scholarly journals Short-duration hypothermia completed prior to reperfusion prevents intracranial pressure elevation following ischaemic stroke in rats

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Daniel Omileke ◽  
Sara Azarpeykan ◽  
Steven W. Bothwell ◽  
Debbie Pepperall ◽  
Daniel J. Beard ◽  
...  
Keyword(s):  
Intracranial Pressure ◽  
Ischaemic Stroke ◽  
Short Duration ◽  
Infarct Volume ◽  
Arterial Occlusion ◽  
Reperfusion Therapy ◽  
Artery Occlusion ◽  
Experimental Stroke ◽  
Stroke Patients ◽  
Post Stroke

AbstractReperfusion therapies re-establish blood flow after arterial occlusion and improve outcome for ischaemic stroke patients. Intracranial pressure (ICP) elevation occurs 18–24 h after experimental stroke. This elevation is prevented by short-duration hypothermia spanning the time of reperfusion. We aimed to determine whether hypothermia-rewarming completed prior to reperfusion, also prevents ICP elevation 24 h post-stroke. Transient middle cerebral artery occlusion was performed on male outbred Wistar rats. Sixty-minute hypothermia to 33 °C, followed by rewarming was induced prior to reperfusion in one group, and after reperfusion in another group. Normothermia controls received identical anaesthesia protocols. ΔICP from pre-stroke to 24 h post-stroke was measured, and infarct volumes were calculated. Rewarming pre-reperfusion prevented ICP elevation (ΔICP = 0.3 ± 3.9 mmHg vs. normothermia ΔICP = 5.2 ± 2.1 mmHg, p = 0.02) and reduced infarct volume (pre-reperfusion = 78.6 ± 23.7 mm3 vs. normothermia = 125.1 ± 44.3 mm3, p = 0.04) 24 h post-stroke. There were no significant differences in ΔICP or infarct volumes between hypothermia groups rewarmed pre- or post-reperfusion. Hypothermia during reperfusion is not necessary for prevention of ICP rise or infarct volume reduction. Short-duration hypothermia may be an applicable early treatment strategy for stroke patients prior to- during-, and after reperfusion therapy.

scholarly journals Hypothermia and rewarming prior to reperfusion, prevents intracranial pressure elevation after ischaemic stroke in rats: an investigation to define the importance of cooling during reperfusion

2021 ◽  
Author(s):  
Daniel Omileke ◽  
Sara Azarpeykan ◽  
Steven W Bothwell ◽  
Debbie Pepperall ◽  
Daniel J Beard ◽  
...  
Keyword(s):  
Intracranial Pressure ◽  
Ischaemic Stroke ◽  
Short Duration ◽  
Infarct Volume ◽  
Arterial Occlusion ◽  
Reperfusion Therapy ◽  
Artery Occlusion ◽  
Experimental Stroke ◽  
Stroke Patients ◽  
Post Stroke

Abstract Reperfusion therapies re-establish blood flow after arterial occlusion and improve outcome for ischaemic stroke patients. Intracranial pressure (ICP) elevation occurs 18–24 h after experimental stroke. This elevation is prevented by short-duration hypothermia spanning the time of reperfusion. We aimed to determine whether hypothermia-rewarming completed prior to reperfusion, also prevents ICP elevation 24 h post-stroke. Transient middle cerebral artery occlusion was performed on male outbred Wistar rats. Sixty-minute hypothermia to 33℃, followed by rewarming was induced prior to reperfusion in one group, and after reperfusion in another group. Normothermia controls received identical anaesthesia protocols. ΔICP from pre-stroke to 24 h post-stroke was measured, and infarct volumes were calculated. Rewarming pre-reperfusion prevented ICP elevation (ΔICP = 0.3 ± 3.9 mmHg vs. normothermia ΔICP = 5.2 ± 2.1 mmHg, p = 0.02) and reduced infarct volume (pre-reperfusion = 78.6 ± 23.7 mm3 vs. normothermia = 125.1 ± 44.3 mm3, p = 0.04) 24 h post-stroke. There were no significant differences in ΔICP or infarct volumes between hypothermia groups rewarmed pre-or post-reperfusion. Hypothermia during reperfusion is not necessary for prevention of ICP rise or infarct volume reduction. Short-duration hypothermia is a broadly applicable potential early treatment strategy for stroke patients prior to- during-, and after reperfusion therapy.

