Attenuates Blood Brain Barrier Research Articles

MiR-671-5p Upregulation Attenuates Blood–Brain Barrier Disruption in the Ischemia Stroke Model Via the NF-кB/MMP-9 Signaling Pathway

Blood-brain barrier (BBB) disruption can induce further hemorrhagic transformation in ischemic stroke (IS). miR-671-5p, a micro-RNA, is abundant in the cortex of mammalian brains. Herein, we investigated the roles and potential mechanisms for the effects of miR-671-5p on BBB permeability in IS. Results showed that miR-671-5p levels were significantly downregulated in the cerebral cortex of middle cerebral artery occlusion/reperfusion (MCAO/R) C57/BL6 mice in vivo. miR-671-5p agomir administration via right intracerebroventricular injection significantly reduced infarct volume, improved neurological deficits, the axon of neurons and nerve fiber, attenuated cell injury and apoptosis, as well as reduced BBB permeability in MCAO/R mice. Treatment with miR-671-5p agomir alleviated tight junction proteins degradation, including claudin, occludin, and ZO-1 in MCAO/R mice, and these effects were reversed following NF-κB overexpression. Bend.3 brain endothelial cells were subjected to oxygen and glucose deprivation/reoxygenation (OGD/R) treatment in vivo, and then miR-671-5p agomir was transfected into the cells. This resulted in reduction of cytotoxicity, improved cell viability, trans-endothelial electrical resistance, reduced fluorescein sodium permeability, and inhibited tight junction degradation in Bend.3 OGD/R cells. However, these effects were reversed following NF-κB overexpression. These results demonstrated that upregulation of miR-671-5p in IS models in vivo and in vitro alleviated BBB permeability by targeting NF-κB/MMP-9. In summary, miR-671-5p is a potential therapeutic target for protecting BBB permeability in IS to minimize cerebral hemorrhage transformation.

Selective sphingosine-1-phosphate receptor 1 modulator attenuates blood–brain barrier disruption following traumatic brain injury by inhibiting vesicular transcytosis

BackgroundTraumatic brain injury (TBI) provokes secondary pathological damage, such as damage to the blood–brain barrier (BBB), ischaemia and inflammation. Major facilitator superfamily domain-containing 2a (Mfsd2a) has been demonstrated to be critical in limiting the increase in BBB vesicle transcytosis following brain injury. Recent studies suggest that a novel and selective modulator of the sphingosine-1-phosphate receptor 1 (S1P1), CYM-5442, maintains the integrity of the BBB by restricting vesicle transcytosis during acute ischaemic stroke. In the current study, we investigated whether CYM-5442, evaluated in a short-term study, could protect the brains of mice with acute-stage TBI by reversing the increase in vesicle transport due to reduced Mfsd2a expression after TBI.MethodsWe used the well-characterized model of TBI caused by controlled cortical impact. CYM-5442 (0.3, 1, 3 mg/kg) was intraperitoneally injected 30 min after surgery for 7 consecutive days. To investigate the effect of CYM-5442 on vesicle transcytosis, we downregulated and upregulated Mfsd2a expression using a specific AAV prior to evaluation of the TBI model. MRI scanning, cerebral blood flow, circulating blood counts, ELISA, TEM, WB, and immunostaining evaluations were performed after brain injury.ResultsCYM-5442 significantly attenuated neurological deficits and reduced brain oedema in TBI mice. CYM-5442 transiently suppressed lymphocyte trafficking but did not induce persistent lymphocytopenia. After TBI, the levels of Mfsd2a were decreased significantly, while the levels of CAV-1 and albumin were increased. In addition, Mfsd2a deficiency caused inadequate sphingosine-1-phosphate (S1P) transport in the brain parenchyma, and the regulation of BBB permeability by Mfsd2a after TBI was shown to be related to changes in vesicle transcytosis. Downregulation of Mfsd2a in mice markedly increased the BBB permeability, neurological deficit scores, and brain water contents after TBI. Intervention with CYM-5442 after TBI protected the BBB by significantly reducing the vesicle transcytosis of cerebrovascular endothelial cells.ConclusionIn addition to transiently suppressing lymphocytes, CYM-5442 alleviated the neurological deficits, cerebral edema and protective BBB permeability in TBI mice by reducing the vesicle transcytosis of cerebrovascular endothelial cells.

