American Heart Association

basic sciences

Investigating Stem Cell Treatment in Stroke-Associated Retinal Ischemia

Melissa Trotman-Lucas, PhD
@TrolucaM

Nguyen H, Lee JY, Sanberg PR, Napoli E, Borlongan CV. Eye Opener in Stroke: Mitochondrial Dysfunction and Stem Cell Repair in Retinal Ischemia. Stroke. 2019;50:2197–2206.

Retinal damage is a significant stroke-associated outcome, with 92% of patients suffering visual impairments during the initial recovery phase. Partial, and in some cases complete, recovery can occur; however, 20% of patients will suffer persistent or permanent visual impairment. The anatomic link between the ophthalmic artery and the middle cerebral artery is a potential factor in the reduction of retinal blood flow during middle cerebral artery occlusion (MCAO). The reduced blood flow leads to ischemic retinal damage and subsequent visual impairment. Visual disability is much less evident than other motor or speech deficits following stroke, yet can significantly affect a patient’s rehabilitation, including functional recovery and quality of life. Reduction in rapid eye movements, visual acuity and visual field defects can occur, affecting daily activities and capabilities such as reading, mobility, postural stability, spatial recognition and more. These directly affect a patient’s independence, increasing fear and disorientation, reducing confidence and leading to social withdrawal. Current therapy for stroke-associated visual impairment is neurovisual rehabilitation, involving guiding a patient to learn coping strategies to improve quality of life. Retinal ischemia also shares parallels in pathology to other ocular vascular diseases, such as diabetic retinopathy, glaucoma, retinal vein occlusion and central retinal artery occlusion. There is a need to better understand the similarities and relationship between cerebral ischemia and retinal ischemia, particularly ischemic stroke that incorporates retinal ischemic damage. The lack of current understanding may contribute to the absence of effective treatments for this prevalent post-stroke outcome.

Burst of Stress Hormone is Necessary for Poststroke Survival

Lin Kooi Ong, PhD
@DrLinOng

Yang J, Kim E, Beltran C, Cho S. Corticosterone-Mediated Body Weight Loss Is an Important Catabolic Process for Poststroke Immunity and Survival. Stroke. 2019;50:2539–2546.

“Stress is bad for you, right? Well, not necessarily. The devil is in the dose, and how you perceive the stress.”1
—Dr. Lila Landowski, University of Tasmania

In response to stroke, the hypothalamic-pituitary-adrenal axis is activated and releases glucocorticoids such as cortisol. Cortisol is involved in stress responses, regulation of energy and immune reactions. Yang et al. aimed to elucidate the acute actions of corticosterone in body weight loss, immunity responses and survival after experimental stroke in mice. Corticosterone is a major catabolic steroid hormone produced from the adrenal gland in rodents (cortisol in humans). The team observed a small burst of corticosterone levels around 1 to 3 hours and decreased back to baseline around 6 hours after stroke. Further, they noted that the degree of weight loss at day 3 estimates the severity of the stroke as well as the infiltration of peripheral immune cells into the brain. As the role of corticosterone during the acute stroke phase is controversial, the team tested the concept by surgically removing the adrenal glands prior to induction of experimental stroke. All mice with intact adrenal glands survived after stroke, and only 1 out of 8 mice following adrenalectomy survived. Interestingly, treating adrenalectomy mice with corticosterone partially rescued the survival rate to 4 out of 10. Based on the findings, the authors suggested that the adrenal corticosterone-mediated catabolic process is necessary for poststroke immunity and survival.

Microstimulation Guidance Results in Accurate and Reproducible Preclinical Lacunar Infarcts, Modeled in the Rat

Melissa Trotman-Lucas, PhD
@TrolucaM

Wen TC, Sindhurakar A, Contreras Ramirez V, Park H, Gupta D, Carmel JB. Targeted Infarction of the Internal Capsule in the Rat Using Microstimulation Guidance. Stroke. 2019;50:2531-2538.

