scholarly journals BMS-986020, a Specific LPA1 Antagonist, Provides Neuroprotection against Ischemic Stroke in Mice

Antioxidants ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 1097
Author(s):  
Bhakta Prasad Gaire ◽  
Arjun Sapkota ◽  
Ji Woong Choi
Keyword(s):  
Ischemic Stroke ◽  
Survival Rate ◽  
Cell Apoptosis ◽  
Functional Disability ◽  
Brain Infarction ◽  
Tissue Loss ◽  
Neurological Deficits ◽  
Neuroprotective Effects ◽  
Acute Injuries

Stroke is a leading cause of death. Stroke survivors often suffer from long-term functional disability. This study demonstrated neuroprotective effects of BMS-986020 (BMS), a selective lysophosphatidic acid receptor 1 (LPA1) antagonist under clinical trials for lung fibrosis and psoriasis, against both acute and sub-acute injuries after ischemic stroke by employing a mouse model with transient middle cerebral artery occlusion (tMCAO). BMS administration immediately after reperfusion significantly attenuated acute brain injuries including brain infarction, neurological deficits, and cell apoptosis at day 1 after tMCAO. Neuroprotective effects of BMS were preserved even when administered at 3 h after reperfusion. Neuroprotection by BMS against acute injuries was associated with attenuation of microglial activation and lipid peroxidation in post-ischemic brains. Notably, repeated BMS administration daily for 14 days after tMCAO exerted long-term neuroprotection in tMCAO-challenged mice, as evidenced by significantly attenuated neurological deficits and improved survival rate. It also attenuated brain tissue loss and cell apoptosis in post-ischemic brains. Mechanistically, it significantly enhanced neurogenesis and angiogenesis in injured brains. A single administration of BMS provided similar long-term neuroprotection except survival rate. Collectively, BMS provided neuroprotection against both acute and sub-acute injuries of ischemic stroke, indicating that BMS might be an appealing therapeutic agent to treat ischemic stroke.

scholarly journals Replicating infant astrocyte behavior in the adult after brain injury improves outcomes

2020 ◽  
Author(s):  
Leon Teo ◽  
Anthony G. Boghdadi ◽  
Jihane Homman-Ludiye ◽  
Iñaki Carril-Mundiñano ◽  
William C. Kwan ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Brain Injury ◽  
Brain Injuries ◽  
Adult Patients ◽  
Long Term Outcomes ◽  
Neuroprotective Effects ◽  
Age Dependent ◽  
Underlying Mechanisms ◽  
Glial Scarring

AbstractInfants and adults respond differently to brain injuries. Specifically, improved neuronal sparing along with reduced astrogliosis and glial scarring often observed earlier in life, likely contributes to improved long-term outcomes. Understanding the underlying mechanisms could enable the recapitulation of neuroprotective effects, observed in infants, to benefit adult patients after brain injuries. We reveal that in primates, Eph/ ephrin signaling contributes to age-dependent reactive astrocyte behavior. Ephrin-A5 expression on astrocytes was more protracted in adults, whereas ephrin-A1 was associated only with infant astrocytes. Furthermore, ephrin-A5 exacerbated major hallmarks of astrocyte reactivity via EphA2 and EphA4 receptors, which was subsequently alleviated by ephrin-A1. Rather than suppressing reactivity, ephrin-A1 signaling shifted astrocytes towards GAP43+ neuroprotection, accounting for improved neuronal sparing in infants. Reintroducing ephrin-A1 after middle-aged ischemic stroke significantly attenuated glial scarring, improved neuronal sparing and preserved circuitry. Therefore, beneficial infant mechanisms can be recapitulated in adults to improve outcomes after CNS injuries.

