Neuroinflammation, Stroke, Blood-Brain Barrier Dysfunction, and Imaging Modalities

Abstract

Maintaining blood-brain barrier (BBB) integrity is crucial for the homeostasis of the central nervous system. Structurally comprising the BBB, brain endothelial cells interact with pericytes, astrocytes, neurons, microglia, and perivascular macrophages in the neurovascular unit. Brain ischemia unleashes a profound neuroinflammatory response to remove the damaged tissue and prepare the brain for repair. However, the intense neuroinflammation occurring during the acute phase of stroke is associated with BBB breakdown, neuronal injury, and worse neurological outcomes. Here, we critically discuss the role of neuroinflammation in ischemic stroke pathology, focusing on the BBB and the interactions between central nervous system and peripheral immune responses. We highlight inflammation-driven injury mechanisms in stroke, including oxidative stress, increased MMP (matrix metalloproteinase) production, microglial activation, and infiltration of peripheral immune cells into the ischemic tissue. We provide an updated overview of imaging techniques for in vivo detection of BBB permeability, leukocyte infiltration, microglial activation, and upregulation of cell adhesion molecules following ischemic brain injury. We discuss the possibility of clinical implementation of imaging modalities to assess stroke-associated neuroinflammation with the potential to provide image-guided diagnosis and treatment. We summarize the results from several clinical studies evaluating the efficacy of anti-inflammatory interventions in stroke. Although convincing preclinical evidence suggests that neuroinflammation is a promising target for ischemic stroke, thus far, translating these results into the clinical setting has proved difficult. Due to the dual role of inflammation in the progression of ischemic damage, more research is needed to mechanistically understand when the neuroinflammatory response begins the transition from injury to repair. This could have important implications for ischemic stroke treatment by informing time- and context-specific therapeutic interventions.

Clinical Value of the Prognostic Nutrition Index in the Assessment of Prognosis in Critically Ill Patients with Stroke: A Retrospective Analysis

“…Collagenase, gelatinase, ROS, and proteases are secreted by activated leukocytes on the surface of damaged brain tissues and blood vessels. Second, activated phospholipase in leukocytes promotes secretion of active substances, e.g., prostaglandins, eicosanoids, platelet activating factors, and leukotrienes, which induce vasoconstriction and prolong platelet aggregation [ 29 ]. At last, some immune modulators and proinflammatory cytokines are secreted by infiltrated leukocytes in the penumbra zone around the infarct center, which may damage more neurons [ 30 ].…”

Targeted BRD4 protein degradation by dBET1 ameliorates acute ischemic brain injury and improves functional outcomes associated with reduced neuroinflammation and oxidative stress and preservation of blood–brain barrier integrity

“…BBB highly restricts transcellular movement of solutes and paracellular diffusion across the barrier either into or out of the brain, which plays essential roles in cerebral homeostasis. BBB disruption following secondary injuries such as inflammation and oxidative stress are known to exacerbate ischemia-induced brain injury and limit functional recovery [ 16 , 51 ]. Brain endothelial cells comprising the BBB interact with pericytes, astrocytes, neurons, microglia, and perivascular macrophages in the neurovascular unit.…”

“…Following ischemic insults, reactive astrocytes assist in buffering changes in extracellular ion homeostasis, such as glutamate, altering the osmoregulation, counteracting the development of brain edema, and repairing the integrity of the BBB [ 41 ]. Studies suggest that Nrf2 downstream target genes that encode for phase II defense enzymes and antioxidant proteins, such as heme oxygenase-1 (HO1) and NAD(P)H dehydrogenase [quinone] 1 (NQO1), are particularly enriched in glia cells, supporting the key role of reactive gliosis process in regulating inflammatory and oxidative responses following ischemia [ 16 , 30 ]. dBET1 attenuated the damaging progression of reactive gliosis in microglia and astrocytes in the peri-infarct areas, which conferred protection against ischemic insult.…”

“…Several lines of evidence using in vitro oxidative stress models have revealed the protective role of BET inhibition against oxidative damage through upregulating the Nrf2 signaling pathway and its target antioxidant genes, suggesting that BET proteins inhibits Nrf2 signaling [ 12 – 15 ]. Following primary ischemic injury, secondary inflammatory and oxidative damage gradually occurs as a consequence of destructive cellular and molecular events, which further exacerbates BBB breakdown through various structural and functional components of the BBB [ 2 , 16 , 17 ]. Therefore, BRD4 blockade has attracted increasing interest in translational and clinical fields.…”

Mediation Analyses of the Role of Apathy on Motoric Cognitive Outcomes

“…Another mechanism that warrants further exploration is the relationship between blood–brain barrier (BBB) disruption, which can occur in normal aging, and disease states including cerebrovascular disease and metabolic syndrome [ 70 , 71 , 72 ]. The loss of BBB integrity is associated with neuroinflammation and contributes to neurodegeneration [ 73 , 74 , 75 ].…”