienoic acid (10 mg/kg, iv) also reduced infarct size. These results indicate that inhibitors of the synthesis or vasoconstrictor effects of 20-HETE reduce infarct size in rats after cerebral ischemia. The effects of TS-011 are not associated with changes in the area at risk or CBF and may be because of a potential protective effect in neurons subjected to ischemic stress.

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Use of mild intraischemic hypothermia versus mannitol to reduce infarct size after temporary middle cerebral artery occlusion in rats

Journal of Neurosurgery ◽

10.3171/jns.1995.83.1.0093 ◽

1995 ◽

Vol 83 (1) ◽

pp. 93-98 ◽

Cited By ~ 47

Author(s):

Hiroshi Karibe ◽

Gregory J. Zarow ◽

Philip R. Weinstein

Keyword(s):

Blood Flow ◽

Infarct Size ◽

Infarct Volume ◽

Artery Occlusion ◽

Content Type ◽

Infarct Area ◽

Group A ◽

Group B ◽

Cerebral Artery Occlusion ◽

Fine Print

✓ To determine which of two treatments for reducing ischemic injury after temporal focal ischemia is more effective, the effects of mild (33°C) intraischemic hypothermia were compared with those of mannitol, the most commonly used neuroprotective agent. Four groups of Sprague-Dawley rats underwent 1 hour of endovascular middle cerebral artery occlusion followed by 23 hours of normothermic reperfusion. The four experimental groups were as follows: Group A, saline control; Group B, mannitol (25%, 1 g/kg); Group C, hypothermia; and Group D, hypothermia plus man-nitol. Laser-Doppler estimates of cortical blood flow showed that hypothermia did not affect blood flow during ischemia or reperfusion. Mannitol increased cortical blood flow during ischemia and reperfusion under both normothermic and hypothermic conditions (p < 0.05). Neurological deficit was significantly less severe in treated rats (Group B, p < 0.05; Group C or D, p < 0.01) than in controls (Group A). Infarct volume, measured on semiserial Nissl-stained sections, was significantly smaller in treated rats (p < 0.01) than in controls. Infarct volume was also significantly smaller in rats treated with hypothermia than in those treated with mannitol (Group C vs. Group B, p < 0.05); there was no difference between rats treated with mannitol and those treated with mannitol and hypothermia. All three treatments reduced infarct area in the ischemic penumbra; hypothermia with or without mannitol also reduced infarct area in the ischemic core. These results demonstrate that both mild intraischemic hypothermia and mannitol reduce infarct size and neurological deficit: hypothermia reduces infarct size more effectively than mannitol, and mannitol adds no significant protection to hypothermia, whereas hypothermia adds significant protection beyond that afforded by mannitol after brief focal ischemia followed by reperfusion in rats. The results suggest that mild intraischemic hypothermia alone, or in combination with mannitol, may be useful in avoiding ischemic injury from temporary vessel occlusion during cerebrovascular surgery.

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Neuroprotective Effects of Insulin-Like Growth Factor-Binding Protein Ligand Inhibitors in Vitro and in Vivo

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/01.wcb.0000087091.01171.ae ◽

2003 ◽

Vol 23 (10) ◽

pp. 1160-1167 ◽

Cited By ~ 39

Author(s):

Kenneth B Mackay ◽

Sarah A Loddick ◽

Gregory S Naeve ◽

Alicia M Vana ◽

Gail M Verge ◽

...

Keyword(s):

