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.

scholarly journals Impact of Key Nicotinic AChR Subunits on Post-Stroke Pneumococcal Pneumonia

Vaccines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 253
Author(s):  
Sandra Jagdmann ◽  
Claudia Dames ◽  
Daniel Berchtold ◽  
Katarzyna Winek ◽  
Luis Weitbrecht ◽  
...  
Keyword(s):  
Artery Occlusion ◽  
Experimental Stroke ◽  
Medical Complication ◽  
Α7 Nicotinic Acetylcholine Receptor ◽  
Post Stroke ◽  
Cholinergic Signaling ◽  
Cerebral Artery Occlusion ◽  
Pathogen Clearance ◽  
The Impact ◽  
Alveolar Capillary

Pneumonia is the most frequent severe medical complication after stroke. An overactivation of the cholinergic signaling after stroke contributes to immunosuppression and the development of spontaneous pneumonia caused by Gram-negative pathogens. The α7 nicotinic acetylcholine receptor (α7nAChR) has already been identified as an important mediator of the anti-inflammatory pathway after stroke. However, whether the α2, α5 and α9/10 nAChR expressed in the lung also play a role in suppression of pulmonary innate immunity after stroke is unknown. In the present study, we investigate the impact of various nAChRs on aspiration-induced pneumonia after stroke. Therefore, α2, α5, α7 and α9/10 nAChR knockout (KO) mice and wild type (WT) littermates were infected with Streptococcus pneumoniae (S. pneumoniae) three days after middle cerebral artery occlusion (MCAo). One day after infection pathogen clearance, cellularity in lung and spleen, cytokine secretion in bronchoalveolar lavage (BAL) and alveolar-capillary barrier were investigated. Here, we found that deficiency of various nAChRs does not contribute to an enhanced clearance of a Gram-positive pathogen causing post-stroke pneumonia in mice. In conclusion, these findings suggest that a single nAChR is not sufficient to mediate the impaired pulmonary defense against S. pneumoniae after experimental stroke.

scholarly journals Impaired meningeal lymphatic vessel development worsens stroke outcome

2019 ◽  
Vol 40 (2) ◽  
pp. 263-275 ◽  
Author(s):  
Pavel Yanev ◽  
Katherine Poinsatte ◽  
Devon Hominick ◽  
Noor Khurana ◽  
Kielen R Zuurbier ◽  
...  
Keyword(s):  
Lymphatic Vessels ◽  
Growth Factor Receptor ◽  
Young Male ◽  
Artery Occlusion ◽  
Stroke Outcomes ◽  
Post Stroke ◽  
Sagittal Sinus ◽  
The Central Nervous System ◽  
Vessel Development ◽  
The Impact

The discovery of meningeal lymphatic vessels (LVs) has sparked interest in identifying their role in diseases of the central nervous system. Similar to peripheral LVs, meningeal LVs depend on vascular endothelial growth factor receptor-3 (VEGFR3) signaling for development. Here we characterize the effect of stroke on meningeal LVs, and the impact of meningeal lymphatic hypoplasia on post-stroke outcomes. We show that photothrombosis (PT), but not transient middle cerebral artery occlusion (tMCAo), induces meningeal lymphangiogenesis in young male C57Bl/J6 mice. We also show that Vegfr3wt/mut mice develop significantly fewer meningeal LVs than Vegfr3wt/wt mice. Again, meningeal lymphangiogenesis occurs in the alymphatic zone lateral to the sagittal sinus only after PT-induced stroke in Vegfr3wt/wt mice. Interestingly, Vegfr3wt/mut mice develop larger stroke volumes than Vegfr3wt/wt mice after tMCAo, but not after PT. Our results reveal differences between PT and tMCAo models of stroke and underscore the need to consider method of stroke induction when investigating the role of meningeal lymphatics. Taken together, our data indicate that ischemic injury can induce the growth of meningeal LVs and that the absence of these LVs can impact post-stroke outcomes.

scholarly journals The regulation of glycemia in the recovery phase after stroke counteracts the detrimental effect of obesity-induced type 2 diabetes on neurological recovery

2020 ◽  
Author(s):  
Ada Admin ◽  
Ingrid Lovise Augestad ◽  
Hiranya Pintana ◽  
Martin Larsson ◽  
Camilla Krizhanovskii ◽  
...  
Keyword(s):  
Chronic Phase ◽  
Clinical Situation ◽  
Recovery Phase ◽  
Artery Occlusion ◽  
Stroke Recovery ◽  
Neurological Recovery ◽  
Standard Diet ◽  
Dipeptidyl Peptidase 4 ◽  
Post Stroke ◽  
The Impact