Semen Ziziphi Spinosae attenuates blood–brain barrier dysfunction induced by lipopolysaccharide by targeting the FAK-DOCK180-Rac1-WAVE2-Arp3 signaling pathway

Semen Ziziphi Spinosae (SZS) has been extensively used in the daily diet as a functional food for neuroprotective health-benefit in China for many years. However, the neuroprotective mechanism of SZS associated with blood–brain barrier (BBB) integrity remains unexplored. The present study suggests SZS could protect against lipopolysaccharide (LPS)-induced BBB dysfunction. Proteomics indicate that 135 proteins in rat brain are significantly altered by SZS. These differentially expressed proteins are mainly clustered into cell–cell adhesion and adherens junctions, which are closely related with BBB integrity. SZS reversed LPS-induces BBB breakdown by activating the FAK-DOCK180-Rac1-WAVE2-Arp3 pathway. Molecular docking between signaling pathway proteins and identified SZS components in rat plasma reveals that 6”‘-feruloylspinosin, spinosin, and swertisin strongly binds to signaling proteins at multiple amino acid sites. These novel findings suggest a health benefit of SZS in prevention of cerebral diseases and contributes to the further application of SZS as a functional food.

Lithium attenuates blood-brain barrier damage and brain edema following intracerebral hemorrhage via an endothelial Wnt/β-catenin signaling-dependent mechanism in mice.

BackgroundVasogenic cerebral edema resulting from blood–brain barrier (BBB) damage aggravates the devastating consequences of intracerebral hemorrhage (ICH). Although augmentation of endothelial Wnt/β‐catenin signaling substantially alleviates BBB breakdown in animals, no agents based on this mechanism are clinically available. Lithium is a medication used to treat bipolar mood disorders and can upregulate Wnt/β‐catenin signaling.MethodsWe evaluated the protective effect of lithium on the BBB in a mouse model of collagenase IV‐induced ICH. Furthermore, we assessed the effect and dependency of lithium on Wnt/β‐catenin signaling in mice with endothelial deletion of the Wnt7 coactivator Gpr124.ResultsLithium treatment (3 mmol/kg) significantly decreased the hematoma volume (11.15 ± 3.89 mm3 vs. 19.97 ± 3.20 mm3 in vehicle controls, p = 0.0016) and improved the neurological outcomes of mice following ICH. Importantly, lithium significantly increased the BBB integrity, as evidenced by reductions in the levels of brain edema (p = 0.0312), Evans blue leakage (p = 0.0261), and blood IgG extravasation (p = 0.0009) into brain tissue around the hematoma. Mechanistically, lithium upregulated the activity of endothelial Wnt/β‐catenin signaling in mice and increased the levels of tight junction proteins (occludin, claudin‐5 and ZO‐1). Furthermore, the protective effect of lithium on cerebral damage and BBB integrity was abolished in endothelial Gpr124 knockout mice, suggesting that its protective effect on BBB function was mainly dependent on Gpr124‐mediated endothelial Wnt/β‐catenin signaling.ConclusionOur findings indicate that lithium may serve as a therapeutic candidate for treating BBB breakdown and brain edema following ICH.

Andrographolide Attenuates Blood-Brain Barrier Disruption, Neuronal Apoptosis, and Oxidative Stress Through Activation of Nrf2/HO-1 Signaling Pathway in Subarachnoid Hemorrhage.