Lacunar stroke occurs when a penetrating arteriole becomes blocked, leading to ischemic damage to deep brain structures such as subcortical white matter or deep grey matter. Lacunes are small areas of cell damage that can cause significant disability to the sufferer. This type of cerebral ischemic occurrence accounts for a fifth of all strokes, resulting in varied clinical presentations. Lacunar stroke of the internal capsule, or IC, is associated with lasting motor deficits and poor recovery. It is critical to develop a reliable preclinical model, focusing on corticospinal tract (CST) damage located within the IC, as this damage is a reliable predictor of stroke severity and clinical outcome.

In this article commentary, the recent publication by Tong-Chun Wen and colleagues reporting lacunar infarction induction using microstimulation guidance is discussed. Microstimulation was used by the group as a guide as the IC is a small subcortical structure, within already limited rat white matter, with an elongated irregular shape that can vary with age, sex and strain. Wen et al. set out to develop a reliable preclinical IC stroke model that could produce tightly focused lesions to improve upon the various preclinical methods currently used, including chemical, physical and photo induced models. Chemical induction can result in off target injuries due to unpredictable diffusion of the inducting solution and physical induction, although closely imitating the mechanism of human lacunar stroke induction, requires significant surgical expertise. The group utilized photothrombolysis, where a photosensitive dye is first injected into the blood stream and then target vessels are illuminated by a laser light source inducing thrombus formation. The group enhanced this method with the addition of micro-electrical stimulation to guide placement of the illuminating optical fibre. This was achieved through the use of an optrode, a combined electrode and optical-fibre probe.

Article Commentary: “Cannabis and Cannabinoid Biology in Stroke”

Pamela Cheng, DO

Choi S-H, Mou Y, Silva AC. Cannabis and Cannabinoid Biology in Stroke: Controversies, Risks, and Promises. Stroke. 2019;50:2640–2645.

Stroke remains one of the leading causes of death and disability in the United States. Currently, the main therapeutic approach includes thrombolysis and mechanical thrombectomy. However, immediate reperfusion therapy does not tell the whole story. Following a stroke, there are complex biochemical events that occur that lead to excitotoxicity and oxidative stress, which may contribute to long-term functional outcomes. As such, there has been great interest and research in the field of neuroprotection. While there are currently no approved neuroprotective treatment options for stroke, there have been some promising yet conflicting results on the endocannabinoid system (ECS).

The ECS is composed of endogenous, lipid-based neurotransmitters that bind to the cannabinoid receptors. The ECS has shown promise in a wide range of pathological conditions and neurological disorders. In stroke, there is evidence that the ECS is altered in both animals and humans, and may contribute to the consequences of ischemic stroke. While studies have been conflicting in either supporting or refuting the use of cannabinoids, they remain a prominent research focus.

Poststroke Hypertension: Beneficial or Harmful?

Melissa Trotman-Lucas, PhD, BSc
@TroLucaM

Thakkar P, McGregor A, Barber PA, Paton JFR, Barrett C, McBryde F. Hypertensive Response to Ischemic Stroke in the Normotensive Wistar Rat: Mechanisms and Therapeutic Relevance. Stroke. 2019;50:2522-2530.

Sudden increased blood pressure (BP), known as hypertension, following an ischaemic insult is the scenario for ~80% of acute ischaemic stroke (AIS) patients. This poststroke hypertension is the subject of continued scientific debate, with both the mechanism and its therapeutic relevance still poorly understood. There are two potential sides to the role of poststroke hypertension in AIS tissue damage: exacerbation and protection. Exacerbation of damage to vulnerable ischemic tissue may occur alongside promotion of edema formation; moreover, this abrupt increase in BP can increase the risk of cardiovascular events, including further strokes and heart attacks. On the flip side, this increased BP may be a reaction by the body to increase blood supply to the brain tissue, increasing oxygenation of the penumbral tissue. Therefore, creating the conundrum that treatment to reduce BP levels in AIS may be protective but, on the other hand, it may also escalate tissue damage and increase the risk of a poorer patient outcome.

