62 (1) protect the brain from blood-borne substances and (2) to provide nutrient supply to the brain parenchyme by specia- lised transport systems (Rubin and Staddon 1999). The main structures responsible for this barrier property are the TJ. TJ are strongly developed in endothelial cells of the BBB but only moderately formed between endothelial cells of the peripheral vasculature: leaky blood vessels in the body allow many molecules to cross through to tissue, but the tight construction of the vessels in the CNS guards against brain entry, leading to high electrical resistance in the range of 1,500—2,000 cm2, depending on the species investigated. In BBB-forming brain capillary endothelial cells (BCECs) the TJ proteins occludin and claudin-5, clau- din-3, claudin-1 and claudin-12 were demonstrated by immunoXuorescence and western blot analysis (Förster et al. 2007; Wolburg and Lippoldt 2002). Under physiological conditions, brain microvascular endothelial cells form a barrier limiting the extravasation of cells of the immune system like monocytes, lymphocytes and other leukocytes. It has been shown in this context that leukocytes can transmigrate to the BBB without net changes in vascular permeability and cell–cell contacts (Cramer 1992). However, increased leukocyte migration as in multiple sclerosis (MS) has been reported to lead to a re- organisation of the actin cytoskeleton and breakdown of the TJ proteins occludin and ZO-1 (Couraud 1998; Förster et al. 2007). MS is characterised as a chronic and progres- sive CNS disease with a remitting-relapsing proWle. In the course of the disease, both demyelination and microvascu- lar inXammation have been described as central patho- physiological insults. From an animal model for MS, experimental allergic encephalomyelitis (EAE) (Korner and Sedgwick 1996), the inXammatory cytokines TNF and IL-1 have been delineated to be the key mediators inducing alterations in BBB permeability. Clinically matching data have been collected from MS patients, who show an eleva- tion in TNF and/or IL-1 in cerebrospinal Xuid (CSF) (Weber and Rieckmann 1995). Cytokine-promoted opening of the BBB has been shown to occur due to degradation and decreased synthesis of TJ proteins (Chang and Werb 2001; Harkness et al. 2000; Silwedel and Förster 2006; Yang et al. 2006), resulting in compromised junctional integrity. Particularly, the TJ proteins occludin and ZO-1 have been shown to be negatively aVected by the presence of these pro-inXammatory cytokines. Searching for the mechanism of TJ protein degradation, consecutive studies showed, that in many neuroinXammatory conditions, including MS, the matrix metalloproteinases (MMP) play an important role in disrupting the BBB. Amongst these, it has been demon- strated that selectively, MMP-9 (gelatinase B) is increased in CSF levels in MS patients. Tissue inhibitors of metallo- proteinases (TIMPs) form complexes with either activated 123 Histochem Cell Biol (2008) 130:55–70 MMPs or with their pro-forms after their secretion, thus regulating MMP activity under physiological conditions (Brew et al. 2000; Yong et al. 2001). Levels of TIMP-1 are however reduced in MS patients relative to control patients, suggesting an imbalance in MMP-9/TIMP-1 ratios in MS (Avolio et al. 2005). MMP-9-mediated opening of the BBB then allows ampliWcation of the inXammation, as demon- strated by radioisotopes (Kermode et al. 1990). Looking for therapeutical agents restoring the unbalaced MMP-9/ TIMP-1 ratios in MS, Förster et al. (2007) showed that glu- cocorticoid treatment reduces the levels of MMP-9 mark- edly in a cell culture model of the BBB, an eVect which was shown to be based on glucocorticoid-mediated transcrip- tional activation of the TIMP-1 gene. This study further demonstrated that the administration of the glucocorticoids dexamethasone and hydrocortisone preserved the func- tional integrity of the TJs and adherens junctions under pro- inXammatory conditions, chieXy by maintaining the levels of the TJ components occludin, claudin-1, claudin-12, ZO- 1 and VE-cadherin, while dexamethasone eVects on clau- din-5 were negligible (Blecharz et al. 2008; Förster et al. 2007). Another study demonstrated diVerential susceptibility of cerebral and cerebellar endothelial cell lines to BBB breakdown in response to inXammatory stimuli (Silwedel and Förster 2006): increased fragility of the cerebellar BBB had been reported, as the typical caudal to rostral lesion development of MS and EAE with a preference of the cerebellum indicates (Cross et al. 1993; Juhler et al. 1984; Namer et al. 1993). Matching those studies, the authors could demonstrate a faster and more pronounced increase in permeability in the cerebellar BBB manifested by reduced TER and reduced TJ protein expression using the cerebellar BBB model cell line cerebEND (Silwedel and Förster 2006). The stronger eVects of TNF on endo- thelial cells of the cerebellum as compared the the cere- brum could be explained on the cellular level, where the TJ protein levels of claudin-5 and occludin were shown to be diVerently aVected in cerebellar and cerebral microvas- cular endothelial cells: eVects on occludin were more pro- nounced in cerebellar endothelial cells, while cerebral endothelial cells of the BBB showed a stronger decrease in claudin-5. Since it was shown that the main protein buid- ing up the barrier appears to be occludin, while claudin-5 protein, which is also well detectable in non-BBB endo- thelial cells, does not seem to inXuence barrier properties to the same extent (Foerster et al. 2002, 2005, 2006; Wol- burg and Lippoldt 2002). One may speculate that the lower overall occludin contents of endothelial cells of the cere- bellar BBB compared to the cerebral BBB can partly explain the greater sensitivity of the cerebellar BBB to inXammatory stimuli.