The interplay between obesity and T2D in post-stroke recovery is unclear. Moreover, the impact of glucose control during the chronic phase after stroke is undetermined. <p>We investigated whether obesity-induced T2D impairs neurological recovery after stroke by using a clinically relevant experimental design. We also investigated the potential efficacy of two clinically-used T2D drugs: the dipeptidyl peptidase-4 inhibitor linagliptin and the sulfonylurea glimepiride.</p> <p>We induced transient middle cerebral artery occlusion (tMCAO) in T2D/obese mice (after 7 months of high-fat diet (HFD)) and age-matched controls. After stroke, we replaced HFD with standard diet for 8 weeks to mimic the post-stroke clinical situation. Linagliptin or glimepiride were administered daily from 3 days after tMCAO for 8 weeks.<b> </b>We assessed neurological recovery weekly by upper-limb grip strength. Brain damage, neuroinflammation, stroke-induced neurogenesis and atrophy of parvalbumin (PV)+ interneurons were quantified by immunohistochemistry.</p> <p>T2D/obesity impaired post-stroke neurological recovery in association with hyperglycemia, neuroinflammation and atrophy of PV+ interneurons. Both drugs counteracted these effects. In non-diabetic mice, only linagliptin accelerated recovery.</p> These findings shed light on the interplay between obesity and T2D in stroke recovery. Moreover, they promote the use of rehabilitative strategies based on efficacious glycemia regulation, even if initiated days after stroke.

scholarly journals Temporal and Spatial Dynamics of Inflammasome Activation After Ischemic Stroke

2021 ◽  
Vol 12 ◽  
Author(s):  
Danli Lu ◽  
Mengyan Hu ◽  
Bingjun Zhang ◽  
Yinyao Lin ◽  
Qiang Zhu ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Spatial Dynamics ◽  
Size Control ◽  
Inflammasome Activation ◽  
Therapeutic Effects ◽  
Ischemic Lesion ◽  
Stroke Outcomes ◽  
Post Stroke ◽  
Caspase 1 ◽  
The Impact

Background: The inflammasome represents a highly pro-inflammatory mechanism. It has been identified that inflammasome was activated after ischemic stroke. However, the impact of inflammasomes on stroke outcomes remains contradictory. The participating molecules and the functioning arena of post-stroke inflammasome activation are still elusive.Methods: In the present study, blood samples from stroke patients were collected and analyzed with flow cytometry to evaluate the correlation of inflammasome activation and stroke outcomes. A stroke model was established using male C57/Bl6 mice with transient middle cerebral artery occlusion (tMCAO, 1 h). The dynamics of inflammasome components, cell type, and location of inflammasome activation and the therapeutic effects of inhibiting post-stroke inflammasome executors were evaluated.Results: We found that a high level of inflammasome activation might indicate detrimental stroke outcomes in patients and mice models. Post-stroke inflammasome activation, especially NLRP3, cleaved Caspase-1, cleaved Caspase-11, IL-1β, IL-18, and GSDMD, peaked at 3–5 days and declined at 7 days with the participation of multiple components in mice. Macrophage that infiltrated into the ischemic lesion was the main arena for post-stroke inflammasome activation among myeloid cells according to the data of mice. Among all the members of the Caspase family, Caspase-1 and −11 served as the main executing enzymes. Inhibiting Caspase-1/−11 signaling efficiently suppressed DAMPs-induced macrophage inflammasome activation and displayed neuroprotection to stroke models including infarct size (Control: 48.05 ± 14.98; Cas1.i: 19.34 ± 12.21; Cas11.i: 21.43 ± 14.67, P &lt; 0.001) and neurological deficit score (0 d-Control: 2.20 ± 0.63; 0 d-Cas1.i: 2.20 ± 0.63; 0 d-Cas11.i: 2.20 ± 0.63; 1 d-Control: 2.50 ± 0.53; 1 d-Cas1.i: 1.50 ± 0.71; 1 d-Cas11.i: 2.00 ± 0.67; 2 d-Control: 2.30 ± 0.48; 2 d-Cas1.i: 1.30 ± 0.48; 2 d-Cas11.i: 1.50 ± 0.53; 3 d-Control: 2.00 ± 0.67; 3 d-Cas1.i: 1.20 ± 0.42; 3 d-Cas11.i: 1.30 ± 0.48, P &lt; 0.001).Conclusions: Taken together, inflammasome activation played a detrimental role in stroke pathology. Targeting post-stroke inflammasome executing enzymes fitting in the dynamics of macrophages might obtain potential and efficient therapeutic effects.

