Amyloid Beta-Mediated Neurovascular Toxicity in Alzheimer's Disease.

The brain vascular system receives one-fifth of the total oxygen from the cardiac output, and this transport system is highly dependent on blood-brain barrier (BBB) integrity. The cerebral blood flow is controlled by neurovascular coupling through neurovascular units (NVUs). The NVU includes different types of cells, such as mural cells, astrocytes, pericytes, endothelial cells (ECs), and vascular smooth muscle cells (VSMCs). The cellular composition of NVU varies throughout the vascular tree. Amyloid ß (Aß) is abundantly present in the central nervous system, but the pathological accumulation of misfolded Aß protein causes vascular damage, resulting in neurovascular dysfunction. Aß aggregation can activate the astrocytes and endothelial cells. It is followed by pericyte degeneration which results in dysregulation of cerebral blood flow (CBF), neurovascular uncoupling, and BBB breakdown. Thus, understanding the cellular and molecular mechanisms of Aß-induced neurovascular toxicity is crucial for determining normal and diseased brain function. This chapter discusses the components of NVU, neurovascular uncoupling, Aß-induced cerebrovascular reactivity, and cerebral blood flow reduction in neurodegenerative disorders, with special emphasis on Alzheimer's disease.

Refined Qingkailing protects the in vitro neurovascular unit against oxygen-glucose deprivation and re-oxygenation-induced injury.

Since the proposal of the neurovascular unit (NVU) theory, it has become almost mandatory for neuroprotective medicines against ischaemic stroke (IS) to focus on this unit. Refined Qingkailing (RQKL) is a compound composed of hyodeoxycholic acid, geniposide, baicalin and cholic acid, which has shown great potential in the treatment of IS, but its effect on NVU has not been fully studied. The purpose of this study was to investigate the potential biological pathways that underlie the protective effects of RQKL against NVU damage induced by oxygen-glucose deprivation and re-oxygenation (OGD/R). Using in vitro OGD/R models, we looked into whether RQKL protects the NVU. In order to create an in vitro NVU that resembles IS, we created an OGD/R injury model using primary cultures of brain microvascular endothelial cells, neurons, and astrocytes. Based on our results, we present evidence, for the first time, that RQKL treatment of the injury caused by OGD/R significantly (1) kept the blood brain barrier (BBB) functioning and maintained the architecture of the neurons, (2) mitigated the oxidative stress damage, inflammatory cytokine release, and neuronal death, and (3) upregulated the expression of neurotrophic factors generated from glial cells and the brain in the in vitro model. Therefore, RQKL has a variety of preventive effects against NVU damage caused by OGD/R. RQKL may be a suitable medication for treating IS in a clinical setting.

Immune regulation in neurovascular units after traumatic brain injury.

Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Survivors may experience movement disorders, memory loss, and cognitive deficits. However, there is a lack of understanding of the pathophysiology of TBI-mediated neuroinflammation and neurodegeneration. The immune regulation process of TBI involves changes in the peripheral and central nervous system (CNS) immunity, and intracranial blood vessels are essential communication centers. The neurovascular unit (NVU) is responsible for coupling blood flow with brain activity, and comprises endothelial cells, pericytes, astrocyte end-feet, and vast regulatory nerve terminals. A stable NVU is the basis for normal brain function. The concept of the NVU emphasizes that cell-cell interactions between different types of cells are essential for maintaining brain homeostasis. Previous studies have explored the effects of immune system changes after TBI. The NVU can help us further understand the immune regulation process. Herein, we enumerate the paradoxes of primary immune activation and chronic immunosuppression. We describe the changes in immune cells, cytokines/chemokines, and neuroinflammation after TBI. The post-immunomodulatory changes in NVU components are discussed, and research exploring immune changes in the NVU pattern is also described. Finally, we summarize immune regulation therapies and drugs after TBI. Therapies and drugs that focus on immune regulation have shown great potential for neuroprotection. These findings will help us further understand the pathological processes after TBI.

Neurovascular coupling and central nervous system diseases / 中国药理学通报

Neurovascular coupling is the function of regulating blood flow of the central nervous system at the level of neurovascular units. The central nervous system diseases related to neurovascular coupling mainly include cerebrovascular diseases such as chronic cerebral ischemia and neurodegenerative diseases such as Alzheimer's disease,Parkinson's disease and Lewy body dementia. The main mechanism of neurovascular coupling dysfunction leading to the above diseases is cerebrovascular dysfunction or loss,which leads to serious damage to neuronal ischemia and affects its function. Therefore,this paper reviews the research status of neurovascular coupling and its related central nervous system diseases,in order to guide the follow-up research. The purpose of this paper is to provide a basis for the prevention,relief and treatment of central nervous system diseases related to neurovascular coupling through the mechanism of neurovascular coupling.