Cerebral Ischemia ◽

Infarct Size ◽

Infarct Volume ◽

Artery Occlusion ◽

Dependent Manner ◽

Neuroprotective Effects ◽

In Vivo Models ◽

Igf I

The role of brain insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) in neuroprotection was further investigated using in vitro and in vivo models of cerebral ischemia by assessing the effects of IGF-I, IGF-II, and high affinity IGFBP ligand inhibitors (the peptide [Leu24, 59, 60, Ala31]hIGF-I (IGFBP-LI) and the small molecule NBI-31772 (1-(3,4-dihydroxybenzoyl)-3-hydroxycarbonyl-6, 7-dihydroxyisoquinoline), which pharmacologically displace and elevate endogenous, bioactive IGFs from IGFBPs. Treatment with IGF-I, IGF-II, or IGFBP-LI (2 μg/mL) significantly ( P < 0.05) reduced CA1 damage in organotypic hippocampal cultures resulting from 35 minutes of oxygen and glucose deprivation by 71%, 60%, and 40%, respectively. In the subtemporal middle cerebral artery occlusion (MCAO) model of focal ischemia, intracerebroventricular (icv) administration of IGF-I and IGF-II at the time of artery occlusion reduced ischemic brain damage in a dose-dependent manner, with maximum reductions in total infarct size of 37% ( P < 0.01) and 38% ( P < 0.01), respectively. In this model of MCAO, icv administration of NBI-31772 at the time of ischemia onset also dose-dependently reduced infarct size, and the highest dose (100 μg) significantly reduced both total (by 40%, P < 0.01) and cortical (by 43%, P < 0.05) infarct volume. In the intraluminal suture MCAO model, administration of NBI-31772 (50 μg icv) at the time of artery occlusion reduced both cortical infarct volume (by 40%, P < 0.01) and brain swelling (by 24%, P < 0.05), and it was still effective when treatment was delayed up to 3 hours after the induction of ischemia. These results further define the neuroprotective properties of IGFs and IGFBP ligand inhibitors in experimental models of cerebral ischemia.

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Abstract 176: Platelet Cyclophilin D Mediates Neutrophil Recruitment and Ischemic Stroke Outcomes in Mice

Stroke ◽

10.1161/str.51.suppl_1.176 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Frederik Denorme ◽

Bhanukanth Manne ◽

Yasuhiro Kosaka ◽

Jennifer Majersik ◽

Benjamin Kile ◽

...

Keyword(s):

Ischemic Stroke ◽

Infarct Size ◽

Infarct Volume ◽

Human Platelets ◽

Artery Occlusion ◽

Cyclophilin D ◽

Stroke Outcomes ◽

Fold Reduction ◽

Cerebral Artery Occlusion

Rationale: Besides their role in thrombosis, platelets also mediate inflammation through platelet-neutrophil aggregates (PNA). Recently, cyclophilin D (CypD)-mediated platelet necrosis emerged as a potential mediator of detrimental PNA during thrombosis. However, the role of platelet CypD in ischemic stroke has never been examined. Objective: Here, we investigate the contribution of platelet CypD following ischemic stroke. Methods: We generated mice lacking CypD specifically in platelets (KO). Both wild-type (WT) and KO mice were subjected to a 1h transient middle cerebral artery occlusion (tMCAO) stroke model. Twenty-four hours after occlusion, neurological and motor function, and stroke infarct size were determined. We also examined if the CypD pathway was altered in human platelets after ischemic stroke. Results: Loss of platelet CypD significantly improved neurological (p<0.001) and motor (p<0.005) functions compared to WT mice after tMCAO. Furthermore, platelet CypD deficient significantly reduced ischemic stroke infarct volume (39.1±15.7mm 3 vs. 78.6±27.7mm 3 , n=15; p<0.0001). Smaller infarcts in KO mice was not due to difference in blood flow during the ischemia stage. Twenty-four hours after stroke, a greater than 2-fold reduction in neutrophils was observed in the brains from KO mice (p<0.0001). In addition, we observed significantly fewer circulating and cerebral PNA (p<0.01). Depletion of neutrophils significantly (p<0.05) reduced infarct size and neurological damage following ischemic stroke in WT mice, however, no additional protective effect was observed in KO mice, suggesting necrotic PNAs are critical during ischemic stroke. RNA-sequencing on platelets isolated from ischemic stroke patients (n=8) and healthy aged, gender matched controls (n=7) revealed significant increases in several targets involved in CypD-mediated necrosis, including MCUR1, TMEM16F and calpain2 (p<0.005). Conclusion: Our results demonstrate necrotic platelets interact with neutrophils to exacerbate brain injury following ischemic stroke. As inhibiting platelet necrosis does not compromise hemostasis, targeting platelet CypD may be a potential therapeutic strategy to limit brain damage after ischemic stroke.