Neuroprotection via AT2 receptor agonists in ischemic stroke

2018 ◽  
Vol 132 (10) ◽  
pp. 1055-1067 ◽  
Author(s):  
Douglas M. Bennion ◽  
U. Muscha Steckelings ◽  
Colin Sumners
Keyword(s):  
Ischemic Stroke ◽  
Neuronal Damage ◽  
Recombinant Tissue Plasminogen Activator ◽  
Neurological Deficits ◽  
At2 Receptor ◽  
Neuroprotective Effects ◽  
Receptor Agonists ◽  
Stroke Epidemiology ◽  
The Brain

Stroke is a devastating disease that afflicts millions of people each year worldwide. Ischemic stroke, which accounts for ~88% of cases, occurs when blood supply to the brain is decreased, often because of thromboembolism or atherosclerotic occlusion. This deprives the brain of oxygen and nutrients, causing immediate, irreversible necrosis within the core of the ischemic area, but more delayed and potentially reversible neuronal damage in the surrounding brain tissue, the penumbra. The only currently approved therapies for ischemic stroke, the thrombolytic agent recombinant tissue plasminogen activator (rtPA) and the endovascular clot retrieval/destruction processes, are aimed at restoring blood flow to the infarcted area, but are only available for a minority of patients and are not able in most cases to completely restore neurological deficits. Consequently, there remains a need for agents that will protect neurones against death following ischemic stroke. Here, we evaluate angiotensin II (Ang II) type 2 (AT2) receptor agonists as a possible therapeutic target for this disease. We first provide an overview of stroke epidemiology, pathophysiology, and currently approved therapies. We next review the large amount of preclinical evidence, accumulated over the past decade and a half, which indicates that AT2 receptor agonists exert significant neuroprotective effects in various animal models, and discuss the potential mechanisms involved. Finally, after discussing the challenges of delivering blood–brain barrier (BBB) impermeable AT2 receptor agonists to the infarcted areas of the brain, we summarize the evidence for and against the development of these agents as a promising therapeutic strategy for ischemic stroke.

Abstract WP291: Diabetes Impairs Long-term Functional Recovery in an Embolic Stroke Model in Sex Independent Manner

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Weiguo Li ◽  
Sherif Hafez ◽  
John Paul Valenzuela ◽  
Rebecca Ward ◽  
Guangkuo Dong ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Functional Recovery ◽  
Hemorrhagic Transformation ◽  
Cognitive Outcome ◽  
Embolic Stroke ◽  
Neurological Deficits ◽  
Independent Manner ◽  
Male And Female ◽  
The Impact

Ischemic stroke is a leading cause of death and disability. Diabetes not only increases the risk of stroke, it also worsens the outcomes, increases the risk of hemorrhagic transformation (HT) and impairs recovery after stroke. It is well established that young females are more protected and show better outcomes than males after stroke. However, the impact of diabetes on long term recovery after stroke in both sexes was not clear. Accordingly, this study tested the hypothesis that diabetes impairs long term functional recovery after ischemic stroke in a sex independent manner. Methods: Diabetes was induced in male and female Wistar rats using high fat diet and low dose streptozotocin (30 mg/Kg). After 8 weeks of diabetes, animals were subjected to embolic stroke. Male and female Wistar normoglycemic age matched rats were used as controls. Motor (composite score: 14 best outcome and adhesive removal-ART) and cognitive (novel object recognition, NOR) deficits were assessed at day1, 3, 7 and 14. Results: Female control animals had better outcomes compared to the males. Mortality was higher in diabetic animals, especially in males. The neurological deficits were greater in diabetic animals with no difference between males and females. Conclusion: Diabetes impaired functional and cognitive outcome and recovery after ischemic stroke in a sex independent manner.

Abstract 162: 12-Month Epilepsy Outcomes in Patients With Acute Ischemic Stroke 12-Month Epilepsy Outcomes in Patients With Acute Ischemic Stroke

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Erwin Chiquete ◽  
Guillermo Ramirez-Garcia ◽  
Valeria Sandoval-Rodriguez ◽  
Fernando Flores-Silva ◽  
Jose L Ruiz-Sandoval ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Functional Outcome ◽  
Functional Disability ◽  
Brain Infarction ◽  
Cox Proportional Hazards Model ◽  
Seizure Recurrence ◽  
Factors Associated ◽  
Acute Seizures