The Important Double-Edged Role of Astrocytes in Neurovascular Unit After Ischemic Stroke.

In recent years, neurovascular unit (NVU) which is composed of neurons, astrocytes (Ast), microglia (MG), vascular cells and extracellular matrix (ECM), has become an attractive field in ischemic stroke. As the important component of NVU, Ast closely interacts with other constituents, which has been playing double-edged sword roles, beneficial or detrimental after ischemic stroke. Based on the pathophysiological changes, we evaluated some strategies for targeting Ast in treating ischemic stroke. The present review is focused on the roles of Ast in NVU and its complex signaling molecular network after ischemic stroke, which may be a prospective approach to the treatment of ischemic diseases in central nervous system.

LncRNAS-modulators of neurovascular units in diabetic retinopathy.

As the number of people with diabetes increases, diabetic retinopathy (DR) has become a significant health problem. However, the exact mechanism remains unclear. In recent years, people have tended to think that DR is a neurovascular disease. In the healthy retina, neurons, glial cells, and vascular cells interact with each other to maintain retinal environmental homeostasis and physiological functions. Long noncoding RNAs (lncRNAs) that do not encode proteins regulate various cellular components in the neurovascular unit and are key regulatory molecules involved in processes such as microangiopathy, neurodegeneration, and apoptosis in DR. Here we review the interactions between neurovascular units and the regulation of various cellular components by lncRNAs in an attempt to prove the promise of targeting lncRNAs for the treatment of DR.

Neuroprotective effects of synthetic borneol and natural borneol based on the neurovascular unit against cerebral ischaemic injury.

OBJECTIVES: Natural borneol and synthetic borneol were commonly used to treat ischaemic stroke in clinical practice. This study evaluated their different neuroprotective effects on the remodelling and repair of the neurovascular unit (NVU) after cerebral ischaemia. METHODS: We evaluated the different effects of borneol through neurological test and staining methods in cerebral ischaemia injury. Western blot, immunohistochemistry and transmission electron microscopy were used to evaluate the reparative effects of borneol on NVU. KEY FINDINGS: The prevention and treatment of borneol could prolong recovery time, reduce body temperature and cerebral infarction rate and improve pathological conditions. Further investigations revealed that borneol could inhibit the expression of DII4, Hes1, Hes5 and p65 and increase the Nissl body number and microvessel density. They also inhibited the activation of the microglia. It was also observed through an ultramicroelectron microscope that the structural stability of the NVU has also been repaired. Moreover, natural borneol shows better results in most indicators when compared with synthetic borneol. CONCLUSIONS: Natural borneol showed a stronger effectiveness and had better regulation and neuroprotection on the NVU when compared with synthetic borneol, indicating that it may be better to use natural borneol in the prescription of Chinese patent medicine in clinical practice.

Pathological changes in neurovascular units: Lessons from cases of vascular dementia.

Vascular dementia (VD) is the second leading cause of dementia after Alzheimer's disease (AD). The decrease of cerebral blood flow (CBF) to different degrees is one of the main causes of VD. Neurovascular unit (NVU) is a vessel-centered concept, emphasizing all the cellular components play an integrated role in maintaining the normal physiological functions of the brain. More and more evidence shows that reduced CBF causes a series of changes in NVU, such as impaired neuronal function, abnormal activation of glial cells, and changes in vascular permeability, all of which collectively play a role in the pathogenesis of VD. In this paper, we review NVU changes as CBF decreases, focusing on each cellular component of NVU. We also highlight remote ischemic preconditioning as a promising approach for VD prevention and treatment from the NVU perspective of view.

Research progress of neurogenesis and repair after cerebral ischemia and effect of Chinese medicine / 中国药理学通报

Cerebral ischemia can induce weak endogenous neurogenesis, which is not enough to repair neural injury after cerebral ischemia.In the treatment of cerebral ischemic diseases with Chinese medicine, different treatment methods based on syndrome differentiation are adopted according to the pathological mechanism of the diseases, and the advantages of neural repair after cerebral ischemia are well shown through comprehen-sive regulation.And in this paper, the effects of inflammation, neurovascular units, exogenous stem cell transplantation, exo- somes and other factors on neurogenesis and repair after cerebral ischemia and the intervention of Chinese medicine are described.