Andrographolide (Andro), a diterpene of the labdane family extracted from the Asian plant Andrographis paniculata, is neuroprotective against stroke and Alzheimer's disease. However, whether Andro protected the brain against subarachnoid hemorrhage (SAH) was still unknown. Thus, we explored whether Andro attenuated blood-brain barrier (BBB) disruption and neuronal apoptosis and inhibited oxidative stress to protect the brain against SAH both in vitro and in vivo and detected underlying mechanisms of Andro's neuroprotective effects in the present study. Oxyhemoglobin (OxyHb)-treated neuronal PC12 cells were used as an in vitro model. An in vivo model was established using Sprague-Dawley rats. Moreover, we used an inhibitor of heme oxygenase-1 (HO-1) (ZnPPIX) in vitro and in vivo experiments to evaluate whether the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) cascade acted as one protective molecular mechanism of Andro against SAH. Our results revealed that, in vitro, Andro increased cell viability, inhibited apoptosis, and activated Nrf2/HO-1 cascade of neuronal PC12 cells treated with OxyHb. In vivo, Andro attenuated the neurological dysfunction, neuronal apoptosis, BBB disruption, brain edema, and oxidative stress and activated the Nrf2/HO-1 pathway. ZnPPIX reversed the effects of Andro in vitro and in vivo. Our research suggested that Andro alleviated BBB disruption, neuronal apoptosis, and oxidative stress in SAH, possibly via the Nrf2/HO-1 signaling pathway.

Activation of the sigma-1 receptor attenuates blood–brain barrier disruption by inhibiting amyloid deposition in Alzheimer’s disease mice

The sigma-1 receptor is an important target for drug development in several neuropsychiatric diseases, including Alzheimer’s disease (AD). Accumulating evidence has shown that the integrity and functional activity of the blood–brain barrier (BBB) in AD are impaired, which is closely related to the movement of amyloid beta (Aβ) across the BBB and the formation of Aβ plaques. In this study, we investigated the effects of sigma-1 receptor activation on BBB disruption and Aβ levels in AD mice. We found that PRE-084, a sigma-1 receptor agonist, attenuated learning and memory deficits in Aβ–injected mice, significantly increased levels of low-density lipoprotein receptor-related protein 1 (LRP-1), and lowered the Aβ level synergistically in the brain. Moreover, the upregulation of vascular endothelial growth factor (VEGF) levels through the sigma-1 receptor may be involved in the reduction of the BBB permeability by PRE-084. The identification of this previously unexplored role of the sigma-1 receptor in alleviating BBB disruption via upregulating the levels of VEGF and LRP-1 in AD suggests that reversing BBB dysfunction through sigma-1 receptor activation may be a promising treatment for AD.

Vitamin D3 Supplement Attenuates Blood-Brain Barrier Disruption and Cognitive Impairments in a Rat Model of Traumatic Brain Injury.

This study was designed to study the effects of vitamin D3 supplementation on the cognitive dysfunction and neurological function of traumatic brain injury (TBI) and the possible underlying mechanisms. To this purpose, different doses of vitamin D3 were intraperitoneally injection to TBI rats for one week before TBI surgery and three consecutive weeks after TBI. Brain edema evaluation was conducted on the third day and Evans blue staining for blood-brain barrier (BBB) permeability on the seventh day after TBI. Rat behavior was assessed by evaluation of neurological scores and morris water maze. It was revealed that vitamin D levels increased in serum after the administration of vitamin D3 for one week. TBI led to neurological deficit, together with brain edema, BBB disruption and inflammation. Vitamin D3 supplement ameliorated neurological deficit and cognitive impairments induced by TBI. Vitamin D3 administration reduced brain edema and impairments of blood-brain barrier induced by TBI, as well as decreased inflammatory response in TBI rat brain. Our results showed that vitamin D3 administration alleviated neurobehavioral deficits and improved brain edema after TBI. Vitamin D3 inhibited inflammatory cytokines and decreased BBB disruption in TBI rats. Vitamin D3 may be used for the treatment of TBI as a protective intervention.

Withaferin A alleviates traumatic brain injury induced secondary brain injury via suppressing apoptosis in endothelia cells and modulating activation in the microglia