scholarly journals Decreased Intracranial Pressure Elevation and Cerebrospinal Fluid Outflow Resistance: A Potential Mechanism of Hypothermia Cerebroprotection Following Experimental Stroke

2021 ◽  
Vol 11 (12) ◽  
pp. 1589
Author(s):  
Daniel Omileke ◽  
Steven W. Bothwell ◽  
Debbie Pepperall ◽  
Daniel J. Beard ◽  
Kirsten Coupland ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Intracranial Pressure ◽  
Ischaemic Stroke ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Experimental Stroke ◽  
Outflow Resistance ◽  
Hypothermia Treatment ◽  
Post Stroke ◽  
Intracranial Pressure Elevation

Background: Elevated intracranial pressure (ICP) occurs 18–24 h after ischaemic stroke and is implicated as a potential cause of early neurological deterioration. Increased resistance to cerebrospinal fluid (CSF) outflow after ischaemic stroke is a proposed mechanism for ICP elevation. Ultra-short duration hypothermia prevents ICP elevation 24 h post-stroke in rats. We aimed to determine whether hypothermia would reduce CSF outflow resistance post-stroke. Methods: Transient middle cerebral artery occlusion was performed, followed by gradual cooling to 33 °C. At 18 h post-stroke, CSF outflow resistance was measured using a steady-state infusion method. Results: Hypothermia to 33 °C prevented ICP elevation 18 h post-stroke (hypothermia ∆ICP = 0.8 ± 3.6 mmHg vs. normothermia ∆ICP = 4.4 ± 2.0 mmHg, p = 0.04) and reduced infarct volume 24 h post-stroke (hypothermia = 78.6 ± 21.3 mm3 vs. normothermia = 108.1 ± 17.8 mm3; p = 0.01). Hypothermia to 33 °C did not result in a significant reduction in CSF outflow resistance compared with normothermia controls (0.32 ± 0.36 mmHg/µL/min vs. 1.07 ± 0.99 mmHg/µL/min, p = 0.06). Conclusions: Hypothermia treatment was protective in terms of ICP rise prevention, infarct volume reduction, and may be implicated in CSF outflow resistance post-stroke. Further investigations are warranted to elucidate the mechanisms of ICP elevation and hypothermia treatment.

scholarly journals Ultra-Short Duration Hypothermia Prevents Intracranial Pressure Elevation Following Ischaemic Stroke in Rats

2021 ◽  
Vol 12 ◽  
Author(s):  
Daniel Omileke ◽  
Debbie Pepperall ◽  
Steven W. Bothwell ◽  
Nikolce Mackovski ◽  
Sara Azarpeykan ◽  
...  
Keyword(s):  
Intracranial Pressure ◽  
Ischaemic Stroke ◽  
Short Duration ◽  
Animal Studies ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Rapid Cooling ◽  
Long Duration ◽  
Intracranial Pressure Elevation ◽  
Cooling Methods

There is a transient increase in intracranial pressure (ICP) 18–24 h after ischaemic stroke in rats, which is prevented by short-duration hypothermia using rapid cooling methods. Clinical trials of long-duration hypothermia have been limited by feasibility and associated complications, which may be avoided by short-duration cooling. Animal studies have cooled faster than is achievable in patients. We aimed to determine whether gradual cooling at a rate of 2°C/h to 33°C or 1°C/h to 34.5°C, with a 30 min duration at target temperatures, prevented ICP elevation and reduced infarct volume in rats. Transient middle cerebral artery occlusion was performed, followed by gradual cooling to target temperature. Hypothermia to 33°C prevented significant ICP elevation (hypothermia ΔICP = 1.56 ± 2.26 mmHg vs normothermia ΔICP = 8.93 ± 4.82 mmHg; p = 0.02) and reduced infarct volume (hypothermia = 46.4 ± 12.3 mm3 vs normothermia = 85.0 ± 17.5 mm3; p = 0.01). Hypothermia to 34.5°C did not significantly prevent ICP elevation or reduce infarct volume. We showed that gradual cooling to 33°C, at cooling rates achievable in patients, had the same ICP preventative effect as traditional rapid cooling methods. This suggests that this paradigm could be translated to prevent delayed ICP rise in stroke patients.

scholarly journals MiR-29a Knockout Aggravates Neurological Damage by Pre-polarizing M1 Microglia in Experimental Rat Models of Acute Stroke

