TIMP-1 attenuates blood–brain barrier permeability in mice with acute liver failure

Blood–brain barrier (BBB) dysfunction in acute liver failure (ALF) results in increased BBB permeability that often precludes the patients from obtaining a life-saving liver transplantation. It remains controversial whether matrix metalloproteinase-9 (MMP-9) from the injured liver contributes to the deregulation of BBB function in ALF. We selectively upregulated a physiologic inhibitor of MMP-9 (TIMP-1) with a single intracerebroventricular injection of TIMP-1 cDNA plasmids at 48 and 72 hours, or with pegylated-TIMP-1 protein. Acute liver failure was induced with tumor necrosis factor-α and 𝒟-(+)-galactosamine in mice. Permeability of BBB was assessed with sodium fluorescein (NaF) extravasation. We found a significant increase in TIMP-1 within the central nervous system (CNS) after the administration of TIMP-1 cDNA plasmids and that increased TIMP-1 within the CNS resulted in an attenuation of BBB permeability, a reduction in activation of epidermal growth factor receptor and p38 mitogen-activated protein kinase signals, and a restoration of the tight junction protein occludin in mice with experimental ALF. Pegylated TIMP-1 provided similar protection against BBB permeability in mice with ALF. Our results provided a proof of principle that MMP-9 contributes to the BBB dysfunction in ALF and suggests a potential therapeutic role of TIMP-1 in ALF.     

Expression of the apoptosis-related proteins caspase-3 and NF-κB in the hippocampus of Tg2576 mice

Objective

To investigate the relations between neuroapoptosis and the onset and development of Alzheimer’s disease (AD), especially the role of NF-κB in the regulation of neuroapoptosis.

Methods

Caspase-3 and NF-κB (p50) expressions in the CA3 region of the hippocampus in APPswe Tg2576 transgenic mice were studied from postnatal day 0–180, using Nissl staining, immunohistochemistry and RT-PCR methods.

Results

Both neuronal apoptosis and NF-κB activity decreased gradually with the increase of age in wild type and Tg2576 mice. However, the number of caspase-3-positive or NF-κB-positive pyramidal cells in Tg2576 mice was greater than that in age-matched wild type mice, with significant differences after postnatal day 14 (P < 0.01 or P < 0.05). Linear regression analyses of caspase-3 and NF-κB expression demonstrated a correlation between neuroapoptosis and activity of NF-κB.

Conclusion

The process of neuroapoptosis is consistent with the onset and development of AD. Furthermore, the observed correlation between neuroapoptosis and NF-κB activity suggests a role of NF-κB in hippocampal neuroapoptosis.     

Not only a bad guy:potential proneurogenic role of the RAGE/NF-κB axis in Alzheimer's disease brain

正The receptor for advanced glycation endproducts(RAGE)is a receptor of the immunoglobulin superfamily of cell surface molecules which plays important contributions under both physiological and pathological conditions.Over the years extensive research work supported the detrimental role of RAGE in Alzheimer’s disease(AD)pathophysiology,ranging from its involvement in beta amyloid(Aβ)brain influx and clearance,     

Expression of brain nuclear factor-κB (P50) in mice with traumatic brain injury after hyperbaric oxygen treatment

Objective To investigate the relation between the therapeutic effect of hyperbaric oxygen treatment and nuclear factor-κB (NF-κB) (P50) expression in the brain tissue in mice with traumatic brain injury (TBI). Methods A total of 120 SD rats were randomly divided into sham-operated, TBI model, normobaric oxygen and hyperbaric oxygen (0.2 MPa) groups, and in the latter 3 groups, TBI was induced using Feeney's method. At 6 h and 1, 3, 5, and 7 d following TBI (6 rats at each time point), the rats were sacrificed to observe the pathological changes in the brain tissues under light microscope and detect the expression of NF-κB (P50) using immunohistochemistry. Results The rats in hyperbaric oxygen group showed lessened brain edema as compared with those in TBI model and normobaric oxygen groups. Only trace amount of NF-κB (P50) expression was observed in the sham-operated group, while in the 3 groups with TBI, NF-κB (P50) expression began to increase as early as 6 h after TBI and kept increasing till reaching the peak level at 5 days. At each of the time points for observation, the expression ofNF-κB (PS0) in hyperbaric oxygen group was significantly higher than those in TBI and normobaric oxygen groups (P<0.05). Conclusion Hyperbaric oxygen treatment offers protection of the injured neural cells and promotes their repair in rats following TBI. Increased NF-κB (P50) expression in the brain tissue may serve as one of the pathways mediating the neuroprotective effect of hyperbaric oxygen treatment.     