Traumatic brain injury (TBI) is a major public health concern with high rates of morbidity and mortality worldwide. Currently used medications, though effective, are also associated with several adverse effects. Development of effective neuroprotective agents with fewer side-effects would be of clinical value. Previous studies have shown that withaferin compounds have a potential neuroprotective effect in nervous system disorders. However, the effect of withaferin compounds, especially withaferin A (WFA), on traumatic brain injury is unclear. In the present study, both in vivo and in vitro models were used to assess whether WFA could exert a neuroprotective effect after TBI and were used to explore the associated mechanisms. The results showed that WFA significantly improved neurobehavioral function in a dose-dependent fashion and alleviated histological alteration of injury to tissues in TBI mice. In vitro models of TBI revealed that dose-dependent WFA treatment increased the viability of SH-SY5Y cells. In addition, WFA treatment could attenuate blood–brain barrier disruption and brain edema via suppressing apoptosis in endothelial cells. Furthermore, both our in vivo and in vitro results reveal that WFA treatment could significantly reduce levels of several neuroinflammation cytokines (IL-1β, IL-6, and TNF-α), which correlate with an overall reduction in microglial activation. These data suggest that the neuroprotection by WFA is, at least in part, related to regulation of microglial activation and inhibition of vascular endothelial cell apoptosis. Taken together, these findings support further investigation of WFA as a promising therapeutic agent for promoting functional recovery after traumatic brain injury.

Abstract TP274: Post-stroke Treatment With Docosanoids Promote Functional Recovery, Neurogenesis and Angiogenesis, Attenuate Blood-brain Barrier After Experimental Ischemic Stroke

Objective: Ischemic injury induces neurogenesis in the subventricular zone (SVZ) of the lateral ventricles and subgranular zone (SGZ) of dentate gyrus (DG) promotes the migration of neuroblasts, guided by blood vessels, into the ischemic damaged area. Neurogenesis leads the functional and histological recovery in the ischemic-damaged brain through the proliferation, migration, differentiation and integration of newly generated neural cells into the existing neural circuit. Recently, we have shown that Docosahexaenoic acid (DHA) and Neuroprotectin D1 (NPD1) therapy improves functional and histological outcomes following experimental stroke. It has also been shown that DHA promotes neurite outgrowth of immature neurons, such as embryonic hippocampal cells and embryonic cortical cells. The objective of this study was to explore underlying mechanisms of docosanoid neuroprotection after cerebral ischemia. Methods: Male Sprague-Dawley rats were anesthetized with isoflurane/nitrous oxide, underwent 2h of middle cerebral artery occlusion (MCAo) and treated with DHA (5mg/kg, IV) or NPD1 (5μg/per rat, ICV) and vehicles 1h after. Neuro-behavioral assessments were conducted on days 1, 2, 3 and on weeks 1, 2, 3 or 4. BrdU was injected on days 4, 5 and 6, immunohistochemistry was performed on week 2 or 4, MRI on day 7 and lipidomic analysis at 4 and 5h after onset of stroke. Results: DHA improved short- and long-term behavioral functions and reduced cortical, subcortical and total infarct volumes (by 42%, 47% and 31%, respectively) after 2 weeks and reduced tissue loss by 50% after 4 weeks. DHA increased the number of BrdU + /Ki-67 + , BrdU + /DCX + and BrdU + /NeuN + cells in the cortex, subventricular zone and dentate gyrus and potentiated NPD1 synthesis in the penumbra at 5h after MCAo. NPD1 improved behavior, reduced lesion volumes, protected ischemic penumbra, increased NeuN, GFAP, SMI-71 positive cells and vessels, axonal regeneration in the penumbra and attenuated blood-brain barrier (BBB) after MCAo. Conclusion: We conclude that docosanoid administration increases neurogenesis, angiogenesis, activates NPD1 synthesis in the penumbra and diminishes BBB, which correlates to long-term neurobehavioral recovery after experimental ischemic stroke.

Overexpression of Mfsd2a attenuates blood brain barrier dysfunction via Cav-1/Keap-1/Nrf-2/HO-1 pathway in a rat model of surgical brain injury

