Pathophysiology of blood brain barrier dysfunction during chronic cerebral hypoperfusion in vascular cognitive impairment

Theranostics, Год журнала: 2022, Номер 12(4), С. 1639 - 1658

Опубликована: Янв. 1, 2022

The prevalence of cerebrovascular disease increases with age, placing the elderly at a greater lifetime risk for dementia. Vascular cognitive impairment (VCI) encompasses spectrum deficits from mild to VCI and its most severe form, vascular dementia (VaD), is becoming major public health concern worldwide. As growing efforts are being taken understand VaD in animal models humans, pathogenesis actively explored. It postulated that chronic cerebral hypoperfusion (CCH) cause VCI. CCH activates molecular cellular injury cascade leads breakdown blood brain barrier (BBB) neurodegeneration. BBB tightly regulates movement substances between brain, thereby regulating microenvironment within parenchyma. Here we illustrate how damage causal through increased activation pathways related excitotoxicity, oxidative stress, inflammation matrix metalloproteinases lead downstream perivascular damage, leukocyte infiltration white matter changes brain. Thus, CCH-induced may initiate contribute vicious cycle, resulting progressive neuropathological This review outlines mechanisms govern during highlights clinical evidence identifying at-risk patients.

Язык: Английский

---

Dimethyl fumarate improves cognitive deficits in chronic cerebral hypoperfusion rats by alleviating inflammation, oxidative stress, and ferroptosis via NRF2/ARE/NF-κB signal pathway

International Immunopharmacology, Год журнала: 2021, Номер 98, С. 107844 - 107844

Опубликована: Июнь 18, 2021

Язык: Английский

---

The microbiota-gut-brain axis participates in chronic cerebral hypoperfusion by disrupting the metabolism of short-chain fatty acids

Microbiome, Год журнала: 2022, Номер 10(1)

Опубликована: Апрель 17, 2022

Abstract Background Chronic cerebral hypoperfusion (CCH) underlies secondary brain injury following certain metabolic disorders and central nervous system (CNS) diseases. Dysregulation of the microbiota-gut-brain axis can exacerbate various CNS through aberrantly expressed metabolites such as short-chain fatty acids (SCFAs). Yet, its relationship with CCH remains to be demonstrated. And if so, it is interest explore whether restoring gut microbiota maintain SCFA metabolism could protect against CCH. Results Rats subjected bilateral common carotid artery occlusion (BCCAO) a model exhibited cognitive impairment, depressive-like behaviors, decreased motility, compromised barrier functions. The 16S ribosomal RNA gene sequencing revealed an abnormal profile relative abundance some representative producers, hippocampal SCFAs further evidence. Using fecal transplantation (FMT), rats recolonized balanced microbiome acquired higher level SCFAs, well neuroinflammation when exposed lipopolysaccharide. Healthy FMT promoted motility functions, improved decline behaviors by inhibiting neuronal apoptosis in BCCAO rats. Long-term supplementation confirmed neuroprotective effect terms relieving inflammatory response BCCAO. Conclusion Our results demonstrate that modulating via ameliorate BCCAO-induced dysbiosis, decline, possibly enhancing SCFA-producing floras subsequently increasing levels.

Язык: Английский

---

Emerging role of STING signalling in CNS injury: inflammation, autophagy, necroptosis, ferroptosis and pyroptosis

Journal of Neuroinflammation, Год журнала: 2022, Номер 19(1)

Опубликована: Окт. 4, 2022

Abstract Stimulator of interferons genes (STING), which is crucial for the secretion type I and proinflammatory cytokines in response to cytosolic nucleic acids, plays a key role innate immune system. Studies have revealed participation STING pathway unregulated inflammatory processes, traumatic brain injury (TBI), spinal cord (SCI), subarachnoid haemorrhage (SAH) hypoxic–ischaemic encephalopathy (HIE). signalling markedly increased CNS injury, agonists might facilitate pathogenesis injury. However, effects STING-regulated activation are not well understood. Aberrant increases events, interferon responses, cell death. cGAS primary that induces activation. Herein, we provide comprehensive review latest findings related cGAS–STING highlight control mechanisms their functions Furthermore, summarize explore most recent advances toward obtaining an understanding involvement programmed death (autophagy, necroptosis, ferroptosis pyroptosis) during We also potential therapeutic agents capable regulating pathway, facilitates our value this as treatment target.

Язык: Английский

---

The role of inflammasomes in vascular cognitive impairment

Molecular Neurodegeneration, Год журнала: 2022, Номер 17(1)

Опубликована: Янв. 9, 2022

There is an increasing prevalence of Vascular Cognitive Impairment (VCI) worldwide, and several studies have suggested that Chronic Cerebral Hypoperfusion (CCH) plays a critical role in disease onset progression. However, there limited understanding the underlying pathophysiology VCI, especially relation to CCH. Neuroinflammation significant contributor progression VCI as increased systemic levels proinflammatory cytokine interleukin-1β (IL-1β) has been extensively reported patients. Recently it established CCH can activate inflammasome signaling pathways, involving NLRP3 AIM2 inflammasomes critically regulate IL-1β production. Given neuroinflammation early event important we understand its molecular cellular mechanisms enable development disease-modifying treatments reduce structural brain damage cognitive deficits are observed clinically elderly. Hence, this review aims provide comprehensive insight into involved pathogenesis CCH-induced VCI.

