American Heart Association

basic sciences

AST-004 Treatment Reduces Brain Infarct Volume in a Nonhuman Primate Ischemic Stroke Model

Kristina Shkirkova, BSc

Liston TE, Hama A, Boltze J, Poe RB, Natsume T, Hayashi I, Takamatsu H, Korinek WS, Lechleiter JD. Adenosine A1R/A3R (Adenosine A1 and A3 Receptor) Agonist AST-004 Reduces Brain Infarction in a Nonhuman Primate Model of Stroke. Stroke. 2022;53:238-248. 

Adenosine A1 and A3 receptors (A1R and A3R) are involved in supply of energy, oxygen, and nutrients to the brain. Under pathological conditions of brain injury, these receptors may play an important role in functional balance and neuroprotection.1 Studies in mice have shown that activation of A1R and A3R with agonists results in reduction of cerebral lesion volume in ischemic stroke models. Adenosine A1 and A3 receptors are viable therapeutic targets for stroke treatment; however, there remains a need to establish appropriate dosing and timing of A1R/A3R agonist treatment that could be translated for its use in clinical studies.

By |April 13th, 2022|basic sciences|Comments Off on AST-004 Treatment Reduces Brain Infarct Volume in a Nonhuman Primate Ischemic Stroke Model

Microvascular Circadian Rhythmicity and Subarachnoid Hemorrhage-Induced Injury

Kristina Shkirkova, BSc

Lidington D, Wan H, Dinh DD, Ng C, Bolz SS. Circadian Rhythmicity in Cerebral Microvascular Tone Influences Subarachnoid Hemorrhage–Induced Injury. Stroke. 2022;53:249–259.

Clinical and epidemiological evidence suggests that cerebrovascular events are influenced by circadian rhythms. Due to changes in coagulative balance and vascular tone during a 24-hour period, strokes are observed to occur more often in the mornings followed by evenings, the second most prevalent time.1 Similarly, it was previously reported that variations in circadian blood pressure and microvascular perfusion influenced the incidence of subarachnoid hemorrhage (SAH).2

SAH neuronal damage and poor outcomes have been associated with changes to tissue perfusion. Since cellular mechanisms controlling circadian rhythms play an important role in cerebral blood flow autoregulation, circadian oscillation of microcirculation following SAH drive the cerebral perfusion rhythm. However, the evidence of circadian influence on neuronal injury after SAH remains elusive. The authors of the study by Lidington et al., recently published in Stroke, looked at cerebral resistance artery myogenic reactivity, a mechanism of cerebral blood flow autoregulation, which is strongly correlated with cerebral perfusion and neuronal injury after SAH. 

By |April 6th, 2022|basic sciences|Comments Off on Microvascular Circadian Rhythmicity and Subarachnoid Hemorrhage-Induced Injury

Role of Ferric Ions in Formation of Arteriolar Microvasospasms After Subarachnoid Hemorrhage

Kristina Shkirkova, BSc

Liu H, Schwarting J, Terpolilli NA, Nehrkorn K, Plesnila N. Scavenging Free Iron Reduces Arteriolar Microvasospasms After Experimental Subarachnoid Hemorrhage. Stroke. 2021;52:4033–4042.

This study investigated the role of Ferric ions (Fe3+) in the mechanism of microvasospasms secondary to subarachnoid hemorrhage (SAH). Unlike a rapid spike and decrease in intracranial pressure immediately after subarachnoid hematoma, prolonged reduction in cerebral blood flow due to microvasospasms produces a global state of cerebral ischemia that lasts beyond the acute phase of SAH. The acute nature of SAH hematoma damage coupled with prolonged and often delayed states of vasospasm contributes to tissue ischemia and subsequent posthemorrhagic brain damage in SAH.

Previous studies have implicated the role of nitric oxide (NO) in the regulation of cerebral blood flow in the brain and observed a significant decrease in NO levels after SAH. A reduction in microvasospasms was observed when exogenous NO was supplied after SAH.