Perturbations of the cerebrovascular matrisome: A convergent mechanism in small vessel disease of the brain?

The term matrisome refers to the ensemble of proteins constituting the extracellular matrix (ECM) (core matrisome) as well as the proteins associated with the ECM. Every organ has an ECM with a unique composition that not only provides the support and anchorage for cells, but also controls fundamental cellular processes as diverse as differentiation, survival, proliferation, and polarity. The current knowledge of the matrisome of small brain vessels is reviewed with a focus on the basement membrane (BM), a specialized form of ECM located at the interface between endothelial cells, contractile cells (smooth muscle cells and pericytes), and astrocyte endfeet—a very strategic location in the communication pathway between the cerebral microcirculation and astrocytes. We discuss some of the most recent genetic data and relevant findings from experimental models of nonamyloid cerebral small vessel disease (SVD). We propose the concept that perturbations of the cerebrovascular matrisome is a convergent pathologic pathway in monogenic forms of SVD, and is likely relevant to the sporadic disease.     

Vitamin D3-enriched diet correlates with a decrease of amyloid plaques in the brain of AβPP transgenic mice

In addition to its function in calcium and bone metabolism, vitamin D is neuroprotective and important for mitigating inflammation. Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the central nervous system, characterized by neuronal loss in many areas of the brain, and the formation of senile (neuritic) plaques, which increase in number and size over time. The goal of this project was to investigate whether vitamin D3 supplementation would affect amyloid plaque formation in amyloid-β protein precursor (AβPP) transgenic mice that spontaneously develop amyloid plaques within 3-4 months of birth. AβPP mice were fed control, vitamin D3-deficient or vitamin D3-enriched diets for five months, starting immediately after weaning. At the end of the study, the animals were subjected to behavioral studies, sacrificed, and examined for bone changes and brain amyloid load, amyloid-β (Aβ) peptide levels, inflammatory changes, and nerve growth factor (NGF) content. The results obtained indicate that a vitamin D3-enriched diet correlates with a decrease in the number of amyloid plaques, a decrease in Aβ peptides, a decrease in inflammation, and an increase in NGF in the brains of AβPP mice. These observations suggest that a vitamin D3-enriched diet may benefit AD patients.     

Fatal brain edema in a child after ingestion of amitriptyline: Is the culprit amitriptyline?

Tricyclic antidepressants are among the drugs most frequently involved in pediatric exposures. We report here a case of a fatality in a 2.5-year-old boy after he ingested an overdose of amitriptyline . He developed seizure, hypotension, and his pupils became dilated which were interpreted as signs of TCA overdosages at first. However, his serum Na level was low (110 mEq L⁻¹) and his clinical and laboratory data were consistent with SIADH. Hypotonic fluid administration with SIADH contributed to fatal outcome and hyponatremia and cerebral edema appeared to be the main pathological processes.     

Overexpression of human cystatin C in transgenic mice does not affect levels of endogenous brain amyloid β peptide

Cystatin C, an inhibitor of cysteine proteases, colocalizes with amyloid β (Aβ) in parenchymal and vascular amyloid deposits in brains of Alzheimer’s disease (AD) patients, suggesting that cystatin C has a role in AD. Cystatin C also colocalizes with β amyloid precursor protein (βAPP) in transfected cultured cells. In vitro analysis of the association between the two proteins revealed that binding of cystatin C to full-length βAPP does not affect the level of Aβ secretion. Here we studied the effect of in vivo overexpression of cystatin C on the levels of endogenous brain Aβ. We have generated lines of transgenic mice expressing either wild-type human cystatin C or the Leu68Gln variant that forms amyloid deposits in the cerebral vessels of Icelandic patients with hereditary cerebral hemorrhage, under control sequences of the human cystatin C gene. Western blot analysis of brain homogenates was used to select lines of mice expressing various levels of the transgene. Analysis of Aβ40 and Aβ42 concentrations in the brain showed no difference between transgenic mice and their nontransgenic littermates. Thus, in vivo overexpression of human cystatin C does not affect Aβ levels in mice that do not deposit Aβ.     

Aquaporins in cerebrovascular disease: a target for treatment of brain edema?