2021 ◽  
Vol 12 ◽  
Author(s):  
Fangfang Zhao ◽  
Haiping Zhao ◽  
Junfen Fan ◽  
Rongliang Wang ◽  
Ziping Han ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Stroke ◽  
Molecular Mechanisms ◽  
Infarct Volume ◽  
Glutamate Release ◽  
Artery Occlusion ◽  
Experimental Stroke ◽  
Neurological Damage ◽  
Stroke Patients ◽  
Rat Models

ObjectiveBy exploring the effects of miR-29a-5p knockout on neurological damage after acute ischemic stroke, we aim to deepen understanding of the molecular mechanisms of post-ischemic injury and thus provide new ideas for the treatment of ischemic brain injury.MethodsmiR-29a-5p knockout rats and wild-type SD rats were subjected to transient middle cerebral artery occlusion (MCAO). miR-29a levels in plasma, cortex, and basal ganglia of ischemic rats, and in plasma and neutrophils of ischemic stroke patients, as well as hypoxic glial cells were detected by real-time PCR. The infarct volume was detected by TTC staining and the activation of astrocytes and microglia was detected by western blotting.ResultsThe expression of miR-29a-5p was decreased in parallel in blood and brain tissue of rat MCAO models. Besides, miR-29a-5p levels were reduced in the peripheral blood of acute stroke patients. Knockout of miR-29a enhanced infarct volume of the MCAO rat model, and miR-29a knockout showed M1 polarization of microglia in the MCAO rat brain. miR-29a knockout in rats after MCAO promoted astrocyte proliferation and increased glutamate release.ConclusionKnockout of miR-29a in rats promoted M1 microglial polarization and increased glutamate release, thereby aggravating neurological damage in experimental stroke rat models.

scholarly journals Glyceryl trinitrate for the treatment of ischaemic stroke: Determining efficacy in rodent and ovine species for enhanced clinical translation

2021 ◽  
pp. 0271678X2110189
Author(s):  
Annabel J Sorby-Adams ◽  
Annastazia E Learoyd ◽  
Philip M Bath ◽  
Fiona Burrows ◽  
Tracy D Farr ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Ischaemic Stroke ◽  
Glyceryl Trinitrate ◽  
Infarct Volume ◽  
Imaging Spectroscopy ◽  
Artery Occlusion ◽  
Laser Speckle ◽  
Post Stroke ◽  
Physiological Outcomes

Hypertension is a leading risk factor for death and dependency after ischaemic stroke. However, administering anti-hypertensive medications post-stroke remains contentious with concerns regarding deleterious effects on cerebral blood flow and infarct expansion. This study sought to determine the effect of glyceryl trinitrate (GTN) treatment in both lissencephalic and gyrencephalic pre-clinical stroke models. Merino sheep underwent middle cerebral artery occlusion (MCAO) followed by GTN or control patch administration (0.2 mg/h). Monitoring of numerous physiologically relevant measures over 24 h showed that GTN administration was associated with decreased intracranial pressure, infarct volume, cerebral oedema and midline shift compared to vehicle treatment (p < 0.05). No significant changes in blood pressure or cerebral perfusion pressure were observed. Using optical imaging spectroscopy and laser speckle imaging, the effect of varying doses of GTN (0.69–50 µg/h) on cerebral blood flow and tissue oxygenation was examined in mice. No consistent effect was found. Additional mice undergoing MCAO followed by GTN administration (doses varying from 0–60 µg/h) also showed no improvement in infarct volume or neurological score within 24 h post-stroke. GTN administration significantly improved numerous stroke-related physiological outcomes in sheep but was ineffective in mice. This suggests that, whilst GTN administration could potentially benefit patients, further research into mechanisms of action are required.

