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Aims: Intracerebral hemorrhage (ICH) is a condition that arises due to the rupture of cerebral blood vessels, leading to the flow of blood into the brain tissue. One of the pathological alterations that occurs during an acute ICH is an impairment of the blood-brain barrier (BBB), which leads to severe perihematomal edema and an immune response., Discussion: A complex interplay between the cells of the BBB, for example, pericytes, astrocytes, and brain endothelial cells, with resident and infiltrating immune cells, such as microglia, monocytes, neutrophils, T lymphocytes, and others accounts for both damaging and protective mechanisms at the BBB following ICH. However, the precise immunological influence of BBB disruption has yet to be richly ascertained, especially at various stages of ICH., Conclusion: This review summarizes the changes in different cell types and molecular components of the BBB associated with immune-inflammatory responses during ICH. Furthermore, it highlights promising immunoregulatory therapies to protect the integrity of the BBB after ICH. By offering a comprehensive understanding of the mechanisms behind BBB damage linked to cellular and molecular immunoinflammatory responses after ICH, this article aimed to accelerate the identification of potential therapeutic targets and expedite further translational research., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Stroke is the second leading cause of death worldwide, estimated that one-sixth of the world population will suffer it once in their life. The most common type of this medical condition is the ischemic stroke (IS), produced by a thrombotic or embolic occlusion of a major cerebral artery or its branches, leading to the formation of a complex infarct region caused by oxidative stress, excitotoxicity, and endothelial dysfunction. Nowadays, the immediate treatment for IS involves thrombolytic agents or mechanical thrombectomy, depending on the integrity of the blood-brain barrier (BBB). A common stroke complication is the hemorrhagic transformation (HT), which consists of bleeding into the ischemic brain area. Currently, better treatments for IS are urgently needed. As such, the neurohormone melatonin has been proposed as a good candidate due to its antioxidant, anti-inflammatory, and neuroprotective effects, particularly against lipid peroxidation and oxidative stress during brain ischemia. Here, we proposed to develop intravenous or intranasal melatonin nanoformulation to specifically target the brain in patients with stroke. Nowadays, the challenge is to find a formulation able to cross the barriers and reach the target organ in an effective dose to generate the pharmacological effect. In this review, we discuss the current literature about stroke pathophysiology, melatonin properties, and its potential use in nanoformulations as a novel therapeutic approach for ischemic stroke.

Mast cells are first responders to intracerebral hemorrhage. They release potent mediators that can disrupt the blood-brain barrier promoting injury, vasogenic edema formation, and hematoma exacerbation. Also, mast cells recruit other inflammatory cells that maintain and amplify brain damage. Given their early role in the cascade of events in intracerebral hemorrhage, mast cells may offer an alternative target for antichemotactic interventions.

T lymphocytes migrate into the brain after intracerebral hemorrhage (ICH) and promote cerebral inflammation, thus exacerbating neuronal injury. However, the relationship between of T lymphocytes infiltration and blood-brain barrier (BBB) injury after ICH has not been clarified. In this study, we investigated the spatial-temporal distribution of infiltrating T lymphocytes after ICH in C57BL/6 mice by immunofluorescence and flow cytometry, and the accompanying change rules of BBB permeability were detected by Evans blue dye leakage and tight junction protein expression. Furthermore, T lymphocyte-deficient nude mice and T lymphocyte-decreased C57BL/6 mice treated with fingolimod were used to verify the relationship between T lymphocytes infiltration and BBB leakage after ICH. Here, we reported that brain-infiltrating T lymphocytes in the hemorrhagic hemisphere began to accumulate on the first day and peaked on the fifth day after ICH; BBB leakage also at peaked on the fifth day. Moreover, T lymphocyte-deficient nude mice showed minor BBB leakage after ICH compared with C57BL/6 control mice. Similarly, fingolimod treatment can significantly decrease T lymphocyte infiltration and promote BBB integrity compared with a vehicle control. Overall, our results suggested that suppression of T lymphocyte infiltration may be a novel way to improve BBB integrity after ICH., (Copyright © 2017. Published by Elsevier B.V.)