In cerebrovascular disease, edema formation is frequently observed within the first 7 days and is characterized by molecular and cellular changes in the neurovascular unit. The presence of water channels, aquaporins (AQPs), within the neurovascular unit has led to intensive research in understanding the underlying roles of each of the AQPs under normal conditions and in different diseases. In this review, we summarize some of the recent knowledge on AQPs, focusing on AQP4, the most abundant AQP in the central nervous system. Several experimental models illustrate that AQPs have dual, complex regulatory roles in edema formation and resolution. To date, no specific therapeutic agents have been developed to inhibit water flux through these channels. However, experimental results strongly suggest that this is an important area for future investigation. In fact, early inhibition of water channels may have positive effects in the prevention of edema formation. At later time points during the course of disease, AQP is important for the clearance of water from the brain into blood vessels. Thus, AQPs, and in particular AQP4, have important roles in the resolution of edema after brain injury. The function of these water channel proteins makes them an excellent therapeutic target.     

Involvement of p38/NF-κB signaling pathway in the nucleus accumbens in the rewarding effects of morphine in rats

The nucleus accumbens (NAc) is one of the important brain regions for the acquisition of morphine-induced conditioned place preference (CPP), which is a valuable paradigm for detecting the rewarding effects of drugs. However, the underlying molecular mechanisms remain largely unknown. In the present study, we investigated the role of p38 and nuclear factor kappa B (NF-κB) in the NAc in the acquisition of morphine-induced CPP. The results showed that repeated morphine treatment induced the acquisition of CPP and increased the phosphorylation of p38, IκB-α and NF-κB p65 in the NAc. Microinjection of p38 inhibitor SB203580 into the NAc prior to the application of morphine prevented the acquisition of CPP and inhibited the activation of p38, IκB-α and NF-κB p65. Furthermore, pre-infusion of pyrrolidine dithiocarbamate (PDTC), a selective NF-κB inhibitor, into the NAc blocked the CPP but also the phosphorylation of NF-κB p65 induced by morphine. It is concluded that the activation of p38/NF-κB p65 signaling pathway in the NAc plays a critical role in the morphine CPP.     

PPARγ activation induces acute PAI-1 gene expression in the liver but not in adipose tissues of diabetic model mice

Insulin resistance in patients with type II diabetes has recently been treated with thiazolidinediones, a class of peroxisome proliferator-activated receptor γ (PPARγ) agonists. However, these compounds are possibly associated with a significant increase in the risk of cardiovascular events. We examined the effect of the PPARγ agonist rosiglitazone on the expression of plasminogen activator inhibitor-1 (PAI-1) that is the primary inhibitor of fibrinolysis in the liver of diabetic mice and cultured mouse and human hepatocytes. Concentrations of plasma PAI-1 and levels of its mRNA expression in the liver were significantly elevated in accordance with hepatic PPARγ1 and PPARγ2 mRNA accumulation in genetically diabetic db/db mice. An intraperitoneal injection of rosiglitazone significantly increased plasma PAI-1 concentrations in parallel with hepatic, but not with adipose mRNA levels in db/db mice, and did not affect these parameters in wild-type mice. Rosiglitazone as well as the PPARα agonist bezafibrate significantly induced PAI-1 mRNA expression in cultured mouse hepatocytes. Furthermore, both rosiglitazone and pioglitazone significantly induced, whereas bezafibrate did not affect PAI-1 mRNA expression in the human liver carcinoma cell line HepG2. The transient induction of PAI-1 gene expression mediated by PPARγ in the fatty liver might be involved in the increased risk of cardiovascular events associated with thiazolidinediones in diabetic patients through decreasing fibrinolytic activity.     

S100B in neuropathologic states: The CRP of the brain?

In recent years there has been a proliferation of interest in the brain-specific protein S100B, its many physiologic roles, and its behaviour in various neuropathologic conditions. Since the mid-1960s, its wide variety of intracellular and extracellular activities has been elucidated, and it has also been implicated in an increasing number of central nervous system (CNS) disorders. S100B is part of a superfamily of proteins, some of which (including S100B) have been implicated as calcium-dependent regulatory proteins that modulate the activity of effector proteins or cells. S100B is primarily an astrocytic protein. Within cells, it may have a role in signal transduction, and it is involved in calcium homeostasis. Information about the functional implication of S100B secretion by astrocytes into the extracellular space is scant but there is substantial evidence that secreted glial S100B exerts trophic or toxic effects depending on its concentration. This review summarises the historic development and current knowledge of S100B, including recent interesting findings relating S100B to a diversity of CNS pathologies such as traumatic brain injury, Alzheimer's disease, Down's syndrome, schizophrenia, and Tourette's syndrome. These broad implications have led some workers to describe S100B as 'the CRP (C-reactive protein) of the brain.' This review also examines S100B's potential role as a neurologic screening tool, or biomarker of CNS injury, analogous to the role of CRP as a marker of systemic inflammation.     