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Neuroprotective effects of preischemia intraarterial magnesium sulfate in reversible focal cerebral ischemia

Journal of Neurosurgery ◽

10.3171/jns.1996.85.1.0117 ◽

1996 ◽

Vol 85 (1) ◽

pp. 117-124 ◽

Cited By ~ 134

Author(s):

Marin B. Marinov ◽

Kimberly S. Harbaugh ◽

P. Jack Hoopes ◽

Harold J. Pikus ◽

Robert E. Harbaugh

Keyword(s):

Infarct Size ◽

Focal Cerebral Ischemia ◽

Infarct Volume ◽

Neuroprotective Effect ◽

Artery Occlusion ◽

Suture Technique ◽

Neuroprotective Effects ◽

Tetrazolium Chloride ◽

Content Type ◽

Fine Print

✓ The known cytoprotective properties of MgSO4 led the authors to study its effects on infarct size in rats when administered intraarterially before reversible focal ischemia. Following an intracarotid infusion of MgSO4 in the amount of 30 mg/kg (24 animals), 90 mg/kg (18 animals), or an equal volume of vehicle (23 animals), middle cerebral artery occlusion was produced in rats by means of an intraluminal suture technique. Reperfusion occurred after 1.5 (42 animals) or 2 hours (23 animals) of ischemia. Automated, volumetric measurements of 2′,3′,5′-triphenyl-2H-tetrazolium chloride—stained coronal brain sections demonstrated a statistically significant decrease in infarct size for MgSO4 treatment groups compared to controls. Cytoprotection was greater in animals subjected to 1.5 hours of ischemia (28.4% reduction in infarct volume, p ≤ 0.001, Student's t-test), than in those having 2 hours of ischemia (19.3% reduction, p < 0.05). Animals given 90 mg/kg MgSO4 prior to 1.5 hours of ischemia (12 animals) showed a 59.8% reduction in infarct volume compared to controls (11 animals, p < 0.001) and a 43.1% reduction compared to the 30 mg/kg group (11 animals, p < 0.001). Analysis of variance demonstrated the statistically significant effects of MgSO4 doses on infarct volume across all groups (F = 22.95, p < 0.0001). The neuroprotective effect of intraarterial MgSO4 in this model is robust, dose dependent, and related to the duration of ischemia. The compound may be valuable for limiting infarction if given intraarterially before induction of reversible ischemia during cerebrovascular surgery.

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Attenuation of p53 Expression Protects against Focal Ischemic Damage in Transgenic Mice

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1994.119 ◽

1994 ◽

Vol 14 (6) ◽

pp. 887-891 ◽

Cited By ~ 228

Author(s):

R. Christian Crumrine ◽

Amy L. Thomas ◽

Philip F. Morgan

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Infarct Size ◽

Infarct Volume ◽

Artery Occlusion ◽

Control Group ◽

Ischemic Damage ◽

Wild Type ◽

P53 Expression ◽

Wild Type Control

Apoptosis or programmed cell death may be involved in neuronal death in the cerebral cortex after a permanent focal ischemic insult. Studies indicate that protein p53 is a major determinant of the cellular mechanism that leads to programmed cell death. Wild-type C57 mice and two groups of transgenic C57 mice, one homozygous and the other heterozygous for a p53 null gene, were subjected to middle cerebral artery occlusion. As expected, the wild-type mice had a large, consistent infarct volume (22.11 ± 4.59 mm3; n = 10). Both transgenic groups had significantly less ischemic damage than the wild-type control group. However, unexpectedly, the heterozygous group had the least amount of ischemic damage (16.12 ± 1.71 mm3, n = 11; 27% reduction in infarct size). The ischemic damage in the homozygous group (18.72 ± 3.48 mm3, n = 9) was significantly less than in the wild-type control (15% reduction in infarct size) but significantly more than in the heterozygous group. Thus, although the absence of p53 expression was protective, grater protection was afforded by reduced expression of p53. These data suggest that attenuated p53 expression may be protective after an ischemic event.

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