Increase In BBB Permeability Research Articles

Increase of tumor necrosis factor-α in the blood induces the early activation of matrix metalloproteinase-9 in the brain

Increases of cytokine in the blood play important roles in the pathogenesis of influenza-associated encephalopathy. TNF-alpha was administered intravenously to wild-type mice, after which blood, CSF and brain tissue were obtained, and changes in BBB permeability, the amounts of MMP-9 and TIMP-1, and the localization of activated MMP were assessed. There was a significant increase in BBB permeability after 6 and 12 hr. MMP-9 was increased after 3 hr in the brain and cerebrospinal fluid, which was earlier than in the serum. TIMP-1 protein in the brain increased significantly after MMP-9 had increased. Activation of MMP-9 was observed in neurons in the cerebral cortex and hippocampus, and in vascular endothelial cells. These findings suggest that an increase in blood TNF-alpha promotes activation of MMP-9 in the brain, and may also induce an increase in permeability of the BBB. Early activation of MMP-9 in the brain may contribute to an early onset of neurological disorders and brain edema prior to multiple organ failure in those inflammatory diseases associated with highly increased concentrations of TNF-alpha in the blood, such as sepsis, burns, trauma and influenza-associated encephalopathy.

The multiple faces of quercetin in neuroprotection

This review discusses the most recent data on the potential of quercetin to confer neuroprotection. Unfortunately, most of the in vitro studies have used quercetin aglycone, which is not detectable in the plasma or in the brain after oral intake. Moreover, quercetin metabolites and glycosides seem to be less neuroprotective and penetrate the BBB less efficiently than aglycone. Surprisingly, quercetin has beneficial effects on various in vivo models of neural disorders, particularly in cerebrovascular insults; contrasting data also do exist. This may be due to an increase of BBB permeability, described in many of these animal models, which would facilitate quercetin brain penetration. Although quercetin causes no significant toxicity in several animal studies, the risk for neurotoxicity is not negligible because of its narrow therapeutic dose-range in vitro. Notably, this risk may be even higher in the case of increased quercetin access to the brain, which may occur pathologically or artificially (e.g., by liposomal preparations). Based on the referred literature, we doubt that quercetin possesses any significant efficacy in neurodegenerative disorders. Instead, therapeutic trials should focus more on the quercetin efficacy in cerebrovascular insults rather than neurodegeneration.

In vivo study of experimental pneumococcal meningitis using magnetic resonance imaging

BackgroundMagnetic Resonance Imaging (MRI) methods were evaluated as a tool for the study of experimental meningitis. The identification and characterisation of pathophysiological parameters that vary during the course of the disease could be used as markers for future studies of new treatment strategies.MethodsRats infected intracisternally with S. pneumoniae (n = 29) or saline (n = 13) were randomized for imaging at 6, 12, 24, 30, 36, 42 or 48 hours after infection. T1W, T2W, quantitative diffusion, and post contrast T1W images were acquired at 4.7 T. Dynamic MRI (dMRI) was used to evaluate blood-brain-barrier (BBB) permeability and to obtain a measure of cerebral and muscle perfusion. Clinical- and motor scores, bacterial counts in CSF and blood, and WBC counts in CSF were measured.ResultsMR images and dMRI revealed the development of a highly significant increase in BBB permeability (P < 0.002) and ventricle size (P < 0.0001) among infected rats. Clinical disease severity was closely related to ventricle expansion (P = 0.024).Changes in brain water distribution, assessed by ADC, and categorization of brain 'perfusion' by cortex ΔSI(bolus) were subject to increased inter-rat variation as the disease progressed, but without overall differences compared to uninfected rats (P > 0.05). Areas of well-'perfused' muscle decreased with the progression of infection indicative of septicaemia (P = 0.05).ConclusionThe evolution of bacterial meningitis was successfully followed in-vivo with MRI. Increasing BBB-breakdown and ventricle size was observed in rats with meningitis whereas changes in brain water distribution were heterogeneous. MRI will be a valuable technique for future studies aiming at evaluating or optimizing adjunctive treatments

Blood-Brain Barrier and Exercise – a Short Review

Blood-Brain Barrier and Exercise – a Short Review Blood-brain barier (BBB) segregates central nervous system (CNS) from the circulating blood. BBB is formed by the brain capillary endothelial cells with complex tight junctions between them as well as by astrocytes and pericytes. BBB is responsible for transport of selected chemicals into and out of the CNS as well as for its protection from fluctuations in plasma composition following meals, during exercise and from circulating agents such as neurotransmitters, xenobiotics and other potentially harmful substances capable to disturb neural function. BBB may be compromised during CNS injury, infection, fever and in some nerodegenerative diseases. The increase of BBB permeability was observed also during exercise as documented by changes of plasma S-100 protein levels, used as a peripheral marker of BBB integrity. Marked change in BBB integrity during exercise may disturb normal brain function and contribute to the development of central fatigue. Moreover, serum S-100β may indicate level of injury in individuals suffering brain injuries during sports. There are also data suggesting that acute effect of physical exercise on serum S100β levels may not be related with CNS injury. Further studies to establish whether training and which type of it may modulate BBB permeability are needed.