Background and purpose: Acute ischemic stroke (AIS) is the leading cause of adult-onset epilepsy. In the context of current guidelines, AIS patients presenting with seizures are considered at high risk for seizure recurrence and as a consequence, this patients are deemed as nowadays affected by epilepsy. We aimed to describe the factors associated with acute seizures, epilepsy and seizure recurrence after AIS, as well as their impact on the functional outcome at 12-month follow-up. Methods: This is a cohort study on 1,246 non-epileptic patients with AIS included in a multicenter Mexican registry; who received 12-month follow-up after a first-ever or recurrent AIS. Multivariate analyses were performed to evaluate factors associated with acute seizures and the functional outcome at 12 months of follow-up. Results: The frequency of acute seizures (within 7 days after stroke onset) after AIS was 8.1% [95% confidence interval (CI): 6.7% to 9.8%]. In all, 12-month seizure recurrence rate was 4.8% (95% CI: 3.7% to 6.1%). In a binary logistic regression model, risk factors significantly associated with seizures were >10 scoring of the National Institutes of Health Stroke Scale (NIHSSS, US) [odds ratio (OR): 2.21, 95% CI: 1.40-3.47], recurrent ischemic stroke (OR: 2.17, 95% CI: 1.34-3.53) and age <65 years (OR: 1.69, 95% CI: 1.09-2.62). After a Cox-proportional hazards model and Kaplan-Meier actuarial analyses, the presence of acute seizures was significantly associated with the risk of functional disability or death (a modified Rankin scale >3) at 12 months of follow-up [hazard ratio (HR): 1.37, 95% CI: 1.04-1.83], as well as NIHSS >10 (HR: 4.47, 95% CI: 3.53-5.65), age ≥65 years (HR: 1.74, 95% CI: 1.38-2.20), heart failure (HR: 1.61, 95% CI: 1.22-2.13) and atrial fibrillation (HR: 1.35, 95% CI: 1.05-1.74). Conclusions: The frequency of provoked seizures after acute ischemic stroke in this cohort was 8%. Age <65 years and severity of the brain infarction are the main factors associated with seizures, which in turn represent an important risk factor for functional disabilities or death one year after the acute event.

Different Effects of Volatile and Nonvolatile Anesthetic Agents on Long-Term Survival in an Experimental Model of Hemorrhagic Shock

2020 ◽  
Vol 25 (4) ◽  
pp. 346-353
Author(s):  
Wangde Dai ◽  
Jianru Shi ◽  
Juan Carreno ◽  
Robert A. Kloner
Keyword(s):  
Blood Pressure ◽  
Survival Rate ◽  
Hemorrhagic Shock ◽  
Blood Volume ◽  
Brain Infarction ◽  
Anesthetic Agent ◽  
Term Survival ◽  
Long Term Survival ◽  
Isoflurane Group

Background: We investigated whether the cardioprotective, volatile gas anesthetic agent, isoflurane, could improve survival and organ function from hemorrhagic shock in an experimental rat model, compared to standard nonvolatile anesthetic agent ketamine/xylazine. Methods: Sprague Dawley rats (both genders) were randomized to receive either intraperitoneal ketamine/xylazine (K/X, 90 and 10 mg/kg; n = 12) or isoflurane (5% isoflurane induction and 2% maintenance in room air; n = 12) for anesthesia. Blood was withdrawn to maintain mean arterial blood pressure at 30 mm Hg for 1 hour, followed by 30 minutes of resuscitation with shed blood. Rats were allowed to recover and survive for 6 weeks. Results: During the shock phase, the total withdrawn blood volume (expressed as % of estimated total blood volume) to maintain a level of hypotension of 30 mm Hg was significantly higher in the isoflurane group (51.0% ± 1.5%) than in the K/X group (45.3% ± 1.8%; P = .023). Recovery of blood pressure during the resuscitation phase was significantly improved in the isoflurane group compared to the K/X group. The survival rate at 6 weeks was 1 (8.3%) of 12 in rats receiving K/X and 10 (83.3%) of 12 in rats receiving isoflurane ( P < .001). Histology performed at 6 weeks demonstrated brain infarction in the 1 surviving rat receiving K/X; no brain infarction occurred in the 10 surviving rats that received isoflurane. No infarction was detected in heart, lung, liver, or kidneys among the surviving rats. Conclusions: Isoflurane improved blood pressure response to resuscitation and resulted in significantly higher long-term survival rate.