IntroductionDisruption of the blood brain barrier (BBB) and subsequent cerebral edema formation is one of the major adverse effects of brain surgery, leading to postoperative neurological dysfunction. Recently, Mfsd2a has been shown to have a crucial role for the maintenance of BBB functions. In this study, we aimed to evaluate the role of Mfsd2a on BBB disruption following surgical brain injury (SBI) in rats. Materials and methodsRats were subjected to SBI by partial resection of the right frontal lobe. To evaluate the effect of Mfsd2a on BBB permeability and neurobehavior outcome following SBI, Mfsd2a was either overexpressed or downregulated in the brain by administering Mfsd2a CRISPR activation or knockout plasmids, respectively. The potential mechanism of Mfsd2a-mediated BBB protection through the cav-1/Nrf-2/HO-1 signaling pathway was evaluated. ResultsMfsd2a levels were significantly decreased while cav-1, Nrf-2 and HO-1 levels were increased in the right frontal perisurgical area following SBI. When overexpressed, Mfsd2a attenuated brain edema and abolished neurologic impairment caused by SBI while downregulation of Mfsd2a expression further deteriorated BBB functions and worsened neurologic performance following SBI. The beneficial effect of Mfsd2a overexpression on BBB functions was associated with diminished expression of cav-1, increased Keap-1/Nrf-2 dissociation and further augmented levels of Nrf-2 and HO-1 in the right frontal perisurgical area, leading to enhanced levels of tight junction proteins following SBI. The BBB protective effect of Mfsd2a was blocked by selective inhibitors of Nrf-2 and HO-1. ConclusionsMfsd2a attenuates BBB disruption through cav-1/Nrf-2/HO-1 signaling pathway in rats subjected to experimental SBI.

Inhibition of Transient Receptor Potential Vanilloid 1 Attenuates Blood-Brain Barrier Disruption after Traumatic Brain Injury in Mice.

Transient receptor potential vanilloid 1 (TRPV1) is expressed widely in the central nervous system and is activated by various stimuli. Inhibiting TRPV1 has neuroprotective effects in cerebral ischemia. The role of inhibiting TRPV1 to maintain blood-brain barrier (BBB) integrity after traumatic brain injury (TBI) remains unclear, however. Therefore, we investigated the effects of capsazepine-mediated TRPV1 inhibition on the BBB in a mouse model of TBI. Adult male C57BL/6 mice underwent controlled cortical impact injury and received capsazepine (1 μmol/kg body weight, twice daily, intraperitoneally) until sacrifice. Further, mouse brain microvascular endothelial (bEnd.3) cells were cultured and underwent biaxial stretch injury to investigate the mechanisms underlying the protective effects of capsazepine. The TRPV1 expression was upregulated in the pericontusional area after TBI, peaking at 24 h post-TBI. Capsazepine-treated mice demonstrated decreased brain edema (p = 0.010), Evans Blue extravasation (p = 0.001), tissue hemoglobin levels (p = 0.002), and loss of tight junction proteins (p = 0.016 ZO-1 expression; p = 0.013 occludin expression) after TBI compared with the vehicle-treated group. Capsazepine significantly alleviated early-stage apoptosis by attenuating activation of JNK, P38, and caspase-3, resulting in a protective effect on the level of ZO-1 in bEnd.3 cells after stretch injury. We conclude that the expression of TRPV1 is upregulated after TBI, and inhibition of TRPV1 attenuated disruption of the BBB in a mouse model of TBI, at least partly, through its antiapoptotic effects on brain endothelial cells. Blocking TRPV1 may be a promising pharmacotherapeutic intervention to protect against BBB disruption after TBI.

The potential mechanism for Hydroxysafflor yellow A attenuating blood-brain barrier dysfunction via tight junction signaling pathways excavated by an integrated serial affinity chromatography and shotgun proteomics analysis approach

Our previous studies elucidated that hydroxysafflor yellow A (HSYA) exerted anti-inflammatory effects against ischemia stroke by inhibiting TLR4 pathway-mediated signaling transduction. However, only several targets were verified in that limited work. The integrated method of serial affinity chromatography (SAC) and shotgun proteomics analysis (SPA) might be an alternative approach for exploring a potential therapeutic role. SAC was induced to extract specific binding proteins in the brain tissue of 2 h of ischemia stroke mice via HSYA affinity matrices. SPA was conducted by nanoLC-MS/MS, while the identified proteins were mapped on to Gene Ontology and KEGG pathway components analysis. The protection of HSYA for blood-brain barrier in mice with ischemia stroke was assessed with the leakage of Evans Blue. The expression of tight junction proteins of blood-brain barrier: occludin, claudin-5, and ZO-1 were detected with ischemia boundary positive areas staining. The regulation of nonmuscle myosin heavy chain IIA (NMMHC IIA), TLR4-mediated PI3K/AKT/JNK1/2/14-3-3ε/NF-κB p65 signaling pathway were evaluated using western blot analysis. A total of 35 proteins with molecular eights ranging from 27,841.22 to 234,122.79 KD were identified. Gene Ontology annotation and KEGG pathways analysis of the identified proteins were conducted with tight junction and PI3K/AKT signaling pathways. HSYA could significantly reduce the leakage of Evans Blue in mice with ischemia stroke, while attenuating the expression of occludin, claudin-5, and ZO-1. Western blot demonstrated that regulation of NMMHC IIA, TLR4-mediated PI3K/AKT/JNK1/2/14-3-3ε/NF-κB p65 signaling pathway played an essential role in the protective effect of HSYA. The integrated method of SAC and SPA provides the promising explanations for exploring the mechanism underlying blood-brain barrier dysfunction via the tight junction pathway. HSYA could attenuate blood-brain barrier dysfunction in anti-inflammatory patterns in ischemia stroke mice via the tight junction pathway.

