Authored by Arjun Jain*
Abstract
Different neurodegenerative disorders affect millions of people around the world and currently there is no cure for them. Certain neurodegenerative conditions are associated with pathologically elevated Endothelin (ET)-1 levels. There are currently various drugs in use to block the ET system, but these are associated with various side effects. In this paper, the potential use of ET-traps is discussed, which provide a potent way of lowering the pathologically elevated ET-1 levels found in these different neurodegenerative disorders and are non-toxic for use.
Keywords: Endothelin-1; ET-traps; Neurodegenerative disorders; Multiple sclerosis; Alzheimer’s disease; Parkinson’s disease; Amyotrophic lateral sclerosis
Abbreviations: Amyloid Beta; AD: Alzheimer’s Disease; ALS: Amyotrophic Lateral Sclerosis; ET-1: Endothelin-1; BBB: Blood Brain Barrier; CBF: Cerebral blood flow; MS: Multiple Sclerosis; PD: Parkinson’s Disease
Introduction
The ET-traps are molecular constructs that have previously been shown to potently and significantly sequester endothelin (ET)-1 [1]. Further work then showed that the ET-traps effectively returned different markers of diabetes disease pathology back to control, non-disease levels [2,3].
Discussion
Increased ET-1 in neurodegenerative disorders
There are elevated levels of ET-1 in neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Multiple Sclerosis (MS) [4]. It has previously been shown that increased levels of ET-1 in MS resulted in reduced cerebral blood flow (CBF) [5]; given that ET-1 is a potent vasoconstrictor [6], it is unsurprising that it can compromise CBF. Use of an ET-antagonist, such as Bosentan reversed certain markers of disease pathology in MS. CBF was significantly lower in patients with MS than in control subjects and increased to control values after administering bosentan. Therefore, the reduced CBF in MS appears to be mediated by ET-1, and ET-traps, which potently and significantly bind and reduce the levels of circulating ET-1, could become a potential therapy for MS.
In addition to the reduction in CBF caused by circulating ET- 1, the increase in ET-1 levels in the brain itself is caused by the release of ET-1 from astrocytes in brain lesions. It remains to be tested whether ET-traps can cross the blood–brain barrier (BBB). Previous work showed that not only the size but also the level of how hydrophobic a molecule is both determine whether a molecule would be able to cross the BBB [7]. Given that the ET-traps are both small in size (37.1 kDa) and are hydrophobic in nature (37.1%), it is likely that they would be able to cross the BBB. Furthermore, as has been previously reported [3], the ET-traps potently and significantly sequester increased ET-1 levels in the blood. This in turn would reduce the levels of the increased reactive white blood cells that freely cross the cerebral spinal fluid and BBB. The white blood cell count is increased by inflammation [8] and ET-1 is a potent inducer of inflammation [9]. This increase in inflammation is characterized by increases in the levels of reactive white blood cells [9] and systemic inflammation, which affects different organs in the body [10]. The various neurodegenerative disorders mentioned earlier are all associated with systemic inflammation. Thus, a tool such as ET-traps could have an efficacious effect by reducing pathologically elevated ET-1 levels.
In addition to MS, there are various studies showing an important role for systemic inflammation in the pathogenesis of AD. AD is a common cause of dementia, accounting for ~60–90% of all cases [11]. Different disease-modifying therapies for AD, such as immunotherapy against amyloid beta (Aβ), are now under investigation and have been tested in clinical trials, although with little success so far. Therefore, there is an urgent need to identify new therapeutics. Previous AD research using disease models and clinical studies has demonstrated a significant contribution of inflammation in general to pathological features and symptoms of AD.
Systemic inflammation is also an important pathological factor in PD [12,13]. Ferrari and Tarelli reported that systemic inflammation triggers exacerbation of damage in the brain in several neurodegenerative diseases, including PD [13]. Chiang et al. revealed that damage to the white matter of patients with PD is associated with systemic inflammation [12].
Another neurodegenerative disease associated with pathologically elevated ET-1 levels [14] is amyotrophic lateral sclerosis (ALS) which is a fast progressive and disabling neurodegenerative disease that is characterized by upper and lower motor neuron loss, leading to respiratory insufficiency and death after a few years [15]. There is currently no cure for this disease. Current treatments merely delay a patient’s disease progression. Given that ET-1 level is significantly elevated in ALS, perhaps the ETtraps that have been shown to significantly sequester the increased levels of ET-1, may be a cure for this debilitating and devastating disease. Previous in vivo work has also shown that the ET-traps have a positive effect on cardiovascular markers of ventricular function [3] and given that ALS leads to respiratory insufficiency, ET-traps may well help with this condition.
Conclusion
Given the increased levels of ET-1 in different neurodegenerative disorders and that this increased ET-1 is a cause of pathology in these diseases, ET-traps, which potently and significantly reduce the circulating levels of ET-1, would have a therapeutic effect in ameliorating disease pathology.
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