scholarly journals Annexin A2 Deficiency Exacerbates Neuroinflammation and Long-Term Neurological Deficits after Traumatic Brain Injury in Mice

2019 ◽  
Vol 20 (24) ◽  
pp. 6125 ◽  
Author(s):  
Ning Liu ◽  
Yinghua Jiang ◽  
Joon Yong Chung ◽  
Yadan Li ◽  
Zhanyang Yu ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Inflammatory Response ◽  
Neurovascular Unit ◽  
Annexin A2 ◽  
Tissue Loss ◽  
Neurological Deficits ◽  
Endogenous Factors ◽  
The Brain

Our laboratory and others previously showed that Annexin A2 knockout (A2KO) mice had impaired blood–brain barrier (BBB) development and elevated pro-inflammatory response in macrophages, implying that Annexin A2 (AnxA2) might be one of the key endogenous factors for maintaining homeostasis of the neurovascular unit in the brain. Traumatic brain injury (TBI) is an important cause of disability and mortality worldwide, and neurovascular inflammation plays an important role in the TBI pathophysiology. In the present study, we aimed to test the hypothesis that A2KO promotes pro-inflammatory response in the brain and worsens neurobehavioral outcomes after TBI. TBI was conducted by a controlled cortical impact (CCI) device in mice. Our experimental results showed AnxA2 expression was significantly up-regulated in response to TBI at day three post-TBI. We also found more production of pro-inflammatory cytokines in the A2KO mouse brain, while there was a significant increase of inflammatory adhesion molecules mRNA expression in isolated cerebral micro-vessels of A2KO mice compared with wild-type (WT) mice. Consistently, the A2KO mice brains had a significant increase in leukocyte brain infiltration at two days after TBI. Importantly, A2KO mice had significantly worse sensorimotor and cognitive function deficits up to 28 days after TBI and significantly larger brain tissue loss. Therefore, these results suggested that AnxA2 deficiency results in exacerbated early neurovascular pro-inflammation, which leads to a worse long-term neurologic outcome after TBI.

scholarly journals Predicting Early Mortality of Acute Ischemic Stroke

Stroke ◽  
2019 ◽  
Vol 50 (2) ◽  
pp. 349-356 ◽  
Author(s):  
Thomas Gattringer ◽  
Alexandra Posekany ◽  
Kurt Niederkorn ◽  
Michael Knoflach ◽  
Birgit Poltrum ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Stroke Unit ◽  
Functional Disability ◽  
Area Under The Curve ◽  
Early Mortality ◽  
Stroke Severity ◽  
Stroke Patients ◽  
Derivation Cohort ◽  
Temporal Validation

Background and Purpose— Several risk factors are known to increase mid- and long-term mortality of ischemic stroke patients. Information on predictors of early stroke mortality is scarce but often requested in clinical practice. We therefore aimed to develop a rapidly applicable tool for predicting early mortality at the stroke unit. Methods— We used data from the nationwide Austrian Stroke Unit Registry and multivariate regularized logistic regression analysis to identify demographic and clinical variables associated with early (≤7 days poststroke) mortality of patients admitted with ischemic stroke. These variables were then used to develop the Predicting Early Mortality of Ischemic Stroke score that was validated both by bootstrapping and temporal validation. Results— In total, 77 653 ischemic stroke patients were included in the analysis (median age: 74 years, 47% women). The mortality rate at the stroke unit was 2% and median stay of deceased patients was 3 days. Age, stroke severity measured by the National Institutes of Health Stroke Scale, prestroke functional disability (modified Rankin Scale >0), preexisting heart disease, diabetes mellitus, posterior circulation stroke syndrome, and nonlacunar stroke cause were associated with mortality and served to build the Predicting Early Mortality of Ischemic Stroke score ranging from 0 to 12 points. The area under the curve of the score was 0.879 (95% CI, 0.871–0.886) in the derivation cohort and 0.884 (95% CI, 0.863–0.905) in the validation sample. Patients with a score ≥10 had a 35% (95% CI, 28%–43%) risk to die within the first days at the stroke unit. Conclusions— We developed a simple score to estimate early mortality of ischemic stroke patients treated at a stroke unit. This score could help clinicians in short-term prognostication for management decisions and counseling.

