Moreover, homozygous deletion of selleck chemical the COX 2 gene in mice leads to a striking reduction of endotoxin induced inflammation. Therefore, COX 2 may play an important Inhibitors,Modulators,Libraries role in the development of vari ous inflammatory responses such as vascular inflamma tion. In brain, upregulation of COX 2 leads to increased production of PGs, which are potent inflammatory mediators asso ciated with neurodegenerative disorders. Thus, COX 2 and its metabolites PGs may act as a major patho logical factor in brain inflammatory diseases. The endothelium plays an important role in the regu lation of vascular function by producing a large number of biologically active substances that participate in the regulation of vascular functions.

In brain, cerebral capil lary and microvascular endothelial cells play an active role in maintaining cerebral blood flow, microvascular tone, and Inhibitors,Modulators,Libraries blood brain barrier functions. Dys function of the vascular endothelium is an early finding in the development of various vascular diseases and is closely related to clinical events in patients with athero sclerosis and hypertension. Endothelial cells are known to produce vasoactive mediators such as endothelin to maintain hemodynamic responses. Among the ET family, the bioactivity of ET 1 is mediated through potent vasoconstrictor Inhibitors,Modulators,Libraries and proinflam matory action, and has been implicated in the pathogen esis of hypertension and vascular diseases. Two types of ET receptors, ET type A and type B, are responsible for ET 1 triggered biological effects, which are mediated via G protein dependent regulation.

In the central nervous system, ET 1 also plays a substantial role in the normal develop ment or in CNS diseases. Both endothelial Inhibitors,Modulators,Libraries cells and astrocytes are potential sources of ET 1 release in response to hypoxic ischemic injury of the brain. The ETB receptors are located on both endothelial and vas cular smooth muscle cells, and modulate post injury responses of these cells in the CNS. There has been an increasing interest in the regulatory role of endothe lial cells in neurovascular coupling, which matches an adequate supply of cerebral blood flow with the local metabolic demands that are imposed by neural activity. As a fundamental component of the neurovascular unit, endothelium dysfunction has been implicated in neurodegenerative diseases.

Circumstantial evi dence has further demonstrated that overexpression of ET 1 on endothelial cells has deleterious effects on is chemic Inhibitors,Modulators,Libraries brain. Endothelial ET 1 can induce cytokine or chemokine pro Regorafenib clinical trial duction and secretion by non neuronal cells, including astrocytes and endothelial cells, which directly contrib ute to BBB breakdown during CNS inflammation. These findings imply the involvement of ET 1 in neu roinflammation in the CNS. However, the detailed mechanisms responsible for ET 1 action remain unclear.