Endothelins in inflammatory neurological diseases

Abstract

Endothelins were discovered more than thirty years ago as potent vasoactive compounds. Beyond their well-documented cardiovascular properties, however, the contributions of the endothelin pathway have been demonstrated in several neuroinflammatory processes and the peptides have been reported as clinically relevant biomarkers in neurodegenerative diseases. Several studies report that endothelin-1 significantly contributes to the progression of neuroinflammatory processes, particularly during infections in the central nervous system (CNS), and is associated with a loss of endothelial integrity at the blood brain barrier level. Because of the paucity of clinical trials with endothelin-1 antagonists in several infectious and non-infectious neuroinflammatory diseases, it remains an open question whether the 21 amino acid peptide is a mediator/modulator rather than a biomarker of the progression of neurodegeneration. This review focuses on the potential roles of endothelins in the pathology of neuroinflammatory processes, including infectious diseases of viral, bacterial or parasitic origin in which the synthesis of endothelins or its pharmacology have been investigated from the cell to the bedside in several cases, as well as in non-infectious inflammatory processes such as neurodegenerative disorders like Alzheimers Disease or central nervous system vasculitis.

Keywords: Blood-brain barrier (BBB); Central nervous system; Cerebral blood flow (CBF); Chymase; Cytokines; Endothelin subtype A receptor (ET(A)); Endothelin subtype B receptor (ET(B)); Endothelin-1 (ET-1); Mast cells.

Figure 1:. ET-1 and cell-cell interactions in Central Nervous System diseases.

(A) In the sub-endothelial matrix (top of the figure), the biologically inactive precursor big-ET-1 (1–38) is cleaved by mast cell derived chymase, yielding ET-1 (1–31) which is subsequently released into the circulation where it is enzymatically-activated to ET-1 via the membrane bound neutral endopeptidase. As the major circulatory enzyme involved in the generation of ET-1, the endothelin converting enzyme (ECE) directly converts the 38-amino acid precursor to ET-1). Within the vessel lumen, the later peptide signals via two distinct G protein coupled receptors, namely ET_A and/or ET_B (not shown). In response to insults to the endothelium, ET-1 can induce remodeling of endothelial cells, with an increase in adhesion molecule production, and loss of BBB integrity. (B) After endothelial insults, ET-1 also increases the expression of chemokines such as CCL2 from endothelial cells and triggers the release of monocyte-derived CXCL8, resulting in margination of inflammatory cells and diapedesis across the BBB. Macrophages are well known to convert big-ET-1 to ET-1 and can secrete several cytokines such as interleukin-1 and TNFα, chemokines, including CCL2 and CCL5, reactive oxygen species, and ET-1 once differentiated within the CNS. ET-1 can also prompt astrocyte activation and proliferation and subsequent activation of microglial cells, resulting in reactive microgliosis. In neurons, ET-1 via its two receptors may act as a modulator of neuronal conductivity and/or neurotransmission.