By |March 25th, 2022|basic sciences|Comments Off on Role of Ferric Ions in Formation of Arteriolar Microvasospasms After Subarachnoid Hemorrhage

Neuroprotective Effects of Small Extracellular Vesicles in Stroke of the Aged: A Further Step Toward Clinically Relevant Stroke Research

Aurora Semerano, MD

Wang C, Börger V, Mohamud Yusuf A, Tertel T, Stambouli O, Murke F, Freund N, Kleinschnitz C, Herz J, Gunzer M, et al. Postischemic Neuroprotection Associated With Anti-Inflammatory Effects by Mesenchymal Stromal Cell-Derived Small Extracellular Vesicles in Aged Mice. Stroke. 2022;53:e14–e18.

Age is the most important non-modifiable stroke risk factor. Over 80% of ischemic strokes occur in people aged 65 years and older. Elderly patients with stroke have higher mortality, greater disability, and longer hospitalizations, they receive less evidence-based care, and they are less likely to be discharged to their original place of residence.1 Understanding the mechanisms of increased vulnerability that occurs with age is pivotal to reveal new therapeutic opportunities for stroke.

A profound dysregulation of the immune system is observed in elderly people, and it is commonly referred to with the term “inflamm-ageing”,2 characterized by a persistent subtle increase of inflammatory stress accompanied by a blunted inflammatory response to immunogenic triggers. “Inflamm-ageing” likely contributes to the pathophysiology of different age-dependent conditions, including stroke. Patients with ischemic stroke showed increased plasma levels of the pro-inflammatory cytokine TNF-α with age.3 A transcriptomic analysis of peripheral blood RNA in patients with acute ischemic stroke revealed differential expression in aged and young patients, mostly in genes associated with altered B-cell receptor signaling, lymphocyte proliferation, and leukocyte homeostasis.4 In human postmortem brain tissue, age positively correlates with neutrophil infiltration, MMP-9 expression, and hemorrhagic transformation.5 However, studying ageing and its consequences in humans is tricky as other cerebrovascular risk factors can operate as confounders. In this context, experimental stroke in rodents offers the advantage to isolate the effects of ageing. TNF-α inhibition restored the volume of cerebral infarct, neuromotor performance, and survival rates in aged stroke mice to the levels observed in young ones.3 After middle cerebral artery occlusion (MCAO), aged animals reconstituted with young bone marrow showed reduced behavioral deficits and significantly fewer brain-infiltrating neutrophils compared to younger controls.5

By |March 24th, 2022|basic sciences|Comments Off on Neuroprotective Effects of Small Extracellular Vesicles in Stroke of the Aged: A Further Step Toward Clinically Relevant Stroke Research

Regulatory T Cells in Females Provide Endogenous Neuroprotection, But Increase Secondary Neurodegeneration in Males in Neonatal Encephalopathy in Mice

Kristina Shkirkova, BSc

Beckmann L, Obst S, Labusek N, Abberger H, Köster C, Klein-Hitpass L, Schumann S, Kleinschnitz C, Hermann DM, Felderhoff-Müser U, et al. Regulatory T Cells Contribute to Sexual Dimorphism in Neonatal Hypoxic-Ischemic Brain Injury. Stroke. 2022.

Regulatory T cells (Tregs) are specialized T cells that have an ability to suppress immune response. Recent evidence suggests a sexual dimorphism in the role Tregs play after brain injury.

In the study recently published in Stroke by Beckmann et al., experimental administration of hypoxia-ischemia to neonatal mice by ligation of the right common carotid artery, as a model of neonatal encephalopathy, resulted in increased cerebral Tregs infiltration into the brain. Flow cytometry revealed that females experienced significantly higher frequency and total amount of Treg infiltration than males 24 hours after the induced hypoxia-ischemia in the brain but not in the peripheral tissue. To further investigate the functional contribution of Tegs in both sexes, a special agent, DTX, was used to deplete the number of Tregs in mice. As a result of Treg depletion, a more significant injury was observed in female cortex and hippocampus, while in males, the injury was decreased in these areas. Depletion of Tregs also resulted in functional deficits only in females in early forelimb coordination test as well as long-term exploratory activity. In the hippocampus, Treg depletion increased microglial response, endothelial activation, and leukocyte accumulation in female compared to non-depleted females. Females were also observed to have increased basil lamina disruption following Treg depletion, while for males, Treg depletion provided vascular protection. These differences between sexes were not explained by levels of female hormone estradiol, as there was not a difference observed in serum estradiol levels between males and females. Independent of sex hormones, female Tregs were immunosuppressive on effector T cell compared with male, with Myc Targets, mTORC1 signaling and oxidative phosphorylation pathways showing prominence in gene set enrichment analysis.