Abstract WP151: Rapamycin Improves Post-Recanalization Blood Flow After Acute Experimental Stroke in Rats

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Anna Maria Schneider ◽  
Daniel Beard ◽  
Alastair Buchan
Keyword(s):  
Blood Flow ◽  
Infarct Volume ◽  
Mammalian Target Of Rapamycin ◽  
Volume Measurement ◽  
Artery Occlusion ◽  
Experimental Stroke ◽  
Stroke Outcome ◽  
Doppler Flowmetry ◽  
Rapamycin Treatment ◽  
Post Stroke

Background and Purpose: In the era of thrombectomy, there is evidence suggesting that successful recanalization is not always accompanied by complete reperfusion, the so called “no-reflow phenomenon”. Given the importance of reperfusion as a predictor of stroke outcome, this represents a potential target for stroke therapy. Rapamycin, a clinically approved inhibitor of Mammalian Target of Rapamycin (mTOR) has been shown to improve cerebral blood flow (CBF) in Alzheimer’s disease. However, there has been little investigation into the effect of rapamycin on post-stroke microvascular perfusion. The aim of this study was to investigate the effects of rapamycin treatment on post-recanalisation CBF and stroke outcome in an experimental animal model of stroke. Methods: Male Wistar rats (300-350g) were subjected to 90min of transient middle cerebral artery occlusion (tMCAo) followed by randomized administration of 250μg/kg intravenous rapamycin (n=8) or vehicle (n=6), 30min after the onset of MCAo. Laser Doppler flowmetry was used to continuously measure changes in MCA perfusion during MCAo and for min after recanalisation. Neurobehavioral tests were performed 24hrs after MCAo before tissue was collected for infarct volume measurement. Results: MCAo was confirmed by a 70% reduction in MCA perfusion. Rapamycin treatment significantly improved post-recanalization CBF at 55min after recanalization (p<0.01). Rapamycin significantly increased average CBF during the 60min post-recanalization period (p<0.01). Rapamycin showed a trend towards reduced final infarct volume. Rapamycin significantly improved neuroscores (p<0.05). Post-recanalization CBF was significantly inversely correlated with infarct volume (R 2 =0.4994, p<0.05). Conclusion: Rapamycin significantly improved post-recanalization CBF and behavioural outcomes after MCAo. These results suggest that rapamycin may be an effective acute intervention to improve post-recanalisation blood flow to improve stroke outcome. However, further studies are need to determine the mechanism of improved CBF and if improvements in post-stroke CBF and neurological outcome are sustained long-term post-stroke.

Abstract 3851: Temporal Distribution of Stroke Volumes and Clinical-Diffusion Mismatch in Patients with Proximal Arterial Occlusions

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Raul G Nogueira ◽  
David S Liebeskind ◽  
Leticia M Souza ◽  
Qing Hao ◽  
Karen Furie ◽  
...  
Keyword(s):  
Linear Regression ◽  
Infarct Volume ◽  
Linear Regression Analysis ◽  
Significant Proportion ◽  
Arterial Occlusion ◽  
Reperfusion Therapy ◽  
Poor Correlation ◽  
Lesion Volume ◽  
Collateral Flow ◽  
Over Time

Background and Purpose: Previous studies have demonstrated that the benefit of reperfusion therapy declines over time. The Clinical-Diffusion Mismatch (CDM) model has been suggested as surrogate for salvable tissue in acute ischemic stroke (AIS) patients. We sought to describe the temporal behavior profile of infarct volumes and CDM in patients suffering AIS due to proximal arterial occlusion (PAO). Methods: We performed a retrospective analysis of consecutive AIS patients admitted to two large academic institutions fulfilling the following criteria: (1) Baseline NIHSS ≥8; (2) PAO defined as MCA-M1, intracranial ICA, or tandem cervical + ICA/MCA-M1 occlusion on admission CTA/MRA; and (3) MRI-DWI performed ≤8 hours from time of stroke onset/last seen well (TSO). CDM was defined as baseline NIHSS ≥8 and DWI volume ≤25cc (as proposed by Davalos et al). Linear regression analysis was performed to define the changes on DWI lesion volume on presentation over time. The observed TSO to MRI were broken down into quartiles to look for any differences in the distribution of the baseline variables over time. Results: A total of 132 consecutive patients were identified (mean age, 66±16.8 years; 57% females; mean baseline NIHSS 17.5±5.3; occlusion site: MCA-M1, 64%; intracranial-ICA, 29%; tandem, 5%, mean TSO to DWI, 269.5±105.48 minutes). The mean DWI stroke volume on presentation was 46.7±54.8 cc (range, 0.19-436.1) and 63 (46.7%) patients had CDM. There was no significant changes in age, gender, baseline NIHSS, or occlusion site amongst the different time quartiles. Median infarct volume (cc) increased (quartile #1=8.5; #2=30.1; #3=38.5; #4=29.4) and the chances of having a CDM decreased (p<0.0001) across the different time quartiles. However, there was an overall poor correlation between DWI lesion volume on presentation and TSO to MRI (R-square=0.031, Figure ) and a significant proportion of the patients still had a CDM at later time epochs (#1=91.1%[20/22]; #2=47.8%[11/23]; #3=34.4%[21/61]; #4=42.3%[11/26]). Conclusions: Although infarct volume increases and the amount of penumbral tissue decreases over time, many patients with PAO will still have salvable penumbra at the later time epochs. This reflects individual differences in anatomic and physiological characteristics including the strength of collateral flow and highlights that selected patients may benefit from reperfusion therapy even at the later time windows. Figure : Relationship between Baseline DWI Volume (cc) and Time (minutes). Line is best fitted linear regression model.