scholarly journals NCMP-05. THE INCIDENCE AND IMPACT OF POST-OPERATIVE STROKE IN SURGERY FOR LGG

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi180-vi180
Author(s):  
Asaf Berger ◽  
Garry Tzarfati ◽  
Mathias Costa ◽  
Marga Serafimova ◽  
Akiva Korn ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Performance Status ◽  
Tumor Resection ◽  
Neurological Deficits ◽  
Functional Improvement ◽  
Motor Deficit ◽  
Low Grade ◽  
Post Surgery ◽  
One Year

Abstract BACKGROUND Postoperative neurological deficits may outweigh the benefit conferred by maximal resection of gliomas. We evaluated the incidence of ischemic events in patients undergoing surgery for low-grade gliomas (LGG) and the long-term neurological and cognitive sequelae. METHODS Between 2013–2017, 168 patients underwent surgical resection or biopsy for LGG at our center. A full dataset, including pre- and postoperative magnetic resonance imaging (MRI) and long-term clinical evaluation findings, was available for 82 patients (study group). Ischemic complications, overall and progression-free survival, and functional and neurocognitive outcomes were evaluated. RESULTS The immediate postoperative MRI revealed an acute ischemic stroke adjacent to the tumor resection cavity in 19 patients (23%), 13 of whom developed new neurological deficits due to the ischemic event. Infarcts were more common in patients with recurrent tumors, especially those involving the Sylvian fissure (p< 0.05). Surgery for insular gliomas had the strongest association with postoperative infarcts. Survival of patients w/wo a postoperative infarct was the same. The median Karnofsky-Performance Status was lower for the infarct group vs. the non-infarct group at 3 months post-surgery (p=0.016), with a gradual significant improvement for the former over one year (p=0.04). Immediately after surgery, 27% of the patients without infarcts and 58% of those with infarcts experienced a new motor deficit (p=0.037), decreasing to 16% (p=0.028) and 37% (p=0.001), respectively, at one year. Neurocognitive analysis findings before and 3 months after surgery were unchanged, but patients with an infarct had a significant decrease in naming (p=0.04). Confusion during awake craniotomy was a strong predictor of an ischemic stroke. CONCLUSIONS Intraoperative strokes are more prevalent among patients who undergo recurrent surgeries, especially in the insula. Although they do not affect survival, these strokes negatively impact the patients’ activity and performance status, especially during the first 3 postoperative months, with gradual functional improvement over one year.

Abstract 187: Effects of Anesthetic Agents on the Hemodynamic Stabilization and Long Term Survival in an Experimental Model of Hemorrhagic Shock

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_2) ◽  
Author(s):  
Wangde Dai ◽  
Jianru Shi ◽  
Juan Carreno ◽  
Sharon Hale ◽  
Robert A Kloner
Keyword(s):  
Blood Pressure ◽  
Survival Rate ◽  
Blood Volume ◽  
Brain Infarction ◽  
Term Survival ◽  
Long Term Survival ◽  
Shed Blood ◽  
Anesthetic Agents ◽  
Isoflurane Group