Язык: Английский

---

Chronic cerebral hypoperfusion: a critical feature in unravelling the etiology of vascular cognitive impairment

Acta Neuropathologica Communications, Год журнала: 2023, Номер 11(1)

Опубликована: Июнь 12, 2023

Vascular cognitive impairment (VCI) describes a wide spectrum of deficits related to cerebrovascular diseases. Although the loss blood flow cortical regions critically involved in processes must feature as main driver VCI, underlying mechanisms and interactions with disease remain be fully elucidated. Recent clinical studies cerebral measurements have supported role chronic hypoperfusion (CCH) major vascular pathology manifestations VCI. Here we review pathophysiological well neuropathological changes CCH. Potential interventional strategies for VCI are also reviewed. A deeper understanding how CCH can lead accumulation VCI-associated could potentially pave way early detection development disease-modifying therapies, thus allowing preventive interventions instead symptomatic treatments.

Язык: Английский

---

Role of pyroptosis in the pathogenesis of various neurological diseases

Brain Behavior and Immunity, Год журнала: 2024, Номер 117, С. 428 - 446

Опубликована: Фев. 7, 2024

Язык: Английский

---

The Trinity of cGAS, TLR9, and ALRs Guardians of the Cellular Galaxy Against Host-Derived Self-DNA

Frontiers in Immunology, Год журнала: 2021, Номер 11

Опубликована: Фев. 11, 2021

The immune system has evolved to protect the host from pathogens and allergens surrounding their environment. develops in such a way recognize self non-self self-tolerance against self-proteins, nucleic acids, other larger molecules. However, broken immunological leads development of autoimmune or autoinflammatory diseases. Pattern-recognition receptors (PRRs) are expressed by cells on cell membrane cytosol. Different Toll-like (TLRs), Nod-like (NLRs) absent melanoma-2 (AIM-2)-like (ALRs) forming inflammasomes cytosol, RIG (retinoic acid-inducible gene)-1-like (RLRs), C-type lectin (CLRs) some PRRs. DNA-sensing receptor cyclic GMP–AMP synthase (cGAS) is another PRR present cytosol nucleus. review describes role ALRs (AIM2), TLR9, cGAS recognizing DNA as potent damage/danger-associated molecular pattern (DAMP), which moves out its housing organelles (nucleus mitochondria). introduction opens with concept that pathogens, idea horror autotoxicus , failure due emergence diseases (ADs), discovery PRRs revolutionizing immunology. second section cGAS-STING signaling pathway mediated cytosolic self-DNA recognition, evolution, characteristics self-DNAs activating it, different inflammatory conditions. third TLR9 endolysosomes during infections depending various fourth discusses about AIM2 (an ALR), also binds (with 80–300 base pairs bp) inhibits cGAS-STING-dependent type 1 IFN generation but induces inflammation pyroptosis Hence, this trinity potential DAMP comes into action guard cellular galaxy. dysregulation proves dangerous several conditions, including sterile-inflammatory conditions ADs.

Язык: Английский

---

P2X7R/NLRP3 signaling pathway-mediated pyroptosis and neuroinflammation contributed to cognitive impairment in a mouse model of migraine

The Journal of Headache and Pain, Год журнала: 2022, Номер 23(1)

Опубликована: Июль 2, 2022

Abstract Migraine is the second most common form of headache disorder and leading cause disability worldwide. Cognitive symptoms ranked resulting in migraine-related disability, after pain. P2X7 receptor (P2X7R) was recently shown to be involved hyperalgesia migraine. However, role P2X7R cognitive impairment still ill-defined. The aim this study explore molecular mechanisms underlying it. Here we used a well-established mouse model migraine that triggered attacks by application inflammatory soup (IS) dura. Our results showed repeated dural IS stimulation upregulation P2X7R, activation NLRP3 inflammasome, release proinflammatory cytokines (IL-1β IL-18) pyroptotic cell death pathway. Gliosis (microgliosis astrogliosis), neuronal loss also occurred IS-induced model. No significant apoptosis or whiter matter damage observed following attacks. These pathological changes mainly cerebral cortex less extent hippocampus, all which can prevented pretreatment with specific antagonist Brilliant Blue G (BBG). Moreover, BBG alleviate stimulation. identified as key contributor may represent potential therapeutic target for mitigating

Язык: Английский

---

A Study on the Pathogenesis of Vascular Cognitive Impairment and Dementia: The Chronic Cerebral Hypoperfusion Hypothesis

Journal of Clinical Medicine, Год журнала: 2022, Номер 11(16), С. 4742 - 4742

Опубликована: Авг. 14, 2022

The pathogenic mechanisms underlying vascular cognitive impairment and dementia (VCID) remain controversial due to the heterogeneity of causes complexity disease neuropathology. However, one common feature shared among all these is cerebral blood flow (CBF) dysregulation, chronic hypoperfusion (CCH) universal consequence CBF which subsequently results in an insufficient supply brain, ultimately contributing VCID. purpose this comprehensive review emphasize important contributions CCH VCID illustrate current findings about involved CCH-induced pathological changes. Specifically, evidence mainly provided support molecular mechanisms, including Aβ accumulation, inflammation, oxidative stress, blood-brain barrier (BBB) disruption, trophic uncoupling white matter lesions (WMLs). Notably, there are close interactions multiple further research necessary elucidate hitherto unsolved questions regarding interactions. An enhanced understanding features preclinical models could provide a theoretical basis, achieving shift from treatment prevention.

Язык: Английский

---