Abstract TP282: Eotaxin Shows a Sex-specific Association With Positive Ischemic Stroke Outcomes and Post-stroke Peripheral Leukocyte Activation

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Meaghan Roy-O'Reilly ◽  
Sarah Conway ◽  
Ilene Staff ◽  
Gilbert Fortunado ◽  
Madeline Levy ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
T Cell Activation ◽  
Whole Blood ◽  
Experimental Stroke ◽  
Stroke Severity ◽  
Stroke Outcomes ◽  
Post Stroke ◽  
Age Related ◽  
Specific Association ◽  
Peripheral Leukocytes

Background and Purpose: Eotaxin, a TH2 chemokine, has been shown to increase in mouse brain and plasma following experimental stroke. While eotaxin has been associated with age-related deficits in neurogenesis, little is known about its role in ischemic injury. Hypothesis: We tested the hypothesis that serum eotaxin levels are associated with long-term stroke outcome, with follow up mechanistic studies in a mouse model of ischemic stroke. Methods: Serum was taken from patients (n=158) 24 hours after ischemic stroke onset. Levels of serum eotaxin were quantified by ELISA, then analyzed for outcome association. For murine studies, animals (n=14) underwent 90-minute middle cerebral artery occlusion and were sacrificed at 24 hours, with sham surgery mice serving as controls. Blood was incubated with or without eotaxin (100 ng/ml) and stained for leukocyte markers and CD62L (L-selectin). Results: Although eotaxin protein levels were not significantly different between sexes, a multivariate analysis controlling for age, stroke severity and cardiovascular risk factors revealed a male-specific association between higher eotaxin levels at 24 hours post-stroke and a positive functional outcome at three months (p=.010). Analysis of peripheral leukocytes isolated from both sham and stroke mice revealed that addition of eotaxin to whole blood significantly increased the activation of myeloid cells in both in male (p=.0031) and female (p=.0048) animals, as measured by shedding of L-selectin. Further experiments demonstrated that shedding of L-selectin on CD8+ T-cells after treatment of whole blood with eotaxin was significant only in female animals (p=.0008). Conclusion: In conclusion, the results of this study suggest that eotaxin has a sex-specific association with improved stroke outcomes. Murine studies demonstrate that eotaxin causes activation of peripheral leukocytes (as measured by loss of L-selectin), with a sexually dimorphic effect on CD8+ T-cell activation that may alter the character of the post-stroke immune response and support a pro-recovery inflammatory phenotype in males. This research underscores the importance of studying both sexes in future ischemic inflammatory research.

A Mouse Model of Post-Stroke Pneumonia Induced by Intra-Tracheal Inoculation with Streptococcus pneumoniae

2017 ◽  
Vol 43 (3-4) ◽  
pp. 99-109 ◽  
Author(s):  
Eva Mracsko ◽  
Sabine Stegemann-Koniszewski ◽  
Shin-Young Na ◽  
Alexander Dalpke ◽  
Dunja Bruder ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Mouse Model ◽  
Bacterial Pneumonia ◽  
Cytokine Production ◽  
Infectious Complications ◽  
Artery Occlusion ◽  
Experimental Stroke ◽  
Bacterial Counts ◽  
Post Stroke ◽  
Humoral Immune

Background: Stroke-induced immunodeficiency increases the risk of infectious complications, which adversely affects neurological outcome. Among those, pneumonia affects as many as one third of stroke patients and is the main contributor to mortality in the post-acute phase of stroke. Experimental findings on post-stroke susceptibility to spontaneous pneumonia in mice are contradictory. Here, we established a mouse model inducing standardized bacterial pneumonia and characterized the impaired pulmonary cellular and humoral immune responses after experimental stroke. Methods: Bacterial pneumonia was induced by intra-tracheal inoculation with Streptococcus pneumoniae at different time points after transient middle cerebral artery occlusion (MCAO). Bacterial counts in lungs and blood, histological changes, and cytokine production in the lungs were assessed. Furthermore, we investigated the effect of pneumonia on stroke outcome. Results: Intra-tracheal inoculation resulted in reproducible pneumonia and bacteraemia, and demonstrated post-stroke susceptibility to streptococcal pneumonia developing with a delay of at least 24 h after MCAO. Higher bacterial counts in mice infected 3 days after stroke induction correlated with reduced neutrophil and macrophage infiltration in the lungs and lower levels of pro-inflammatory cytokines in the broncho-alveolar lavage compared to sham-operated animals. Pneumonia increased mortality without affecting brain-infiltrating leukocytes. Conclusions: In this standardized mouse model of post-stroke pneumonia, we describe attenuated leukocyte infiltration and cytokine production in response to bacterial infection in the lungs that has a profound effect on outcome.