Background: We investigated the cardiovascular responses to acute bleeding and shed blood restoration under different anesthetic agents, and their effects on long-term survival rate after hemorrhagic shock in rats, after our initial pilot study suggested differences between anesthetics. Methods: Sprague Dawley rats (both genders) were randomized to receive either intraperitoneal ketamine/xylazine (K/X, 90 mg/kg and 10 mg/kg; n=12), or isoflurane (5% isoflurane induction and 2% maintenance in room air; n=12) for anesthesia. Blood was withdrawn from the carotid artery to maintain mean arterial blood pressure (MBP) at 30 mm Hg for one hour, followed by 30 min of resuscitation with shed blood. Rats remained anesthetized for another 30 min before they were allowed to recovery and survive for 6 weeks. Hemodynamics were monitored during the surgical procedure. Results: During the shock phase, the total withdrawn blood volume (expressed as % of estimated total blood volume) to maintain MBP at 30 mmHg was significantly higher in the isoflurane group (51 ± 1.5 %) compared to the K/X group (45.3 ± 1.8 %; p=0.023). The diastolic internal dimension of the left ventricle, which indicated circulating intravascular blood volume, was significantly larger in the isoflurane group at the end of 1 hour of the shock phase (4.5 ± 0.2 mm compared to 3.5 ± 0.2 mm in K/X group; p=0.0003) and at 1 hour after initiation of shed blood reinfusion (6.3 ± 0.2 mm compared to 5.3 ± 0.3 in K/X group; p=0.014). Recovery of blood pressure during the resuscitation phase was significantly improved in the isoflurane group compared to the K/X group. The survival rate at 6 weeks was 1 of 12 (8.3%) in rats receiving K/X and 10 of 12 (83.3%) in rats receiving isoflurane (p < 0.001). Histology demonstrated brain infarction in the 1 surviving rat receiving K/X; no brain infarction in the 10 surviving rats that received isoflurane at 6 weeks. No infarction was detected in heart, lung, liver or kidneys in all surviving rats. Conclusions: These results suggest that isoflurane stabilizes the cardiovascular response to acute blood lose and benefits the perfusion of tissue, which resulted in significantly higher long term survival rate and improved blood pressure response to resuscitation, without end-organ infarction.

scholarly journals Neuroprotective Effects of Early Hypothermia Induced by Phenothiazines and DHC in Ischemic Stroke

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Yun Han ◽  
Xiao-kun Geng ◽  
Hangil Lee ◽  
Fengwu Li ◽  
Yuchuan Ding
Keyword(s):  
Ischemic Stroke ◽  
Brain Damage ◽  
Glucose Transporter ◽  
Infarct Volume ◽  
Neurological Deficits ◽  
Ros Production ◽  
Sprague Dawley ◽  
Drug Induced ◽  
Neuroprotective Effects ◽  
Sprague Dawley Rats

Background and Purpose. Studies have shown that interischemia hypothermia is able to reduce the size of myocardial infarctions and improve their clinical outcomes. The present study determined whether interischemia hypothermia induced by the pharmacological approach induced stronger neuroprotection in ischemic brains. Methods. Adult male Sprague Dawley rats were studied in 4 groups: (1) sham; (2) stroke; (3) stroke treated with pharmacological hypothermia before reperfusion (interischemia hypothermia); and (4) stroke treated with pharmacological hypothermia after reperfusion is initiated (inter-reperfusion hypothermia). The combination of chlorpromazine and promethazine with dihydrocapsaicin (DHC) was used to induce hypothermia. To compare the neuroprotective effects of drug-induced hypothermia between the interischemia and inter-reperfusion groups, brain damage was evaluated using infarct volume and neurological deficits at 24 h reperfusion. In addition, mRNA expressions of NADPH oxidase (NOX) subunits (gp91phox, p67phox, p47phox, and p22phox) and glucose transporter subtypes (GLUT1 and GLUT3) were determined by real-time PCR at 6 and 24 h reperfusion. ROS production was measured by flow cytometry assay at the same time points. Results. In both hypothermia groups, the cerebral infarct volumes and neurological deficits were reduced in the ischemic rats. At 6 and 24 h reperfusion, ROS production and the expressions of NOX subunits and glucose transporter subtypes were also significantly reduced in both hypothermia groups as compared to the ischemic group. While there were no statistically significant differences between the two hypothermia groups at 6 h reperfusion, brain damage was significantly further decreased by interischemia hypothermia at 24 h. Conclusion. Both interischemia and inter-reperfusion pharmacological hypothermia treatments play a role in neuroprotection after stroke. Interischemia hypothermia treatment may be better able to induce stronger neuroprotection after ischemic stroke. This study provides a new avenue and reference for stronger neuroprotective hypothermia before vascular recanalization in stroke patients.

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