Circadian Biology and Stroke

Background and Purpose: Circadian rhythms influence the extent of brain injury following subarachnoid hemorrhage (SAH), but the mechanism is unknown. We hypothesized that cerebrovascular myogenic reactivity is rhythmic and explains the circadian variation in SAH-induced injury. Methods: SAH was modeled in mice with prechiasmatic blood injection. Inducible, smooth muscle cell–specific Bmal1 (brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1) gene deletion (smooth muscle–specific Bmal1 1 knockout [sm-Bmal1 KO]) disrupted circadian rhythms within the cerebral microcirculation. Olfactory cerebral resistance arteries were functionally assessed by pressure myography in vitro; these functional assessments were related to polymerase chain reaction/Western blot data, brain histology (Fluoro-Jade/activated caspase-3), and neurobehavioral assessments (modified Garcia scores). Results: Cerebrovascular myogenic vasoconstriction is rhythmic, with a peak and trough at Zeitgeber times 23 and 11 (ZT23 and ZT11), respectively. Histological and neurobehavioral assessments demonstrate that higher injury levels occur when SAH is induced at ZT23, compared with ZT11. In sm-Bmal1 KO mice, myogenic reactivity is not rhythmic. Interestingly, myogenic tone is higher at ZT11 versus ZT23 in sm-Bmal1 KO mice; accordingly, SAH-induced injury in sm-Bmal1 KO mice is more severe when SAH is induced at ZT11 compared to ZT23. We examined several myogenic signaling components and found that CFTR (cystic fibrosis transmembrane conductance regulator) expression is rhythmic in cerebral arteries. Pharmacologically stabilizing CFTR expression in vivo (3 mg/kg lumacaftor for 2 days) eliminates the rhythmicity in myogenic reactivity and abolishes the circadian variation in SAH-induced neurological injury. Conclusions: Cerebrovascular myogenic reactivity is rhythmic. The level of myogenic tone at the time of SAH ictus is a key factor influencing the extent of injury. Circadian oscillations in cerebrovascular CFTR expression appear to underlie the cerebrovascular myogenic reactivity rhythm.

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“… 26 Thus, it is crucial to incorporate the circadian dimension into stroke research and therapy design. 4 , 26 , 27 …”

Section: Discussionmentioning

confidence: 99%

Circadian Rhythmicity in Cerebral Microvascular Tone Influences Subarachnoid Hemorrhage–Induced Injury

Lidington

Wan

Dinh

et al. 2022

Stroke

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“…In addition to HPA's neurohormonal role, host circadian rhythm also affects MGBA at steady state and in response to stroke. 95 For example, a study using circadian mutant Clock ∆19/∆19 gene knockout mice revealed that a functional circadian signaling is required for the beneficial effects of the gut microbiota on recovery after myocardial infarction 96 ; however, this has not yet been examined in models of stroke.…”

Section: Systemic Circulation (Hormones Cytokines and Metabolites)mentioning

confidence: 99%

Aging Microbiota-Gut-Brain Axis in Stroke Risk and Outcome

Honarpisheh

Bryan

McCullough

2022

Circulation Research

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The microbiota-gut-brain-axis (MGBA) is a bidirectional communication network between gut microbes and their host. Many environmental and host-related factors affect the gut microbiota. Dysbiosis is defined as compositional and functional alterations of the gut microbiota that contribute to the pathogenesis, progression and treatment responses to disease. Dysbiosis occurs when perturbations of microbiota composition and function exceed the ability of microbiota and its host to restore a symbiotic state. Dysbiosis leads to dysfunctional signaling of the MGBA, which regulates the development and the function of the host’s immune, metabolic, and nervous systems. Dysbiosis-induced dysfunction of the MGBA is seen with aging and stroke, and is linked to the development of common stroke risk factors such as obesity, diabetes, and atherosclerosis. Changes in the gut microbiota are also seen in response to stroke, and may impair recovery after injury. This review will begin with an overview of the tools used to study the MGBA with a discussion on limitations and potential experimental confounders. Relevant MGBA components are introduced and summarized for a better understanding of age-related changes in MGBA signaling and its dysfunction after stroke. We will then focus on the relationship between the MGBA and aging, highlighting that all components of the MGBA undergo age-related alterations that can be influenced by or even driven by the gut microbiota. In the final section, the current clinical and preclinical evidence for the role of MGBA signaling in the development of stroke risk factors such as obesity, diabetes, hypertension, and frailty are summarized, as well as microbiota changes with stroke in experimental and clinical populations. We conclude by describing the current understanding of microbiota-based therapies for stroke including the use of pre-/pro-biotics and supplementations with bacterial metabolites. Ongoing progress in this new frontier of biomedical sciences will lead to an improved understanding of the MGBA’s impact on human health and disease.

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“…There are very few reports of REVERB therapies in neurological preclinical or clinical studies; yet, recent interest in the circadian regulation of disease is taking shape. Stroke infarct size has significant circadian variability and is now under great scrutiny for improving outcomes and secondary prevention of injury ( Lo et al, 2021 ).…”

Section: Clock Genes As Targets In Subarachnoid Hemorrhagementioning

confidence: 99%

The Role of Circadian Clock Genes in Critical Illness: The Potential Role of Translational Clock Gene Therapies for Targeting Inflammation, Mitochondrial Function, and Muscle Mass in Intensive Care

Ray

2022

J Biol Rhythms

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The Earth’s 24-h planetary rotation, with predictable light and heat cycles, has driven profound evolutionary adaptation, with prominent impacts on physiological mechanisms important for surviving critical illness. Pathways of interest include inflammation, mitochondrial function, energy metabolism, hypoxic signaling, apoptosis, and defenses against reactive oxygen species. Regulation of these by the cellular circadian clock (BMAL-1 and its network) has an important influence on pulmonary inflammation; ventilator-associated lung injury; septic shock; brain injury, including vasospasm; and overall mortality in both animals and humans. Whether it is cytokines, the inflammasome, or mitochondrial biogenesis, circadian medicine represents exciting opportunities for translational therapy in intensive care, which is currently lacking. Circadian medicine also represents a link to metabolic determinants of outcome, such as diabetes and cardiovascular disease. More than ever, we are appreciating the problem of circadian desynchrony in intensive care. This review explores the rationale and evidence for the importance of the circadian clock in surviving critical illness.

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Circadian Biology and Stroke

Cited by 51 publications

References 129 publications

Circadian Rhythmicity in Cerebral Microvascular Tone Influences Subarachnoid Hemorrhage–Induced Injury

Circadian Rhythmicity in Cerebral Microvascular Tone Influences Subarachnoid Hemorrhage–Induced Injury

Aging Microbiota-Gut-Brain Axis in Stroke Risk and Outcome

The Role of Circadian Clock Genes in Critical Illness: The Potential Role of Translational Clock Gene Therapies for Targeting Inflammation, Mitochondrial Function, and Muscle Mass in Intensive Care

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