Abstract WP68: Tissue Type Plasminogen Activator (t-PA) and Edaravone Combination Therapy Study (YAMATO Study)

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Junya Aoki ◽  
Kazumi Kimura ◽  
Norifumi Metoki ◽  
Yohei Tateishi ◽  
Kenichi Todo ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Arterial Occlusion ◽  
Artery Occlusion ◽  
Free Radical Scavenger ◽  
Favorable Outcome ◽  
Tissue Type ◽  
Radical Scavenger ◽  
Stroke Patients ◽  
Symptomatic Intracerebral Hemorrhage ◽  
Favorable Clinical Outcome

Introduction&Hypothesis: The aim of the present study was to investigate whether administration of edaravone, a free radical scavenger, before or during t-PA administration can increase the rate of early recanalization and improve the clinical outcome in stroke patients with major arterial occlusion. Methods: YAMATO study is an investigator initiated, multicenter (17 hospitals in Japan), prospective, randomized, open labeled study. Acute stroke patients with horizontal (M1) or vertical (M2) portion of the middle cerebral artery occlusion within 4.5 h of onset were studied. The subjects were randomly allocated to the early edaravone (early-E) group (intravenous edaravone [30 mg] was started before or during t-PA administration) and the late edaravone (late-E) group (edaravone was started after t-PA administration). Primary outcome, defined as any early recanalization 1h after t-PA therapy. Secondary outcomes included the rate of the significant recanalization, defined as ≥50% of the territory of the occluded artery on magnetic resonance angiography, or the thrombolysis in cerebral infarction score ≥2b on digital subtraction angiography as well as the incidence of symptomatic intracerebral hemorrhage (sICH), and the favorable clinical outcome (modified Rankin scale [mRS] of 0-2) at 3 months after onset. Results: One-hundred and sixty-six patients (96 men; median age [interquartile range], 78 [69-85] years) were randomized 1:1 to either the early-E group or the late-E group. Twenty-three (13.9%) had proximal M1 occlusion; 60 (36.1%), distal M1 occlusion; 83 (50%), M2 occlusion. Early recanalization was similarly observed in the early-E group and in the late-E group (53.1% vs. 53.0%, P=1.000). The rate of significant recanalization was also similar between the 2 groups (27.2% vs. 33.7%, p=0.399). sICH was occurred in 4 (4.8%) patients in the early-E group and in 2 (2.4%) in the late-E group (p=0.682). Among the 144 patients who were pre-morbid mRS of 0-2 and eligible for 3 months assessment, favorable outcome was seen in 53.9% in the early-E group and 57.4% in the late-E group (p=0.738) Conclusions: The timing of the edaravone infusion should not affect the rate of early recanalization, sICH, or favorable outcome after t-PA therapy.

Abstract P327: Utilizing Iodine Contrast Extravasation Post Reperfusion and Dual Energy Ct Imaging to Predict Risk of Hemorrhagic Conversion in Acute Stroke Patients

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Tri Huynh* ◽  
Niran Vijayaraghavan* ◽  
Hannah Branstetter ◽  
Natalie Buchwald ◽  
Justin De Prey ◽  
...  
Keyword(s):  
Acute Stroke ◽  
Infarct Volume ◽  
Reperfusion Therapy ◽  
Dual Energy ◽  
Ct Imaging ◽  
Dual Energy Ct ◽  
Stroke Patients ◽  
Post Intervention ◽  
Contrast Extravasation ◽  
Post Contrast