By |February 4th, 2022|basic sciences, pathogenesis|Comments Off on Regulatory T Cells in Females Provide Endogenous Neuroprotection, But Increase Secondary Neurodegeneration in Males in Neonatal Encephalopathy in Mice

Targeting Pro-Inflammatory Neuronal Death After Intracerebral Hemorrhage Improves Neurological Deficits in Mice

Kristina Shkirkova, BSc

Yan J, Xu W, Lenahan C, Huang L, Wen J, Li G, Hu X, Zheng W, Zhang JH, Tang J. CCR5 Activation Promotes NLRP1-Dependent Neuronal Pyroptosis via CCR5/PKA/CREB Pathway After Intracerebral Hemorrhage. Stroke. 2021.

Intracerebral hemorrhage (ICH) is the most debilitating stroke subtype, resulting in higher mortality and disability than ischemic stroke. The mechanism of vessel rapture results in blood leaking into the brain tissue, leading not only to physical damage to the surrounding tissue, but also triggering a severe acute inflammatory response in the brain. Acute inflammation is driven by several inflammatory cytokines and inflammasomes that initiate cellular pathways of pyroptosis that ultimately result in neuronal death. 

In this study, the authors focused on a neuronal cell death pathway that involves C-C chemokine receptor 5 (CCR5), which is located in the cell membrane and regulates leukocytes transport in the cells. Using mice with induced IHC, the authors targeted deactivation of this receptor to reduce the inflammatory response in the brain using an antagonist agent to CCR5. After 1 hour of induced ICH in mice, CCR5 antagonist treatment resulted in reduced number of neuronal cells undergoing degeneration and death at 24 and improved neurological motor and sensorimotor functioning at 24 and 72 hours. CCR5 antagonist treatment also significantly increased protein kinase A (PKA) and cAMP response element binding protein (CREB) levels.

By |January 21st, 2022|basic sciences|Comments Off on Targeting Pro-Inflammatory Neuronal Death After Intracerebral Hemorrhage Improves Neurological Deficits in Mice

Activation of T Lymphocytes After Stroke: An Antigen-Specific or Antigen-Independent Mechanism?

Aurora Semerano, MD

Schulze J, Gellrich J, Kirsch M, Dressel A, Vogelgesang A. Central Nervous System-Infiltrating T Lymphocytes in Stroke Are Activated via Their TCR (T-Cell Receptor) but Lack CD25 Expression. Stroke. 2021;52:2939–2947.

Leukocytes from peripheral circulation infiltrate the ischemic brain within hours to days after stroke, and they can contribute to secondary tissue damage, as well as to the subsequent processes of repair and recovery. T lymphocytes are also implied in this response. However, it remains unclear which mechanism of lymphocyte activation plays the most relevant role after stroke: Indeed, both antigen-specific T lymphocytes (reacting against brain antigens) and antigen-independent mechanisms (driven by pro-inflammatory mediators) have been described. These previous studies were mostly conducted with ablative approaches, that’s to say in T-cell-deficient experimental models or upon inhibition of lymphocyte infiltration into the brain.

By |October 21st, 2021|basic sciences|Comments Off on Activation of T Lymphocytes After Stroke: An Antigen-Specific or Antigen-Independent Mechanism?

Brain’s Resident Immune Cells Gone Rogue: Impacts on Thalamic Degeneration After Stroke

Lin Kooi Ong, PhD

Cao Z, Harvey SS, Chiang T, Foltz AG, Lee AG, Cheng MY, Steinberg GK. Unique Subtype of Microglia in Degenerative Thalamus After Cortical Stroke. Stroke. 2021;52:687–698.

