Neuroinflammation is involved in the onset or progression of various neurodegenerative diseases. Initiation of neuroinflammation is triggered by endogenous substances (damage-associated molecular patterns) and/or exogenous pathogens. Activation of glial cells (microglia and astrocytes) is widely recognized as a hallmark of neuroinflammation and triggers the release of proinflammatory cytokines, leading to neurotoxicity and neuronal dysfunction. Another feature associated with neuroinflammatory diseases is impairment of the blood-brain barrier (BBB). The BBB, which is composed of brain endothelial cells connected by tight junctions, maintains brain homeostasis and protects neurons. Impairment of this barrier allows trafficking of immune cells or plasma proteins into the brain parenchyma and subsequent inflammatory processes in the brain. Besides neurons, activated glial cells also affect BBB integrity. Therefore, BBB dysfunction can amplify neuroinflammation and act as a key process in the development of neuroinflammation. BBB integrity is determined by the integration of multiple signaling pathways within brain endothelial cells through intercellular communication between brain endothelial cells and brain perivascular cells (pericytes, astrocytes, microglia, and oligodendrocytes). For prevention of BBB disruption, both cellular components, such as signaling molecules in brain endothelial cells, and non-cellular components, such as inflammatory mediators released by perivascular cells, should be considered. Thus, understanding of intracellular signaling pathways that disrupt the BBB can provide novel treatments for neurological diseases associated with neuroinflammation. In this review, we discuss current knowledge regarding the underlying mechanisms involved in BBB impairment by inflammatory mediators released by perivascular cells.

/pdf/blood-brain-barrier-dysfunction-amplifies-the-development-of-44tk42dfmz.pdf

Blood-Brain Barrier Dysfunction Amplifies the Development of Neuroinflammation: Understanding of Cellular Events in Brain Microvascular Endothelial Cells for Prevention and Treatment of BBB Dysfunction

Vascular disruption is the underlying cause of cerebral hemorrhage, including intracerebral, subarachnoid and intraventricular hemorrhage. The disease etiology also involves cerebral hemorrhage-induced blood-brain barrier (BBB) disruption, which contributes an important component to brain injury after the initial cerebral hemorrhage. BBB loss drives vasogenic edema, allows leukocyte extravasation and may lead to the entry of potentially neurotoxic and vasoactive compounds into brain. This review summarizes current information on changes in brain endothelial junction proteins in response to cerebral hemorrhage (and clot-related factors), the mechanisms underlying junction modification and potential therapeutic targets to limit BBB disruption and, potentially, hemorrhage occurrence. It also addresses advances in the tools that are now available for assessing changes in junctions after cerebral hemorrhage and the potential importance of such junction changes. Recent studies suggest post-translational modification, conformational change and intracellular trafficking of junctional proteins may alter barrier properties. Understanding how cerebral hemorrhage alters BBB properties beyond changes in tight junction protein loss may provide important therapeutic insights to prevent BBB dysfunction and restore normal function.

https://journals.sagepub.com/doi/pdf/10.1177/0271678X18774666

Brain endothelial cell junctions after cerebral hemorrhage: Changes, mechanisms and therapeutic targets.

Obesity-related cognitive impairment: The role of endothelial dysfunction.

Pericytes, as a key cellular part of the blood-brain barrier, play an important role in the maintenance of brain neurovascular unit. These cells participate in brain homeostasis by regulating vascular development and integrity mainly through secreting various factors. Pericytes per se show different restorative properties after blood-brain barrier injury. Upon the occurrence of brain acute and chronic diseases, pericytes provoke immune cells to regulate neuro-inflammatory conditions. Loss of pericytes in distinct neurologic disorders intensifies blood-brain barrier permeability and leads to vascular dementia. The therapeutic potential of pericytes is originated from the unique morphological shape, location, and their ability in providing vast paracrine and juxtacrine interactions. A subset of pericytes possesses multipotentiality and exhibit trans-differentiation capacity in the context of damaged tissue. This review article aimed to highlight the critical role of pericytes in restoration of the blood-brain barrier after injury by focusing on the dynamics of pericytes and cross-talk with other cell types.

/pdf/targeting-pericytes-for-neurovascular-regeneration-vqzl4hpj40.pdf

Targeting pericytes for neurovascular regeneration

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder worldwide. Clinically, it is characterized by a progressive degeneration of dopaminergic neurons (DAn), resulting in severe motor complications. Preclinical and clinical studies have indicated that neuroinflammation can play a role in PD pathophysiology, being associated with its onset and progression. Nevertheless, several key points concerning the neuroinflammatory process in PD remain to be answered. Bearing this in mind, in the present review, we cover the impact of neuroinflammation on PD by exploring the role of inflammatory cells (i.e., microglia and astrocytes) and the interconnections between the brain and the peripheral system. Furthermore, we discuss both the innate and adaptive immune responses regarding PD pathology and explore the gut–brain axis communication and its influence on the progression of the disease.

/pdf/neuroinflammation-and-parkinsons-disease-from-qfetmtml.pdf

Neuroinflammation and Parkinson’s Disease—From Neurodegeneration to Therapeutic Opportunities

Diabetic complications are characterized by the dysfunction of pericytes located around microvascular endothelial cells. The blood–brain barrier (BBB) exhibits hyperpermeability with progression of diabetes. Therefore, brain pericytes at the BBB may be involved in diabetic complications of the central nervous system (CNS). We hypothesized that brain pericytes respond to increased brain thrombin levels in diabetes, leading to BBB dysfunction and diabetic CNS complications. Mice were fed a high-fat diet (HFD) for 2 or 8 weeks to induce obesity. Transport of i.v.-administered sodium fluorescein and 125I-thrombin across the BBB were measured. We evaluated brain endothelial permeability and expression of tight junction proteins in the presence of thrombin–treated brain pericytes using a BBB model of co-cultured rat brain endothelial cells and pericytes. Mice fed a HFD for 8 weeks showed both increased weight gain and impaired glucose tolerance. In parallel, the brain influx rate of sodium fluorescein was significantly greater than that in mice fed a normal diet. HFD feeding inhibited the decline in brain thrombin levels occurring during 6 weeks of feeding. In the HFD fed mice, plasma thrombin levels were significantly increased, by up to 22%. 125I-thrombin was transported across the BBB in normal mice after i.v. injection, with uptake further enhanced by co-injection of unlabeled thrombin. Thrombin-treated brain pericytes increased brain endothelial permeability and caused decreased expression of zona occludens-1 (ZO-1) and occludin and morphological disorganization of ZO-1. Thrombin also increased mRNA expression of interleukin-1β and 6 and tumor necrosis factor-α in brain pericytes. Thrombin can be transported from circulating blood through the BBB, maintaining constant levels in the brain, where it can stimulate pericytes to induce BBB dysfunction. Thus, the brain pericyte–thrombin interaction may play a key role in causing BBB dysfunction in obesity-associated diabetes and represent a therapeutic target for its CNS complications.

/pdf/contribution-of-thrombin-reactive-brain-pericytes-to-blood-14wq0fgg2u.pdf

Contribution of thrombin-reactive brain pericytes to blood-brain barrier dysfunction in an in vivo mouse model of obesity-associated diabetes and an in vitro rat model.

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Contribution of thrombin-reactive brain pericytes to blood-brain barrier dysfunction in an in vivo mouse model of obesity-associated diabetes and an in vitro rat model.