106 - Endothelial depletions of ROR2 and PDZRN3 in mice attenuate Blood Brain Barrier (BBB) disruption in a model of focal cerebral stroke

106 - Endothelial depletions of ROR2 and PDZRN3 in mice attenuate Blood Brain Barrier (BBB) disruption in a model of focal cerebral stroke

Intranasal administration of vitamin D attenuates blood–brain barrier disruption through endogenous upregulation of osteopontin and activation of CD44/P-gp glycosylation signaling after subarachnoid hemorrhage in rats

In this study, we investigated the role of vitamin D3 (VitD3) on endogenous osteopontin (OPN), a neuroprotective glycoprotein, after subarachnoid hemorrhage (SAH). The endovascular perforation SAH model in Sprague-Dawley rats was used to study the effect of intranasal VitD3 (30 ng/kg) before (Pre-SAH + VitD3) and after (Post-SAH + VitD3) subarachnoid hemorrhage. Vitamin D3 (30, 60, 120 ng/kg/day) increased more than one fold endogenous OPN expression in astrocytes and endothelial cells of rat brain. Vitamin D3 significantly decreased brain edema and Evans blue extravasation. In addition, neurobehavioral scores were significantly higher in Pre-SAH + VitD3, but partly higher in Post-SAH + VitD3, group compared with SAH group. These protective effects of vitamin D3 were completely attenuated by intracerebroventricular injection of transcription inhibitor Actinomycin D and significantly inhibited by small interfering ribonucleic acid (siRNA) for vitamin D receptor and OPN in Pre-SAH + VitD3 rats. OPN expression was significantly higher in Pre-SAH + VitD3 rats, specifically A and C, but not B, isomers were upregulated in the astrocytes, leading to CD44 splicing, and P-gp glycosylation in brain endothelial cells. The results show that intranasal vitamin D3 attenuates blood–brain barrier (BBB) disruption through endogenous upregulation of OPN and subsequent CD44 and P-gp glycosylation signals in brain endothelial cells. Furthermore, this study identifies a novel strategy for the cost-effective management of subarachnoid hemorrhage.

Glibenclamide Attenuates Blood–Brain Barrier Disruption in Adult Mice after Traumatic Brain Injury

Glibenclamide is a hypoglycemic drug that is widely used for the treatment of diabetes mellitus type 2 (DM II), but it also plays a protective role following injury to the central nervous system (CNS). However, the precise mechanisms underlying its neuroprotective actions remain to be elucidated. Therefore, the present study evaluated the effects of glibenclamide on the blood-brain barrier (BBB) in a mouse model of traumatic brain injury (TBI). In the present study, 86 adult male C57BL/6 mice were exposed to a controlled cortical impact (CCI) injury and then received glibenclamide (10 μg) for 3 days. Tight junction (TJ) protein levels, BBB permeability, and tissue hemoglobin levels were evaluated following the CCI injury. Additionally, a biaxial stretch injury was applied to cell cultures of bEnd.3 cells using the Cell Injury Controller II system to explore the mechanisms by which glibenclamide inhibits apoptosis-signaling pathways. Compared with the control group, glibenclamide-treated mice exhibited decreases in brain water content (p < 0.05), tissue hemoglobin levels (p < 0.05), and Evans Blue extravasation (p < 0.01) after the CCI injury. Glibenclamide primarily attenuated apoptosis via the JNK/c-jun signaling pathway and resulted in an elevation of stretch injury-induced ZO-1 expression in bEnd.3 cells (p < 0.01).Glibenclamide downregulated the activity of the JNK/c-jun apoptosis-signaling pathway which, in turn, decreased apoptosis in endothelial cells (ECs). This may have prevented the disruption of the BBB in a mouse model of TBI.