Regression of brain metastases of renal cell carcinoma with antiangiogenic therapy

We report the occurrence of a major volume reduction of cerebelar metastasis after 6 weeks of treatment with the antiangiogenic compound sunitinib [1], an oral inhibitor of several tyrosine kinases, including vascular endothelial growth factor receptor (VEGFR) and platelet derived growth factor receptor (PDGFR). A 60-year-old female presented in June 2003 with a tumor developed in the left kidney. There were no distant metastases on total body CT-scan. A radical nephrectomy was performed. The pathological exam found a 9 cm clearcell carcinoma (Furhman grade 4). In May 2005, the patient presented difficulties walking. Brain MRI was performed and two focal lesions were found: the right cerebelar lesion was removed and the right frontal lesion was treated by stereotaxic radiation therapy. Bone metastases (right femoral head) were treated by IV bisphosphonates. In October 2006, 40 months later after the initial diagnosis, two new cerebellar lesions were found on a brain MRI. The right frontal lesion had remained stable (Fig. 1a) .We began a treatment with SUNITINIB 50 mg a day given orally over a period of four weeks. MRI evaluation at week 6 showed a significant regression of the two cerebelar lesions associated with necrosis (Fig. 1b). The frontal lesion remained stable. The treatment with SUNITINIB was then continued alternating with 2-weeks rest periods. Sunitib has demonstrated a significant advantage over interferon-a for the treatment of metastatic RCC in a large phase 3 study [2]. There is a lack of information about sunitinib efficacy on brain metastases because patients with brain metastases were systematically excluded from previous studies. Brain metastases are refractory to most conventional chemotherapy regimens given for the treatment of solid tumors [3]. Putative activity of anti-angiogenic therapy on brain metastases is controversial. VEGF and all the mechanisms pulling (entailing) a dysregulation of the local angiogenesis participate in a global increase of the permeability of the BBB [4]. This increase of BBB permeability allows pericytes from peripheral blood to participate in the forming of neo-vessels intended for the tumor irrigation. VEGF also plays a major role in the brain revascularisation after an ischemic accident by increasing the permeability of the BBB, through NO synthetase [5]. Our observations suggest that sunitinib has significant benefit for the treatment of brain metastases. The safety and the efficacy of this strategy should be addressed in a future prospective trial. We thank the Fondation Martine Midy for support of this study.

Improved Brain Delivery of a Nonsteroidal Anti-Inflammatory Drug with a Synthetic Glyceride Ester: a Preliminary Attempt at a CNS Drug Delivery System for the Therapy of Alzheimer's Disease

1,3-Diacetyl-2-ketoprofen glyceride (DAKG), a prodrug of ketoprofen, was synthesized as a model compound in our attempt to develop a central nervous system (CNS) drug delivery system to treat Alzheimer's disease. The primary purpose of the present study is to test whether DAKG improves the delivery of ketoprofen to the brain and to quantitatively evaluate several factors that influence the brain distribution of this prodrug. ddY mice were injected with either ketoprofen or DAKG at a dose of 40 μmol/kg and then the plasma and brain pharmacokinetics of these agents were assessed. The brain uptake clearance of ketoprofen and DAKG across the BBB was measured by in situ mouse brain perfusion. In addition, the efflux permeability of ketoprofen through the BBB was evaluated using the in vivo mouse brain microdialysis technique. The in vivo metabolism of DAKG in the brain was assessed by a short infusion into the internal carotid artery coupled with the brain metabolism index (BMI) method. Administration of DAKG produced an approximately 3-fold increase in the area under the brain concentration - time curve of ketoprofen, compared with administration of ketoprofen itself. The brain uptake clearance (CLin) of ketoprofen across the BBB was 0.0308 ± 0.0046 mL/min/g whereas the CLin of DAKG was 1.60 ± 0.16 mL/min/g, suggesting a marked increase in BBB permeability following lipidization of ketoprofen. The BMI method confirmed that DAKG is taken up by the brain to rapidly release ketoprofen in a dose-dependent manner. The in vitro metabolism studies revealed that isolated bovine brain capillaries as well as whole brain homogenate have the hydrolysis activity to DAKG. In addition, the brain concentration of ketoprofen after DAKG administration was maintained for a significant period following co-administration of probenecid. These results suggest that DAKG improves the delivery of ketoprofen to the brain, and this improved delivery is due to avid uptake of DAKG across the BBB followed by rapid hydrolysis to ketoprofen within the brain. The ketoprofen produced in the brain was probably cleared by the active efflux system operating in the BBB. Significant inhibition of this efflux system by co-administration of probenecid could result in a sustained concentration of ketoprofen in the brain following DAKG administration.