Dysregulation of the NF-κB pathway as a potential inducer of bipolar disorder

A century of investigations enhanced our understanding of bipolar disorder although it remains a complex multifactorial disorder with a mostly unknown pathophysiology and etiology. The role of the immune system in this disorder is one of the most controversial topics in genetic psychiatry. Though inflammation has been consistently reported in bipolar patients, it remains unclear how the immunologic process influences the disorder. One of the core components of the immune system is the NF-κB pathway, which plays an essential role in the development of innate and adaptive immunity. Remarkably, the NF-κB pathway received only little attention in bipolar studies, as opposed to studies of related psychiatric disorders where immune dysregulation has been proposed to explain the neurodegeneration in patient conditions. If immune dysregulation can also explains the neurodegeneration in bipolar disorder, it will underscore the role of the immune system in the chronicity and pathophysiology of the disorder and may promote personalized therapeutic strategies. This is the first review to summarize the current knowledge of the pathophysiological functions of NF-κB in bipolar disorder.     

Protective effect of Indole-3-carbinol,an NF-κB inhibitor in experimental paradigm of Parkinson’s disease: In silico and in vivo studies

Parkinson’s disease (PD) is a progressive neurodegenerative disorder, majorly with symptoms of motor dysfunction. Study was performed to explore the effect of nuclear factor κB (NF-κB) inhibitors against neurobehavioral abnormalities and neuroinflammation in PD. Cost effective in silico approaches of docking-based ligand -target complex predictions and optimal physicochemical properties were utilised to identify lead NF-κB inhibitor using database. Our studies revealed the potential hit Indole-3-carbinol (I3C) which was considered for the next phase, pharmacological validations. Intranigral administration of lipopolysaccharide (LPS) in rats is utilized as a neuroinflmmation model of PD. In the present study it caused an impairment in motor functions, its coordination, learning and memory as demonstrated in rotarod apparatus, beam balance test, open field test and Morris water maze test. Chronic administration of I3C for 21 days in intranigral LPS treated rats led to a significant improvement in motor functions, coordination, learning and memory which were associated with a decrease in the activity of inflammatory cytokines such as TNF-α and IL-6. Further, it was found to inhibit NF-κB whose levels increased after LPS administration. Moreover, decreased levels of malondialdehyde and increased levels of reduced glutathione, superoxide dismutase and catalase were observed in cortex and striatum after I3C administration in LPS rats. These results suggest a possible neuroprotective effect of I3C via amelioration of LPS-induced behavioural alterations, oxidative damage and neuroinflammation which in turn is attributed to its potent antioxidant and anti-inflammatory (NF-κB inhibition) property. The effect produced by I3C (50 mg/kg) was found to be comparable with levodopa-carbidopa combination (LD:CD) while, I3C (50 mg/kg) in combination with LD:CD exhibited a potentiating effect in improving motor impairments and cognitive deficit. The results thus depict I3C as a promising agent to delay neurodegeneration of the neurons in PD with improvement in motor functions and cognitive function.     

Contrast-enhanced magnetic resonance microangiography reveals remodeling of the cerebral microvasculature in transgenic ArcAβ mice

Amyloid-β (Aβ) deposition in the cerebral vasculature is accompanied by remodeling which has a profound influence on vascular integrity and function. In the current study we have quantitatively assessed the age-dependent changes of the cortical vasculature in the arcAβ model of cerebral amyloidosis. To estimate the density of the cortical microvasculature in vivo, we used contrast-enhanced magnetic resonance microangiography (CE-μMRA). Three-dimensional gradient echo datasets with 60 μm isotropic resolution were acquired in 4- and 24-month-old arcAβ mice and compared with wild-type (wt) control mice of the same age before and after administration of superparamagnetic iron oxide nanoparticles. After segmentation of the cortical vasculature from difference images, an automated algorithm was applied for assessing the number and size distribution of intracortical vessels. With CE-μMRA, cerebral arteries and veins with a diameter of less than the nominal pixel resolution (60 μm) can be visualized. A significant age-dependent reduction in the number of functional intracortical microvessels (radii of 20-80 μm) has been observed in 24-month-old arcAβ mice compared with age-matched wt mice, whereas there was no difference between transgenic and wt mice of 4 months of age. Immunohistochemistry demonstrated strong fibrinogen and Aβ deposition in small- and medium-sized vessels, but not in large cerebral arteries, of 24-month-old arcAβ mice. The reduced density of transcortical vessels may thus be attributed to impaired perfusion and vascular occlusion caused by deposition of Aβ and fibrin. The study demonstrated that remodeling of the cerebrovasculature can be monitored noninvasively with CE-μMRA in mice.