Elucidation of Pathophysiology and Novel Treatment for Diabetic Macular Edema Derived from the Concept of Neurovascular Unit.

The retina transmits light signals to the brain via a complex structure composed of photoreceptor cells, neurons including ganglion cells, glial cells such as astrocytes and Mueller cells, as well as retinal blood vessels that feed the retina. The retina performs such high-level physiological function and maintains homeostasis effectively through interactions among the cells that form the neurovascular units (NVUs). Furthermore, as a component of the blood‒retinal barrier (BRB), the vascular structure of the retina is functionally based on the NVUs, in which the nervous system and the vascular tissues collaborate in a mutually supportive relationship. Retinal neurons such as ganglion cells and amacrine cells are traditionally considered to be involved only in visual function, but multiple functionality of neurons attracted attention lately, and retinal neurons play an important role in the formation and function of retinal blood vessels. In other words, damage to neurons indirectly affects retinal blood vessels. Diabetic macular edema is the leading cause of vision loss in diabetic retinopathy, and this type of edema results in neurological and vascular disorders. In this article, the regulatory mechanism of retinal capillaries in diabetic macular edema is reviewed from the viewpoint of NVU.

The role of peripheral monocytes and macrophages in ischemic stroke.

After acute ischemic stroke (AIS), peripheral monocytes infiltrate into the lesion site within 24 h, peak at 3 to 7 days, and then differentiate into macrophages. Traditionally, monocytes/macrophages (MMs) are thought to play a deleterious role in AIS. Depletion of MMs in the acute phase can alleviate brain injury induced by ischemia. However, several studies have shown that MMs have anti-inflammatory functions, participate in angiogenesis, phagocytose necrotic neurons, and promote neurovascular repair. Therefore, MMs play dual roles in ischemic stroke, depending mainly upon the MM microenvironment and the window of time post-stroke. Because activated microglia and MMs are similar in morphology and function, previous studies have often investigated them together. However, recent studies have used special methods to distinguish MMs from microglia and have found that MMs have properties which differ from microglia. Here, we review the unique role of MMs and the interaction between MMs and neurovascular units, including neurons, astrocytes, microglia, and microvessels. Future therapeutics targeting MMs should regulate the polarization and subset transformation of the MMs at different stages of AIS rather than comprehensively suppressing MM infiltration and differentiation. In addition, more studies are needed to elucidate the cellular and molecular mechanisms of MM subsets and polarization during ischemic stroke.

Modeling blood-brain barrier pathology in cerebrovascular disease in vitro: current and future paradigms.

The complexity of the blood-brain barrier (BBB) and neurovascular unit (NVU) was and still is a challenge to bridge. A highly selective, restrictive and dynamic barrier, formed at the interface of blood and brain, the BBB is a "gatekeeper" and guardian of brain homeostasis and it also acts as a "sensor" of pathological events in blood and brain. The majority of brain and cerebrovascular pathologies are associated with BBB dysfunction, where changes at the BBB can lead to or support disease development. Thus, an ultimate goal of BBB research is to develop competent and highly translational models to understand mechanisms of BBB/NVU pathology and enable discovery and development of therapeutic strategies to improve vascular health and for the efficient delivery of drugs. This review article focuses on the progress being made to model BBB injury in cerebrovascular diseases in vitro.

Effect of acupuncture on neurovascular units after cerebral infarction in rats through PI3K/AKT signaling pathway.