In my previous Blogging Stroke post, it is apparent that brain damage is not only confined to the primary infarction site after ischemic stroke, but also in remote regions of the brain. Indeed, secondary thalamic degeneration has been constantly observed in neuroimaging studies among stroke patients with cortical stroke as well as in experimental stroke models. While the mechanisms involved in the development of secondary thalamic degeneration have not been fully elucidated, studies suggest that neuroinflammation is most likely involved. Microglia are thought to be the primary resident immune cells of the brain mediating neuroinflammatory responses after stroke.

In this study, Cao and colleagues investigated the spatiotemporal changes of neurodegeneration, neuroinflammatory responses, and microglial activation for up to 84 days after experimental cortical stroke. They found that microglial activation occurred rapidly and preceded the progressive neuronal loss in the thalamus after stroke. Results from transcriptome analysis of the thalamus showed robust increase in the expression of neuroinflammation and microglia related genes. Excitingly, using a cell sorting technique, the team discovered a unique subtype of CD11c-positive microglia with disease-associated molecular profiles in the thalamus. These disease-associated microglia include reduced expression of Tmem119 and CX3CR1, and increased expression of ApoE, Axl, LpL, CSF1, and Cst7.

By |April 30th, 2021|basic sciences|Comments Off on Brain’s Resident Immune Cells Gone Rogue: Impacts on Thalamic Degeneration After Stroke

Following Calcium Waves in Microglial Cells

Aurora Semerano, MD

Liu L, Kearns KN, Eli I, Sharifi KA, Soldozy S, Carlson EW, Scott KW, Sluzewski MF, Acton ST, Stauderman KA, et al. Microglial Calcium Waves During the Hyperacute Phase of Ischemic Stroke. Stroke. 2021;52:274–283.

Microglia are the main resident immune cell population of the central nervous system and play a key role in brain development, homeostasis and repair. During ischemic stroke, microglia are rapidly activated, and characterized by morphological, proliferative and functional alterations. The role of microglia activation in ischemic stroke remains highly controversial in the preclinical setting and depends on multiple factors, including the experimental conditions and the phase of the disease. More recently, an additional role for microglial cells has been proposed, since they have been found to be implied in the occurrence, the sensing and the response to cortical spreading depolarization (CSD).1 CSD is defined as a slowly propagating (2–5 mm/min) wave of rapid, near-complete depolarization of neurons and astrocytes followed by a period of electrical suppression of a distinct population of cortical neurons. CSD is considered as the biological substrate of migraine aura, but it has been shown to occur in other neurological conditions, such as ischemic stroke, subarachnoid hemorrhage and traumatic brain injury.2 In other words, CSD consists in a deep perturbation of the ionic environment in the brain, which has been associated with excitotoxicity damage and vaso-occlusive phenomenons after brain injury.

By |April 6th, 2021|basic sciences|Comments Off on Following Calcium Waves in Microglial Cells

ISC 2021 Symposium: Enriched Environments and Recovery

Burton J. Tabaac, MD

International Stroke Conference 2021
March 17–19, 2021
Symposium: Enriched Environments and Recovery (121)

Preclinical work has shown the importance of enriched environments on post-stroke recovery. Enriched environments are designed to enhance sensory, motor, and cognitive stimulation by providing equipment, stimulation, open spaces, and a desire to want to engage in rehabilitative interventions. In rodent experiments, enriched environments include toys, ramps, tubes, mirrors, ropes, and the ability to interact with other animals. Rodents exposed to enriched environments early (but not late) post-stroke showed improved motor performance even on tasks for which they did not receive specific training. The proposed mechanisms of action are plethoric and may relate to multiple molecular pathways. Translating an enriched environment to human patients may take several forms, including access to iPads, books, puzzles, games, music, and interaction with other people. Additionally, one could imagine enrichment using virtual/augmented environments with video games and other technology that would not only increase dose and enjoyment.

By |March 20th, 2021|basic sciences, clinical, Conference|Comments Off on ISC 2021 Symposium: Enriched Environments and Recovery