scholarly journals The regulation of glycemia in the recovery phase after stroke counteracts the detrimental effect of obesity-induced type 2 diabetes on neurological recovery

2020 ◽  
Author(s):  
Ada Admin ◽  
Ingrid Lovise Augestad ◽  
Hiranya Pintana ◽  
Martin Larsson ◽  
Camilla Krizhanovskii ◽  
...  
Keyword(s):  
Chronic Phase ◽  
Clinical Situation ◽  
Recovery Phase ◽  
Artery Occlusion ◽  
Stroke Recovery ◽  
Neurological Recovery ◽  
Standard Diet ◽  
Dipeptidyl Peptidase 4 ◽  
Post Stroke ◽  
The Impact

The interplay between obesity and T2D in post-stroke recovery is unclear. Moreover, the impact of glucose control during the chronic phase after stroke is undetermined. <p>We investigated whether obesity-induced T2D impairs neurological recovery after stroke by using a clinically relevant experimental design. We also investigated the potential efficacy of two clinically-used T2D drugs: the dipeptidyl peptidase-4 inhibitor linagliptin and the sulfonylurea glimepiride.</p> <p>We induced transient middle cerebral artery occlusion (tMCAO) in T2D/obese mice (after 7 months of high-fat diet (HFD)) and age-matched controls. After stroke, we replaced HFD with standard diet for 8 weeks to mimic the post-stroke clinical situation. Linagliptin or glimepiride were administered daily from 3 days after tMCAO for 8 weeks.<b> </b>We assessed neurological recovery weekly by upper-limb grip strength. Brain damage, neuroinflammation, stroke-induced neurogenesis and atrophy of parvalbumin (PV)+ interneurons were quantified by immunohistochemistry.</p> <p>T2D/obesity impaired post-stroke neurological recovery in association with hyperglycemia, neuroinflammation and atrophy of PV+ interneurons. Both drugs counteracted these effects. In non-diabetic mice, only linagliptin accelerated recovery.</p> These findings shed light on the interplay between obesity and T2D in stroke recovery. Moreover, they promote the use of rehabilitative strategies based on efficacious glycemia regulation, even if initiated days after stroke.

scholarly journals A New NF-κB Inhibitor, MEDS-23, Reduces the Severity of Adverse Post-Ischemic Stroke Outcomes in Rats

2021 ◽  
Vol 12 (1) ◽  
pp. 35
Author(s):  
Elina Rubin ◽  
Agnese C. Pippione ◽  
Matthew Boyko ◽  
Giacomo Einaudi ◽  
Stefano Sainas ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Artery Occlusion ◽  
Brain Inflammation ◽  
Neurological Deficits ◽  
Stroke Outcomes ◽  
Post Stroke ◽  
Factor Α ◽  
Cerebral Artery Occlusion ◽  
First Time

Aim: Nuclear factor kappa B (NF-κB) is known to play an important role in the inflammatory process which takes place after ischemic stroke. The major objective of the present study was to examine the effects of MEDS-23, a potent inhibitor of NF-κB, on clinical outcomes and brain inflammatory markers in post-ischemic stroke rats. Main methods: Initially, a Toxicity Experiment was performed to determine the appropriate dose of MEDS-23 for use in animals, as MEDS-23 was analyzed in vivo for the first time. We used the middle cerebral artery occlusion (MCAO) model for inducing ischemic stroke in rats. The effects of MEDS-23 (at 10 mg/kg, ip) on post-stroke outcomes (brain inflammation, fever, neurological deficits, mortality, and depression- and anxiety-like behaviours) was tested in several efficacy experiments. Key findings: MEDS-23 was found to be safe and significantly reduced the severity of some adverse post-stroke outcomes such as fever and neurological deficits. Moreover, MEDS-23 significantly decreased prostaglandin E2 levels in the hypothalamus and hippocampus of post-stroke rats, but did not prominently alter the levels of interleukin-6 and tumor necrosis factor-α. Significance: These results suggest that NF-κB inhibition is a potential therapeutic strategy for the treatment of ischemic stroke.

