Is there a role for mast cells dependent synthesis of Endothelin-1 in
neurodegenerative diseases?
Pedro D’Orléans-Juste-1
, Louisane Desbiens, Denis Gris-2
Departments of Pharmacoly-1 and of Pediatrics-2
, Faculty of Medicine,
Université de Sherbrooke, Sherbrooke, PQ, Canada
Abstract:
Background: In the central nervous system mast cells are found in proximity of neurons and blood vessels. During inflammation, activated mastocytes releases several proteases among which chymase is known to generate the potent vasoactive peptide, Endothelin-1 (ET-1). It is of interest that both mast cell density and ET-1 levels are significantly increased in neurological disorders such as Multiple Sclerosis. Principal Aim: To identify the contribution of chymase and ET-1 in a murine model of experimental allergic encephalomyelitis (EAE).
Methods: The ET-1 producing capacity of a mouse chymase isoform Mast Cell Protease 4 (mMCP-4) will be compared to that of its human isoform using a combined recombinant/triple tof mass spectrometry approach. In addition, the contribution of systemic mMCP-4 in radiotelemetry instrumented-conscious mice will be assessed. Finally, clinical scores (from 0, normal mouse to 5, moribund state) will be assessed in WT or mMCP-4 KO mice with induced EAE.
Results and Conclusions: The present study demonstrates that both mouse and human chymases are involved in the synthesis of ET-1. Furthermore, preliminary results show reduced morbidity of EAE-induced mice genetically repressed for mMCP-4. We conclude that among several proteases secreted by mast cells in the vicinity of spinal lesions, chymase may play a significant role in the morbid events occurring in the mouse model of Multiple Sclerosis.
Endothelin-1 discussed at ISNVD 2015
Endothelin-1 discussed at ISNVD 2015
https://isnvd.org/d/sites/default/files ... %20all.pdf
Re: Endothelin-1 discussed at ISNVD 2015
previous discussions here on endothelin-1: http://www.thisisms.com/forum/chronic-c ... 15731.htmlEndothelin- 1 as a potential target for chronic brain hypoperfusion
Jacques De Keyser, MD, PhD, Free University of Brussels (VUB), Department of
Neurology, Brussels, Belgium
In the brain endothelin-1 (ET-1) is produced and released by endothelial cells lining the blood vessels and by astrocytes. ET-1 exerts its actions through two G-protein coupled receptors subtypes known as ETA and ETB receptors. In basal conditions, the expression of ET-1 in the brain is low, with concentrations of ET-1 in the picomolar range and hardly detectable by immunohistochemical techniques. Significant expression and release of ET-1 by reactive astrocytes occurs in acute CNS injuries, such as ischemic stroke and subarachnoid hemorrhage. It also occurs in a number of neurodegenerative disorders, including Alzheimer’s disease, multiple sclerosis (MS), and subcortical vascular dementia (Binswanger’s disease), which are all associated with chronic brain hypoperfusion. In patients with MS we have been able to show a relationship between chronic brain hypoperfusion and increased ET-1 levels. We found that, compared to controls, plasma ET-1 levels in MS subjects were significantly elevated in blood drawn from both the internal jugular vein and a peripheral vein. The jugular vein/peripheral vein ratio was 1.4 in MS subjects versus 1.1 in controls, indicating that in MS, ET-1 is released from brain to the cerebral circulation. ET-1 immunohistochemistry on postmortem white matter brain samples suggested that the likely source of ET-1 release were reactive astrocytes in MS plaques. Using arterial spin labeling MRI to noninvasively measure CBF we assessed the effect of the administration of the ET-1A/B receptor antagonist bosentan. CBF was significantly lower in MS subjects than in controls, and increased to control values after bosentan.
Chronic brain hypoperfusion in animal models induces mitochondrial energy failure and oxidative stress. White matter is more susceptible than gray matter, and shows axonal degeneration, apoptosis of oligodendrocytes, myelin breakdown, inflammatory reactions and gliosis. However, chronic cerebral hypoperfusion in rats is also associated with cognitive impairment, and neuronal loss in the hippocampal CA1 region. Axonal degeneration, apoptosis of oligodendrocytes, myelin loss and hippocampal atrophy have been observed in MS, subcortical vascular dementia and Alzheimer's disease. Our finding that reduced CBF in subjects with MS is reversible with an ET-1 antagonist opens the door for exploring new therapeutic approaches for neurodegenerative disorders associated with chronic brain hypoperfusion. ET-1 antagonists are available and are a possible strategy. Another approach consists in targeting the mechanisms leading to enhanced ET-1 expression in reactive astrocytes. In MS there is evidence that ET-1 upregulation in reactive astrocytes may be caused by cytokines that are elevated in MS plaques, including tumor necrosis factor-alpha and interleukin-1b. Targeting these inflammatory pathways might reduce ET-1 expression, restore brain perfusion and slow down disease progression. The underlying mechanisms with regard to Alzheimer’s disease and subcortical vascular dementia may be similar, although other mechanisms may be involved.
Refs:
• Khimji AK and Rockey DC. Endothelin--biology and disease. Cellular signalling.
2010;22:1615-25
• Zhang WW, et al. Structural and vasoactive factors influencing intracerebral arterioles in
cases of vascular dementia and other cerebrovascular disease: a review.
Immunohistochemical studies on expression of collagens, basal lamina components and
endothelin-1. Dementia 1994;5:153-62.
• D'Haeseleer M, et al. Cerebral hypoperfusion in multiple sclerosis is reversible and
mediated by endothelin-1. PNAS. 2013;110:5654-8
Re: Endothelin-1 discussed at ISNVD 2015
http://ccsviinms.blogspot.ca/2015/03/20 ... nection%29
Ah, that explanation helps!Endothelin- 1 as a potential target for chronic brain hypoperfusion
Jacques De Keyser, MD, PhD, Free University of Brussels (VUB), Department of Neurology, Brussels, Belgium
This study is near and dear to my heart, as it is looking at how ET-1, a marker of endothelial dysfunction, is related to slowed blood flow in the brain, called hypoperfusion. People with MS have much higher levels of ET 1 in their blood than normals, and much slower cerebral blood flow. We also see this marker elevated in a number of neurodegenerative diseases, like Alzheimer's. In this study, the researchers used bosentan, a blood pressure medication, to treat ET 1 levels. This treatment increased cerebral blood flow in pwMS, and lowered ET-1 levels. (But bosentan has side effects, and is not easy on the liver. Much better, in my opinion, to lower ET-1 levels by addressing endothelial dysfunction, through diet, exercise, and lifestyle.)