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J. Neurochem. (2012) 121, 730-737. Abstract Homeostasis of the brain is dependent on the blood-brain barrier (BBB). This barrier tightly regulates the exchange of essential nutrients and limits the free flow of immune cells into the CNS. Perturbations of BBB function and the loss of its immune quiescence are hallmarks of a variety of brain diseases, including multiple sclerosis (MS), vascular dementia, and stroke. In particular, diapedesis of monocytes and subsequent trafficking of monocyte-derived macrophages into the brain are key mediators of demyelination and axonal damage in MS. Endothelin-1 (ET-1) is considered as a potent pro-inflammatory peptide and has been implicated in the development of cardiovascular diseases. Here, we studied the role of different components of the endothelin system, i.e., ET-1, its type B receptor (ETB) and endothelin-converting enzyme-1 (ECE-1) in monocyte diapedesis of a human brain endothelial cell barrier. Our pharmacological inhibitory and specific gene knockdown studies point to a regulatory function of these proteins in transendothelial passage of monocytes. Results from this study suggest that the endothelin system is a putative target within the brain for anti-inflammatory treatment in neurological diseases. [ABSTRACT FROM AUTHOR]

J. Neurochem. (2010) 113, 447–453. Normal neuronal functioning is dependent on the blood-brain barrier. This barrier is confined to specialized brain endothelial cells lining the inner vessel wall, and tightly controlling transport of nutrients, efflux of potentially harmful molecules and entry of immune cells into the brain. Loss of blood-brain barrier function is an early and significant event which contributes to inflammation in the brain and subsequent progression of neuronal deficits in a number of brain disorders and has been well-documented for the auto-immune disease multiple sclerosis. Extravasation of cells happens by paracellular transport across the endothelial junctions, transcellularly across the endothelial cells, or both, and requires the active participation of endothelial cells. We and others have shown that this process requires the activity of proteases, including tissue-type plasminogen activator. We here describe a novel role for NMDA receptor, a potential cellular target of tissue-type plasminogen activator, in human brain endothelial cells. Our results show that the NMDA receptor subunit 1 (NR1) is expressed in brain endothelial cells, regulates tissue-type plasminogen activator-induced signal transduction and controls the passage of monocytes through the brain endothelial cell barrier. Together, our results hold significant promise for the treatment of chronic inflammation in the brain. [ABSTRACT FROM AUTHOR]