OBJECTIVE: To study the effect of acupuncture on neurovascular units after cerebral infarction (CI) in rats through the phosphatidylinositol 3-hydroxy kinase/protein kinase B (PI3K/AKT) signaling pathway. METHODS: A total of 36 Sprague-Dawley rats were randomly divided into sham group (n = 12), model group (n = 12) and acupuncture group (n = 12). The external carotid artery was only exposed in model group, while the post-CI ischemia-reperfusion model was established using the suture method in the other 2 groups. After modeling, the rats in sham group and model group were fixed and sampled, while those in acupuncture group were treated with acupuncture intervention for 2 weeks and sampled. The neurological deficits of rats were evaluated using the Zea-Longa score, and the spatial learning and memory of rats were detected via water maze test. Moreover, the expressions of vascular endothelial growth factor (VEGF), growth associated protein-43 (GAP-43) and synuclein (SYN) in brain tissues were detected via immunohistochemistry, and the relative protein expressions of PI3K p85, PI3K p110 and p-AKT were detected via Western blotting. The messenger ribonucleic acid (mRNA) expressions of VEGF, GAP-43 and SYN were detected via quantitative polymerase chain reaction (qPCR). RESULTS: The Zea-Longa score was significantly increased in model group and acupuncture group compared with that in sham group (p < 0.05), while it significantly declined in acupuncture group compared with that in model group (p < 0.05). The escape latency was significantly prolonged and the times of crossing platform were significantly reduced in model group and acupuncture group compared with those in sham group (p < 0.05), while the escape latency was significantly shortened and the times of crossing platform were significantly increased in acupuncture group compared with those in model group (p < 0.05). The positive expressions of VEGF, GAP-43 and SYN were obviously increased in model group and acupuncture group compared with those in sham group (p < 0.05), while they were obviously increased in acupuncture group compared with those in model group (p < 0.05). Besides, model group and acupuncture group had significantly higher relative protein expressions of PI3K p85, PI3K p110 and p-AKT than sham group (p < 0.05), while acupuncture group also had significantly higher relative protein expressions of PI3K p85, PI3K p110 and p-AKT than model group (p < 0.05). The relative mRNA expressions of VEGF, GAP-43 and SYN were remarkably increased in model group and acupuncture group compared with those in sham group (p < 0.05), while they were remarkably increased in acupuncture group compared with those in model group (p < 0.05). CONCLUSION: Acupuncture promotes the repair of neurovascular units after CI in rats through activating the PI3K/AKT signaling pathway, thereby exerting a protective effect on neurovascular units.

Lung Cancer Cells-Controlled Dkk-1 Production in Brain Metastatic Cascade Drive Microglia to Acquire a Pro-tumorigenic Phenotype.

OBJECTIVES: Organotropism is primarily determined by tumor-derived exosomes. To date, the role of lung cancer cells-derived exosomes underlying the pre-metastatic niche formation is unclear. MATERIALS AND METHODS: The animal models of retro-orbital and intra-ventricular injection were constructed to administrate lung cancer cells-derived exosomes. Cytokine array was used to screen the cytokines released from brain endothelium after internalization of lung cancer cells-derived exosomes. The cellular co-culture system was established to mimic microglia-vascular niche contained lung cancer cells-derived exosomes. The levels of Dkk-1 and the activities of microglia were analyzed by qRT-PCR, western blot and immunofluorescence. In vivo selections of highly brain metastatic cells were performed to analyze the direct interaction of lung cancer cells with microglia. RESULTS: Animal studies demonstrated that there was a suppressive signal transferred from brain endothelium to microglia after internalization of lung cancer cells-derived exosomes into brain endothelium, which caused an absolutely less M1 phenotypic microglia and a relatively more M2 phenotypic microglia. Further results indicated that lung cancer cells-derived exosomes induced a release of endogenous Dkk-1 from brain endothelium, which rendered microglia to acquire a pro-tumorigenic feature in pre-metastatic niche. Subsequently, the declines of Dkk-1 in metastatic lung cancer cells removed the suppression on microglia and enhanced microglial activation in metastatic niche. CONCLUSION: Our findings shed a new light on the synergistic reaction of the different cells in "neurovascular units" toward the metastatic messages from lung cancer cells and provided a potential therapeutic pathway for lung cancer metastasis to brain.

Microthrombus-Targeting Micelles for Neurovascular Remodeling and Enhanced Microcirculatory Perfusion in Acute Ischemic Stroke.

Reperfusion injury exists as the major obstacle to full recovery of neuron functions after ischemic stroke onset and clinical thrombolytic therapies. Complex cellular cascades including oxidative stress, neuroinflammation, and brain vascular impairment occur within neurovascular units, leading to microthrombus formation and ultimate neuron death. In this work, a multitarget micelle system is developed to simultaneously modulate various cell types involved in these events. Briefly, rapamycin is encapsulated in self-assembled micelles that are consisted of reactive oxygen species (ROS)-responsive and fibrin-binding polymers to achieve micelle retention and controlled drug release within the ischemic lesion. Neuron survival is reinforced by the combination of micelle facilitated ROS elimination and antistress signaling pathway interference under ischemia conditions. In vivo results demonstrate an overall remodeling of neurovascular unit through micelle polarized M2 microglia repair and blood-brain barrier preservation, leading to enhanced neuroprotection and blood perfusion. This strategy gives a proof of concept that neurovascular units can serve as an integrated target for ischemic stroke treatment with nanomedicines.