The Serum Changes of Neuron-Specific Enolase and Intercellular Adhesion Molecule-1 in Patients With Diffuse Axonal Injury Following Progesterone Administration: A Randomized Clinical Trial.

BackgroundImprovement of neurologic outcome in progesterone-administered patients with diffuse axonal injury (DAI) has been found in a recent study. Also, there has been interest in the importance of serum parameters as predictors of outcome in traumatic brain injury.ObjectivesThe aim of this study was to examine the effect of progesterone administration on serum levels of neuron-specific enolase (NSE), and intercellular adhesion molecule-1 (ICAM-1) in clinical DAI.Patients and MethodsIn this study, the serum levels of ICAM-1 and NSE of 32 male DAI patients (18 - 60 years of age, a Glasgow coma scale of 12 or less, and admitted within 4 hours after injury) who were randomized for a controlled phase II trial of progesterone were analyzed. The analysis was performed between the control and progesterone groups at admission time, and 24 hours and six days after DAI, respectively.ResultsA reduction in the serum level of ICAM-1 was noticed in the progesterone group 24 hours after the injury (P < 0.05). There was no significant difference in the serum level of NSE between the study groups during evaluation. At 24 hours after the injury, the level of ICAM-1 in the control group was higher than that at admission time (P < 0.05). The lowest level of NSE in the two groups was seen six days after DAI (P < 0.01).ConclusionsIn summary, progesterone administration reduced serum ICAM-1, and whereby may attenuate blood brain barrier disruption, the latter needs further investigation for confirmation.

Deferoxamine inhibits microglial activation, attenuates blood-brain barrier disruption, rescues dendritic damage, and improves spatial memory in a mouse model of microhemorrhages.

Cerebral microbleeds are strongly linked to cognitive dysfunction in the elderly. Iron accumulation plays an important role in the pathogenesis of intracranial hemorrhage. Deferoxamine (DFX), a metal chelator, removes iron overload and protects against brain damage in intracranial hemorrhage. In this study, the protective effects of DFX against microhemorrhage were examined in mice. C57BL6 and Thy-1 green fluorescent protein transgenic mice were subjected to perforating artery microhemorrhages on the right posterior parietal cortex using two-photon laser irradiation. DFX (100mg/kg) was administered 6h after microhemorrhage induction, followed by every 12h for three consecutive days. The water maze task was conducted 7days after induction of microhemorrhages, followed by measurement of blood-brain barrier permeability, iron deposition, microglial activation, and dendritic damage. Laser-induced multiple microbleeds in the right parietal cortex clearly led to spatial memory disruption, iron deposits, microglial activation, and dendritic damage, which were significantly attenuated by DFX, supporting the targeting of iron overload as a therapeutic option and the significant potential of DFX in microhemorrhage treatment. Irons accumulation after intracranial hemorrhage induced a serious secondary damage to the brain. We proposed that irons accumulation after parietal microhemorrhages impaired spatial cognition. After parietal multiple microhemorrhages, increased irons and ferritin contents induced blood-brain barrier disruption, microglial activation, and further induced dendrites loss, eventually impaired the water maze, deferoxamine treatment protected from these damages.

Partially purified components of Uncaria sinensis attenuate blood brain barrier disruption after ischemic brain injury in mice.