Introduction: Hyperintense acute reperfusion marker (HARM) has been identified on post-contrast magnetic resonance imaging (MRI) to be a marker of hemorrhagic conversion (HC) post reperfusion therapy in acute stroke patients. We have previously described a case where MRI HARM was mimicked on post contrast computed topography (CT) imaging in an acute stroke patient post reperfusion. Dual-Energy (DECT) allows for differentiation between acute blood and iodine contrast extravasation (ICE), and thus can have utility when ICE is present. Here we sought to validate whether post-intervention ICE/CT hyperdensity reperfusion maker (CT HARM), and contrast subtracted on DECT is associated with HC in acute stroke patients. Method: Data was obtained from our Institutional Review Board approved stroke admission database from January 2017 to November 2019, including ischemic stroke patients that received thrombolysis or thrombectomy, had evaluable images within 24 hours of admission, and received a DECT. Ischemic volumes of the stroke was measured on diffusion-weighted image (DWI). ICE was measured on CT head and DECT using the freehand 3D region of interest tool on the Visage Imaging PACS System. Susceptibility weighted MRI sequences were used to grade HC. Data analysis was conducted with regression modeling. Results: A total of 82 patients were included, 49% women, median age 73 (interquartile range (IQR), 61- 77), admission NIHSS 12 (IQR, 7 - 21), 24 hour change in NIHSS 4 (IQR, 0 -13), glucose 125 (IQR, 106 -158), creatinine 1.0 (IQR, 0.8 - 1.2), infarct volume 50.6 ± 7.1 mL, 48% treated with thrombectomy, 7% with PH-1 or PH-2 identified on MRI, and 56% with MCA infarcts. ICE volume was 2.6 ± 1.0 mL and DECT volume was 2.2 ± 1.1mL. ICE increased the likelihood of MRI confirmed PH-1 or PH-2 hemorrhagic conversion (odds ratio (OR) 14.34, 95% confidence interval (CI) 5.74 - 22.94) and decreased likelihood of increase in NIHSS at 24 hours (OR 0.20, 95% CI 0.01 to 0.40). There were no other significant associations with ICE or DECT volumes. Conclusion: Our results are supportive of our proposed association between CT HARM and risk of HC. More studies are needed to study whether quantitative of DECT can be predictive of stroke outcomes post reperfusion therapy.

Abstract P746: Sex Differences in Cognitive and Psychological Outcomes of Stroke: Impact of Diabetes

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Victoria L Wolf ◽  
Aunay Miller ◽  
Raghavendar Chandran ◽  
Weiguo Li ◽  
Adviye Ergul
Keyword(s):  
Artery Occlusion ◽  
Psychological Outcomes ◽  
Experimental Stroke ◽  
Dark Light ◽  
Stroke Outcomes ◽  
Post Stroke ◽  
Stroke Research ◽  
Y Maze ◽  
Male Animal ◽  
The Impact

Diabetes increases risk and severity of post-stroke cognitive impairment (PSCI), a major cause of disability worldwide. While it is known that females suffer more from PSCI, psychological outcomes and underlying reasons are poorly understood. From a preclinical perspective, potential explanations include 1) use of otherwise healthy animals in experimental stroke research without integration of common comorbid diseases like diabetes into the study design, and 2) optimization of most behavioral tests for sensorimotor and cognitive functions using only male animal models. Our hypothesis is that post-stroke outcomes are sex and comorbid disease-dependent. To test this, we validated the Novel Object Recognition (NOR), Y-maze, and Passive Avoidance (PAT) behavioral paradigms in Ctrl and Diabetic (DM) male (M) and female (F) rats pre- and post-stroke (S) via 60 min. middle cerebral artery occlusion (MCAO). We tested the PAT paradigm with a multi-trial method where the animals were habituated to the dark/light chambers without foot shock and then trained in 3 trials where they received foot shock upon entering the dark. We then tested retention following MCAO for their memory of foot shock 2 weeks prior. Multitrial results suggested that there was no difference between groups in learning to associate the dark chamber with the shock, so we revised the multitrial method into a single-trial method for ongoing retention tests to compare the impact of stroke on shock memory recall. PAT revealed (Table 1) disease- and sex-dependent responses to aversive stimulus. NOR revealed that M-DM-S and F-DM-S rats have decreased exploration time, suggesting that they are unmotivated or depressed. Y-maze indicated that males displayed spatial memory recovery, while females remained impaired. In summary, we have observed numerous sex- and disease-dependent post-stroke outcomes with standard behavioral paradigms, causing us to carefully consider how we evaluate preclinical outcomes.

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