Effect of borneol as a penetration enhancer on brain targeting of nanoliposomes: facilitate direct delivery to neurons.

AIM: This study is aimed to evaluate borneol as a penetration enhancer to improve brain target of nanoliposome. MATERIALS & METHODS: Effects of borneol on pharmacokinetics, targeting efficiency, brain subareas distribution and neuron-targeting level and pathway were studied by fluorescence spectrophotometry and immunofluorescence. RESULTS: Borneol did not influence physicochemical property of doxorubicin hydrochloride nanoliposome (Dox-nanoLips). Co-administration of Dox-nanoLips with borneol elevated brain-target efficiency due to selective distribution increase in the cerebral cortex and hippocampus without difference in contralateral hemisphere. Borneol improved neuronal-targeting level of Dox-nanoLips in the cortex, CA3 and dentate gyrus regions via opening tight junctions of blood-brain barrier and then bypassing astrocyte. CONCLUSION: Borneol is potential to be a promising penetration enhancer for nanocarrier to target neurons.

[Endothelial dysfunction in chronic vascular encephalopathy]. / Éndotelial'naia disfunktsiia pri distsirkuliatornoi éntsefalopatii.

In this review, the authors consider endothelial dysfunction as a key pathophysiologic event of chronic vascular encephalopathy. Possible mechanisms of endothelial dysfunction in chronic vascular encephalopathy, especially associated with cerebral small vessel disease, neuroanatomy and pathophysiology of cerebral vascular endothelium are considered. Laboratory and instrumental methods for the diagnosis of endothelial dysfunction and potential approaches to its correction are described.

Cystathionine ß-synthase and PGRMC1 as CO sensors.

Heme oxygenase (HO) is a mono-oxygenase utilizing heme and molecular oxygen (O2) as substrates to generate biliverdin-IXα and carbon monoxide (CO). HO-1 is inducible under stress conditions, while HO-2 is constitutive. A balance between heme and CO was shown to regulate cell death and survival in many experimental models. However, direct molecular targets to which CO binds to regulate cellular functions remained to be fully examined. We have revealed novel roles of CO-responsive proteins, cystathionine ß-synthase (CBS) and progesterone receptor membrane component 1 (PGRMC1), in regulating cellular functions. CBS possesses a prosthetic heme that allows CO binding to inhibit the enzyme activity and to regulate H2S generation and/or protein arginine methylation. On the other hand, in response to heme accumulation in cells, PGRMC1 forms a stable dimer through stacking interactions of two protruding heme molecules. Heme-mediated PGRMC1 dimerization is necessary to interact with EGF receptor and cytochromes P450 that determine cell proliferation and xenobiotic metabolism. Furthermore, CO interferes with PGRMC1 dimerization by dissociating the heme stacking, and thus results in modulation of cell responses. This article reviews the intriguing functions of these two proteins in response to inducible and constitutive levels of CO with their pathophysiological implications.

Houshiheisan compound prescription protects neurovascular units after cerebral ischemia.

Houshiheisan is composed of wind-dispelling (chrysanthemun flower, divaricate saposhnikovia root, Manchurian wild ginger, cassia twig, Szechwan lovage rhizome, and platycodon root) and deficiency-nourishing (ginseng, Chinese angelica, large-head atractylodes rhizome, Indian bread, and zingiber) drugs. In this study, we assumed these drugs have protective effects against cerebral ischemia, on neurovascular units. Houshiheisan was intragastrically administered in a rat model of focal cerebral ischemia. Hematoxylin-eosin staining, transmission electron microscopy, immunofluorescence staining, and western blot assays showed that Houshiheisan reduced pathological injury to the ischemic penumbra, protected neurovascular units, visibly up-regulated neuronal nuclear antigen expression, and down-regulated amyloid precursor protein and amyloid-ß 42 expression. Wind-dispelling and deficiency-nourishing drugs maintained NeuN expression to varying degrees, but did not affect amyloid precursor protein or amyloid-ß 42 expression in the ischemic penumbra. Our results suggest that the compound prescription Houshiheisan effectively suppresses abnormal amyloid precursor protein accumulation, reduces amyloid substance deposition, maintains stabilization of the internal environment of neurovascular units, and minimizes injury to neurovascular units in the ischemic penumbra.