A recent study by Thakkar et al., published in Stroke, sought to answer whether a neurally mediated increase in systemic BP protects cerebral perfusion by opposing the increase in intracranial pressure (ICP) through increasing supply pressure to the tissues. Undertaking this by characterising the cerebrovascular, ICP and cerebral oxygenation responses in a rat AIS model. Testing also the physiological impact of hypertension prevention on the maintenance of oxygenation in the penumbra and on functional recovery poststroke.

NLRP3 Inflammasome as a Therapeutic Target for Ischaemic Stroke: Are We Really There Yet?

Melissa Trotman-Lucas, PhD
@TroLucaM

Lemarchand E, Barrington J, Chenery A, Haley M, Coutts G, Allen JE, et al. Extent of Ischemic Brain Injury After Thrombotic Stroke Is Independent of the NLRP3 (NACHT, LRR and PYD Domains-Containing Protein 3) Inflammasome. Stroke. 2019;50:1232-1239.

Inflammation plays a key role in the fight against infection. However, following ischaemic brain injury, inflammation can play a very different role, exacerbating the severity of damage. Inflammation results in long lasting, ongoing damage from the onset of vessel blockage through to and during reperfusion of the ischaemic brain area. One possible player within the inflammation related post-stroke damage is the NLR family pyrin domain containing 3 (NLRP3) inflammasome. During ischaemic brain injury, NLRP3 senses multiple stroke-induced stimuli leading to the recruitment of the adaptor protein ASC (the apoptosis-associated speck-like pro-caspase-1) resulting in caspase 1 production leading to downstream IL-1β and IL-18 production and release. IL-1β is well-reported to have significant pro-inflammatory and pro-apoptotic effects during acute ischaemic stroke.   

A recent study by Lemarchand et al., published in Stroke, sought to determine the importance of NLRP3 to the damage occurring following ischaemic brain damage. Previous studies have reported associations between NLRP3 and an increase in the severity of ischaemic brain injury, leading to the suggestion that targeting NLRP3 could be a potential therapeutic avenue. These previous studies report NLRP3 inhibition to be protective during ischaemia, alongside data showing that mice deficient in NLRP3 show decreased damage when compared to WT counterparts. However, contrary to this, the group responsible for the paper discussed here have previously reported that ischaemic brain injury develops independent of the NLRP3 inflammasome in a rodent model of stroke, suggesting instead that the NLRC4 (NLR family, CARD containing 4) and AIM2 (absent in melanoma 2) inflammasomes contribute to the resulting brain injury, independent of NLRP3. Lemarchand et al. sought to categorically determine the role of NLRP3 in ischaemic stroke damage, using genetic and pharmacological inhibition of NLRP3. Furthermore, to increase the robustness of the data, the group utilized the FeCl3 (ferric chloride induced thrombosis) model of preclinical ischaemic stroke, where FeCl3 soaked strips are applied to the middle cerebral artery causing localized and immediate thrombus formation, a model that may have considerable clinical relevance.   

Reconsidering Role of Immune System in Neuropathophysiology After Stroke

Lin Kooi Ong, PhD
@DrLinOng

Perego C, Fumagalli S, Miteva K, Kallikourdis M, De Simoni M-G. Combined Genetic Deletion of IL (Interleukin)-4, IL-5, IL-9, and IL-13 Does Not Affect Ischemic Brain Injury in Mice. Stroke. 2019;50:2207–2215

Primary brain injury occurs immediately after the onset of stroke, and triggers a cascade of immune responses including glial activation, recruitment of peripheral immune cells and release of cytokines and chemokines. These inflammation responses may aggravate brain injury by enhancing oxidative stress, production of neurotoxic proteins and disruption of neurovascular unit. On the other hand, inflammation may also participate in waste clearance, production of neurotropic factors and support the survivor of neurons. The recognition of the crucial role of inflammation after stroke has motivated stroke researchers to investigate novel interventions to target brain inflammation processes, leading to improve neurological outcome.