Background and Purpose: Inflammatory responses and blood-brain barrier (BBB) dysfunction play important roles in brain injury after intracerebral hemorrhage (ICH). The metalloprotease ADAMTS 13 (a disintegrin and metalloprotease with thrombospondin type I motif, member 13) was shown to limit inflammatory responses through its proteolytic effects on von Willebrand factor. In the present study, we addressed the role of ADAMTS 13 after experimental ICH., Methods: ICH was induced in mice by intracerebral infusion of autologous blood. The peri-hematomal inflammatory responses, levels of matrix metalloproteinase-9 and intercellular adhesion molecule-1, pericyte coverage on brain capillaries, and BBB permeability were quantified at 24 hours. Functional outcomes, cerebral edema, and hemorrhagic lesion volume were quantified at day 3., Results: Treatment with recombinant ADAMTS 13 (rADAMTS 13) reduced the levels of chemokines and cytokines, myeloperoxidase activity, and microglia activation and neutrophil recruitment after ICH. rADAMTS 13 also decreased interleukin-6 expression in brain endothelial cells stimulated by lipopolysaccharide, whereas recombinant von Willebrand factor reversed this effect. The anti-inflammatory effect of rADAMTS 13 was accompanied by reduced expression of intercellular adhesion molecule-1 and less activation of matrix metalloproteinase, enhanced pericyte coverage of brain microvessels, and attenuated BBB disruption. Furthermore, neutrophil depletion protected against BBB damage, and rADAMTS 13 treatment had no further beneficial effect. Finally, treatment of mice with rADAMTS 13 reduced cerebral edema and hemorrhagic lesion volume and improved neurological functions., Conclusions: Our findings reveal the importance of rADAMTS 13 in regulating pathological inflammation and BBB function and suggest that rADAMTS 13 may provide a new therapeutic strategy for ICH., (© 2015 American Heart Association, Inc.)

Disruption of the blood-brain barrier (BBB) contributes to the inflammatory response and edema formation in the brain, exacerbating brain damage. The present study evaluated the effects of Scutellaria baicalensis (SR) water extracts on BBB disruption after intracerebral hemorrhage (ICH) in rats. ICH was induced by stereotaxic intrastriatal injection of bacterial type VII collagenase, and SR was administrated orally three times (50 mg/ml/kg) during the 48 h after ICH onset. SR treatment significantly reduced the degree of (1) hemorrhage volume and edema percentage of the ipsilateral hemisphere, (2) brain water content, (3) MPO-positive neutrophil infiltration in the peri-hematoma, and (4) BBB permeability measured by Evans blue leakage. In addition, expression of matrix metalloproteinase (MMP)-9, MMP-12, and tissue inhibitor of MMPs (TIMP)-1 were investigated with immunohistochemistry. SR treatment reduced MMP-9 and MMP-12 expression in the peri-hematoma after ICH. These results indicate that SR attenuates the BBB disruption through anti-inflammatory effects and suppression of MMP expression. These findings provide a pharmacological basis for the use of SR in the treatment of the BBB disruption following stroke and trauma.

Neutrophils are thought to contribute to damage after intracerebral hemorrhage (ICH), but there is little direct evidence for this. We depleted circulating blood neutrophils with an anti-polymorphonuclear leukocyte antibody (anti-PMN) before inducing ICH in the rat striatum. Neutrophil infiltration, which was mainly at the edge of the hematoma, was decreased by more than 60% by anti-PMN mediated depletion. We then analyzed neutrophil contributions to BBB breakdown, white matter damage (axons and myelin), and glial and inflammatory responses, both spatially and temporally. Neutrophil depletion reduced BBB leakiness in the peri-hematoma region. Matrix metalloprotease 9, which is thought to contribute to BBB breakdown, was restricted to neutrophils after ICH and was thus reduced by neutrophil depletion. Early perihematomal axonal injury seen at 1 and 3 days after ICH was decreased by depleting neutrophils, and at later times (7 and 14 days), the astrocytic and microglia/macrophage responses were reduced in the perihematoma region and the surrounding striatum. Detailed spatial analysis showed that neutrophil depletion reduced infiltration of activated microglia/macrophages in the peri-hematoma white matter tracts and decreased myelin fragmentation and axon damage. These results show that, in experimental ICH, neutrophils produce matrix metalloprotease9and contribute to blood vessel disruption, BBB breakdown, axon damage, and astrocytic and microglial/macrophage responses that evolve after ICH.