scholarly journals Lempel-Ziv complexity of the EEG predicts long-term functional recovery after stroke in rats

2018 ◽  
Author(s):  
Susan Leemburg ◽  
Claudio L. Bassetti
Keyword(s):  
Motor Function ◽  
Functional Recovery ◽  
Brain Function ◽  
Complexity Analysis ◽  
Recovery Period ◽  
Artery Occlusion ◽  
Multiscale Entropy ◽  
Experimental Stroke ◽  
Reaching Task ◽  
Post Stroke

AbstractNon-linear complexity of the EEG signal can be used to detect abnormal brain function relating to behavioral deficits. Here, we compare the effects of experimental stroke on EEG complexity using Lempel-Ziv complexity analysis (LZC) and multiscale entropy analysis (SampEn).EEG was recorded in bilateral motor cortex at baseline and during a 30-day recovery period after distal middle cerebral artery occlusion in rats. Motor function was assessed using a single pellet reaching task. Stroke caused an acute drop in both LZC and SampEn in the ipsilesional hemisphere in wakefulness, NREM and REM sleep, as well as reduced pellet reaching success. SampEn reductions persisted for at least 10 days post-stroke, whereas LZC had returned to baseline levels by day 4. EEG complexity in the contralesional hemisphere and in sham-operated animals were unaffected.If EEG complexity reflects post-stroke brain function, post-stroke asymmetry could be used to predict behavioral recovery. In rats, acute LZC asymmetry was significantly correlated with the amount of motor function recovery by post-stroke day 31, but SampEn asymmetry was not. EEG LZC may thus be a useful tool for predicting functional recovery after stroke. MSE could be effective in identifying cortical dysfunction, but does not reflect behavioral outcomes.

Abstract P733: Astroglial Activation Following Stroke Contributes to Impaired Synaptic Plasticity Through Increased Cd38-trpm2 Channel Signaling

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Amelia M Burch ◽  
James E Orfila ◽  
Robert Dietz ◽  
Andra Dingman ◽  
Danae Mitchell ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Memory Function ◽  
Hippocampal Slices ◽  
Brain Slices ◽  
Artery Occlusion ◽  
Experimental Stroke ◽  
Post Stroke ◽  
Cd38 Expression ◽  
Trpm2 Channel ◽  
Electrophysiological Recordings

Introduction: Post-stroke cognitive impairment (PSCI) is a major contributor to long-term disability following acute ischemic stroke. Learning and memory deficits are a common feature of PSCI and alterations in hippocampal function are a likely contributor. Interestingly, common experimental stroke models (middle cerebral artery occlusion; MCAO) cause hippocampal dysfunction, despite no direct ischemic insult to the hippocampus, suggesting perturbations in neural circuits. Thus, we utilize electrophysiological recordings of hippocampal plasticity in combination with neurobehavioral assessments of memory function. Hypothesis: Activated astrocytes in the hippocampus following MCAO increase expression of the surface enzyme CD38, which signals to neurons to impair plasticity. Methods: Extracellular field recordings of CA1 neurons were performed in acute hippocampal slices prepared 30 days after recovery from transient MCAO (60 min) in adult (6-8 week) mice. A behavioral fear conditioning paradigm (CFC) was used to evaluate contextual memory. Immunohistochemistry was performed to assess CD38 expression and slices were treated with CD38 inhibitors (78c) to assess plasticity. Results: Recordings obtained in brain slices 30 days after MCAO exhibited loss of hippocampal LTP; 134±6%, n=4 in sham and 107±12%, n=4 30 days after MCAO. Memory function, measured using CFC, was consistent with our LTP findings. MCAO decreased freezing behavior, indicating lack of memory (65±7% in sham mice (n=6) and 37±7% in MCAO mice, n=7). Immunohistochemical data indicates increased CD38 expression in activated astrocytes following MCAO in the hippocampus. Treatment of hippocampal slices with 78c, a potent CD38 inhibitor, after MCAO rescues LTP impairment. Finally, no additive increase in LTP when 78c is co-administered with a TRPM2 channel inhibitor was observed. Conclusion: These data indicate that MCAO is a reproducible model of post-stroke memory dysfunction (PSCI) and remote astrogliosis in the uninjured hippocampus may contribute to altered neuronal function (plasticity). Our data implicates increased levels of CD38 as an upstream activator of neuronal TRPM2 channel in the hippocampus following stroke, resulting in impaired synaptic plasticity.

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