BackgroundUncaria sinensis (US) has long been used in traditional Korean medicine to relieve various nervous-related symptoms and cardiovascular disease. We recently showed the neuroprotective and cerebrovascular protective effects of US on cerebral ischemia; however, its effects on the blood–brain barrier (BBB) are poorly understood. In this study, the effects of partially purified components of US (PPUS) on BBB disruption were investigated in mice subjected to ischemic brain injury.MethodsFocal cerebral ischemia was induced in C57BL/6J mice by photothrombotic cortical ischemia. PPUS was injected intraperitoneally 30 min before ischemic insults. Infarct volume, neurological score, wire-grip test, Evans blue leakage and brain water content were then examined 24 h after ischemic brain injury.ResultsInfarct volume was significantly reduced and neurological deficit and motor deficit were greatly improved in PPUS-pretreated mice relative to those treated with vehicle following photothrombotic cortical ischemia. Brain edema-induced change of Evans blue extravasation and water content in the ipsilateral hemisphere were alleviated by treatment with PPUS. In addition, PPUS significantly reduced ischemic brain injury-induced degradation of tight junction proteins and elevation of matrix metalloproteinase-9 (MMP-9).ConclusionsPPUS prevents cerebral ischemic damage by BBB protection, and these effects were associated with inhibition of tight junction degradation and MMP-9 induction.

Delayed inhibition of VEGF signaling after stroke attenuates blood-brain barrier breakdown and improves functional recovery in a comorbidity-dependent manner.

Diabetes is a common comorbidity in stroke patients and a strong predictor of poor functional outcome. To provide a more mechanistic understanding of this clinically relevant problem, we focused on how diabetes affects blood-brain barrier (BBB) function after stroke. Because the BBB can be compromised for days after stroke and thus further exacerbate ischemic injury, manipulating its function presents a unique opportunity for enhancing stroke recovery long after the window for thrombolytics has passed. Using a mouse model of Type 1 diabetes, we discovered that ischemic stroke leads to an abnormal and persistent increase in vascular endothelial growth factor receptor 2 (VEGF-R2) expression in peri-infarct vascular networks. Correlating with this, BBB permeability was markedly increased in diabetic mice, which could not be prevented with insulin treatment after stroke. Imaging of capillary ultrastructure revealed that BBB permeability was associated with an increase in endothelial transcytosis rather than a loss of tight junctions. Pharmacological inhibition (initiated 2.5 d after stroke) or vascular-specific knockdown of VEGF-R2 after stroke attenuated BBB permeability, loss of synaptic structure in peri-infarct regions, and improved recovery of forepaw function. However, the beneficial effects of VEGF-R2 inhibition on stroke recovery were restricted to diabetic mice and appeared to worsen BBB permeability in nondiabetic mice. Collectively, these results suggest that aberrant VEGF signaling and BBB dysfunction after stroke plays a crucial role in limiting functional recovery in an experimental model of diabetes. Furthermore, our data highlight the need to develop more personalized stroke treatments for a heterogeneous clinical population.

Gestational treatment of folic acid attenuates blood–brain barrier leakage in pregnant- and prepubertal rats after pentylenetetrazole-induced seizure

Objectives: Folic acid (FA) is physiologically important in mammals and is a common vitamin supplement used during pregnancy and lactation. Numerous studies have reported that FA significantly improves endothelial function. The blood–brain barrier (BBB) plays an important role in maintaining the microenvironment required for neuronal function, but its unique structure is damaged by epileptic seizures. The aim of this study was to evaluate the potential protective role of FA on BBB leakage, as well as on the reactive astrogliosis in pregnant rats and their prepubertal offspring during pentylenetetrazole (PTZ)-induced epileptic seizure.Methods: Pregnant rats were treated with FA (5 mg/kg) and PTZ on gestational days 0–19 and 19, respectively. The pups were treated with PTZ at puberty. Evans blue was used to evaluate BBB integrity. Reactive astrogliosis was defined using immunohistochemical analysis for glial fibrillary acidic protein (GFAP). Mean arterial blood pressure (MABP) was measured at the femoral artery.Results: A moderate decrease in BBB leakage was observed in FA-treated pregnant and prepubertal animals (P < 0.05). MABP was decreased significantly in pregnant rats (P < 0.05). The epilepsy-induced increase in MABP was less prominent in pregnant animals (P < 0.05). GFAP intensity decreased in PTZ-treated pregnant animals (P < 0.01) and FA-treated prepubertal rats.Discussion: Our findings suggest that FA, which is used as a maternal vitamin to promote normal fetus development, may be beneficial against seizure-induced neuronal damage by decreasing BBB leakage and reactive astrogliosis in pregnant and prepubertal rats.