basic sciences

Kristina Shkirkova, BSc
@KShkirkova

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. 

Aurora Semerano, MD
@semerano_aurora

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

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.

Lin Kooi Ong, PhD
@DrLinOng

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.