The inflammatory response triggered by stroke has been viewed as harmful, focusing on the influx and migration of blood-borne leukocytes, neutrophils, and macrophages. This review hypothesizes that the brain and meninges have their own resident cells that are capable of fast host response, which are well known to mediate immediate reactions such as anaphylaxis, known as mast cells (MCs). We discuss novel research suggesting that by acting rapidly on the cerebral vessels, this cell type has a potentially deleterious role in the very early phase of acute cerebral ischemia and hemorrhage. Mast cells should be recognized as a potent inflammatory cell that, already at the outset of ischemia, is resident within the cerebral microvasculature. By releasing their cytoplasmic granules, which contain a host of vasoactive mediators such as tumor necrosis factor-alpha, histamine, heparin, and proteases, MCs act on the basal membrane, thus promoting blood-brain barrier (BBB) damage, brain edema, prolonged extravasation, and hemorrhage. This makes them a candidate for a new pharmacological target in attempts to even out the inflammatory responses of the neurovascular unit, and to stabilize the BBB after acute stroke.

Mast cells (MCs) are perivascularly located resident cells of hematopoietic origin, recognized as effectors in inflammation and immunity. Their subendothelial location at the boundary between the intravascular and extravascular milieus, and their ability to rapidly respond to blood- and tissue-borne stimuli via release of potent vasodilatatory, proteolytic, fibrinolytic, and proinflammatory mediators, render MCs with a unique status to act in the first-line defense in various pathologies. We review experimental evidence suggesting a role for MCs in the pathophysiology of brain ischemia and hemorrhage. In new-born rats, MCs contributed to brain damage in hypoxic-ischemic insults. In experimental cerebral ischemia/reperfusion, MCs regulated permeability of the blood-brain barrier, brain edema formation, and the intensity of local neutrophil infiltration. MCs were reported to play a role in the tissue plasminogen activator-mediated cerebral hemorrhages after experimental ischemic stroke, and to be involved in the expansion of hematoma and edema following intracerebral hemorrhage. Importantly, the MC-stabilizing drug cromoglycate inhibited MC-mediated adverse effects on brain pathology and improved survival of experimental animals. This brings us to a position to consider MC stabilization as a novel initial adjuvant therapy in the prevention of brain injuries in hypoxia-ischemia in new-borns, as well as in ischemic stroke and intracerebral hemorrhage in adults.

Background and Purpose: An abnormal expression of some matrix metalloproteinases (MMPs) is related with hemorrhagic transformation events after stroke. Our aim was to investigate MMP-2 and MMP-9 in the ischemic brain and its relation with blood-brain barrier breakdown after hemorrhagic transformation in human stroke., Methods: We assessed 5 cases of fatal ischemic strokes with hemorrhagic complications; brain samples were obtained from infarct, hemorrhagic, and contralateral tissue. MMP-9 and MMP-2 content was analyzed by zymography and immunohistochemistry was performed to localize MMP-9 and to assess collagen IV integrity in the basal lamina. Laser capture microdissection was performed to isolate blood-brain barrier vessels to study these MMPs., Results: Overall, MMP-9 levels were higher both in hemorrhagic and nonhemorrhagic infarcted tissue compared to contralateral areas (P<0.0001 and P<0.05). Moreover, levels of the cleaved MMP-9 85kDa-form were significantly elevated in the hemorrhagic compared to nonhemorrhagic and contralateral areas (P=0.033 and P<0.0001). No changes were found for MMP-2 content. Immunostaining revealed a strong MMP-9-positive neutrophil infiltration surrounding brain microvessels associated with severe basal lamina type IV collagen degradation and blood extravasation. Microdissection confirmed that content of MMP-9 was similarly high in microvessel endothelium from hemorrhagic and infarcted areas compared to contralateral hemisphere vessels (P<0.05), pointing to neutrophils surrounding dissected microvessels as the main source of MMP-9 in hemorrhagic areas., Conclusions: Our results show a strong neutrophil infiltration in the infarcted and hemorrhagic areas with local high MMP-9 content closely related to basal lamina collagen IV degradation and blood-brain barrier breakdown. Microvessel and inflammatory MMP-9 response are associated with hemorrhagic complications after stroke.