Plasma, but Not Endothelial Fn-EDA, Promotes Ischemic Thrombo-Inflammation

Kristina Shkirkova, BSc

Dhanesha N, Chorawala MR, Jain M, Bhalla A, Thedens D, Nayak M, et al. Fn-EDA (Fibronectin Containing Extra Domain A) in the Plasma, but Not Endothelial Cells, Exacerbates Stroke Outcome by Promoting Thrombo-Inflammation. Stroke. 2019;50:1201–1209.

Reperfusion with mechanical thrombectomy and recombinant tissue plasminogen activator is a standard of care for patients with ischemic stroke. However, there is evidence from animal and clinical studies that the process of reperfusion contributes to vascular inflammation, secondary thrombosis and oxidative stress. The molecular mechanisms of this thrombo-inflammatory injury are not well understood.

The recent study by Dhanesha et al. published in Stroke examined the role of cellular fibronectin containing extra domain A (Fn-EDA) in thrombo-inflammatory injury. Fn-EDA is a glycoprotein that is present in a cellular form on the endothelial cells of the arteries and in a non-cellular form in the blood plasma. Previous studies have shown a significant elevation in the levels of plasma Fn-EDA in patients with cardiovascular disease. Additionally, severe vascular dysfunction in stroke is associated with increased expression of cellular Fn-EDA in activated endothelial cells. The aim of this study was to investigate contribution of plasma versus cellular Fn-EDA on stroke injury.

Phosphodiesterase-3 Inhibitors: The New Kid on the Block

Victor J. Del Brutto, MD

Bieber M, Schuhmann MK, Volz J, Kumar GJ, Vaidya JR, Nieswandt, et al. Description of a Novel Phosphodiesterase (PDE)-3 Inhibitor Protecting Mice From Ischemic Stroke Independent From Platelet Function. Stroke. 2018;50:478–486.

Inhibition of phosphodiesterase-3 (PDE-3) in platelets increases intracellular cAMP levels resulting in blockage of platelet aggregation induced by collagen, adenosine diphosphate, arachidonic acid, and epinephrine. In addition, PDE-3 inhibitors have a pleiotropic effect over blood vessels, which include arteriolar vasodilation, endothelial repair, smooth muscle anti-proliferative effect, and reduction of endothelial inflammatory response.

Although considered to have a central antiplatelet mechanism of action, PDE-3 inhibitors exert its vascular protective effect through the diverse therapeutic targets listed above. Cilostazol, a PDE-3 inhibitor prototype, is often used chronically in patients with peripheral vascular disease, as well as for coronary artery disease and stroke secondary prevention, particularly in Asian countries. There is growing evidence on the long-term efficacy and safety of cilostazol used among patients with non-cardioembolic stroke, especially when used in combination with aspirin or clopidogrel. However, little is known about its neuroprotective effects during acute ischemic injury.

Diabetic Condition Worsens Functional Deficits After Stroke

Lin Kooi Ong, PhD
@DrLinOng

Ma S, Wang J, Wang Y, Dai X, Xu F, Gao X, et al. Diabetes Mellitus Impairs White Matter Repair and Long-Term Functional Deficits After Cerebral Ischemia. Stroke. 2018

This article by Wang and colleagues aimed to investigate the impact of diabetes on brain recovery after stroke using a preclinical model, comparing wild type male mice to diabetes (db/db) mice. The team observed a significant decrease in sensorimotor performance in diabetes mice after stroke. It should be noted that the team did not observe deficit in memory function using the Morris water maze. There was an exacerbated white matter damage at both structural and functional levels. Further, there was an enhanced inflammatory response at the white matter in diabetes mice after stroke, such as a shift of microglia/macrophage to pro-inflammatory phenotype and higher levels of IL-1β and IL-6 expression. The inflammatory environment inhibited oligodendrogenesis, a brain repair mechanism to generate new myelinating oligodendrocytes. These findings provide compelling preclinical evidence that diabetic condition exacerbates functional deficits after stroke.