Can we use drugs that Modulate the Renin-Angiotensin system to treat Parkinson's disease?
A little history
The role of the Renin-Angiotensin System (RAS) in blood pressure control was clarified in the 20th century as a signaling pathway that helps regulate blood pressure. The process starts when a decrease in blood pressure is sensed by the kidney. Renin, the enzyme that transforms angiotensinogen produced by the liver into Angiotensin I is released in response. Angiotensin I undergoes conversion to Angiotensin II, by the activity the Angiotensin-Converting Enzyme (ACE). Angiotensin II narrows the space within the artery and contributes to raising systemic blood pressure, helping to keep up blood supply to main organs in response to the initial blood pressure drop.
Biologically active molecules exert their effects by recognizing and activating specific points or molecular sites known as ‘receptors’. If we consider molecules like Angiotensin II as ‘keys’, receptors are specific ‘keyholes’, unlocking biochemical reactions, and biological functions when activated. Angiotensin II mainly binds to two receptors, Type 1 and Type 2, referred to as AT1 and AT2. Activation of AT1 by Angiotensin II leads to vasoconstriction, vascular cell proliferation, and an increase in reactive oxygen species (ROS), detrimental to living cells. Conversely, AT2 receptor activation leads to vasodilation and ROS decrease. Somehow, AT2 receptors’ activation counterbalances AT1 receptors’ overactivation.
But what about the brain?
For the sake of energy economy, living beings use the same molecules for different functions. This is the case for the RAS. Local RAS circuits are spread throughout the body, as found in the brain of humans and other species. This is, Angiotensin II is released by certain cells, e.g. neurons or supporting cells like astrocytes and acts on neighbor AT1 and AT2 receptors without going further away.
Interestingly, several pieces of evidence suggest an active local RAS in the nigrostriatal pathway. Angiotensin II would be released by astrocytes to modulate the activity of dopaminergic neurons, other astrocytes, and microglia. Astrocytes have crucial supporting functions for neurons, while the microglia cells, pertaining to the immune system, are a somewhat brain police, taking care of internal or external threats.
While the function of Angiotensin II is not entirely clear, it seems to stimulate dopamine synthesis by acting on AT1 receptors. These may modulate Angiotensin II release by astrocytes. Figure 1 schematically shows this idea. In turn, AT1 receptor activation stimulates microglial ROS production. These ROS, promote oxidative reactions that impair cell structures function, thus causing cell damage. Accordingly, increased ROS levels mean a serious threat to nigral dopaminergic neurons' survival.
Figure 1
A vicious cycle in Parkinson’s Disease
One of Parkinson’s disease (PD) hallmarks is the death of dopaminergic neurons followed by a decrease in dopaminergic activity in the striatum. This is the event causing many motor and non-motor manifestations of the disease.
One hypothesis proposes that astrocytes might increase the production and release of Angiotensin II when they are no longer inhibited because of a decreased dopaminergic activity. Angiotensin II would stimulate dopamine release (Figure 1). This would act as a physiological feedback mechanism to keep stable synaptic dopamine levels. The physiological importance of this mechanism remains obscure. Notwithstanding, which is clear, is that excessive Angiotensin II levels result in abnormally increased ROS production by the microglia. As shown in Figure 2, ROS will speed up the death of dopaminergic neurons, which would further reduce dopaminergic activity, thus producing an increase in Angiotensin II. Interestingly, something similar may happen in other neurodegenerative diseases, such as Alzheimer’s Disease or Stroke, in which the RAS also appears to be overactive.
Figure 2
RAS modulators for the treatment of PD
Disrupting the RAS vicious cycle should be expected no less than slowing down neurodegeneration in PD.
Three general approaches are suitable to modulate the deleterious effects of the RAS. The two classic ones include blocking AT1 receptor activation or ACE inhibition, considering that ACE transforms Angiotensin I to Angiotensin II. Several drugs currently used in hypertension treatment can block AT1 receptors or inhibit ACE. They have been in the market for decades. By blocking the AT1 receptor, not only its direct effects are blocked but also more Angiotensin II is available to activate AT2 receptors (i.e., the ‘good brother’). The mechanism of action of ACE inhibitors is more complex because the resulting accumulated Angiotensin I is converted into other molecules with other effects on their own.
The third strategy is to activate the AT2 receptor. Several substances able to achieve this goal are in the experimental phase, but not easily accessible at this time. Notwithstanding, this strategy might offer some benefits compared with the others and warrants further exploration.
The effects of AT1 receptor antagonists and ACE inhibitors have been tested in cellular and animal PD models. Scientists use these experimental models to better understand how a disease develops, as in PD, and the potential beneficial effects of certain molecules. Three major classes of models are available. In ascending order of complexity and intrinsic value, these are cell cultures, rodents, and primates. The administration of dopaminergic neurotoxins mimics PD in all these three approaches.
Several scientific studies have shown that AT1 receptor blockers, ACE inhibitors, and AT2 receptor agonists can largely lessen neurotoxin-induced dopaminergic cell death in cell cultures and rodents. So far, there are no studies in primates, which is the most complex model to explore.
So, are we ready for RAS modulating drugs in PD?
Regrettably, we are not. Studies in primates are needed before we may realize the possibility for a study in humans. Still, we are optimistic that clues coming out from observational studies in humans show that ACE inhibitors might cut the likelihood of developing PD. One small study even suggests that they might increase the likelihood of the antiparkinsonian effect of L-DOPA. Further research is warranted, and we will likely witness advances in the near future.
Definitions:
Angiotensin: is a peptide hormone that causes a narrowing of the blood vessels and an increase in blood pressure.
Astrocyte: a star-shaped glial cell of the central nervous system.
Nigrostriatal pathway: is a bilateral dopaminergic pathway in the brain that connects the substantia nigra pars compacta (SNc) in the midbrain with the dorsal striatum (i.e., the caudate nucleus and putamen) in the forebrain.
Reactive Oxygen Species (ROS): ROS are produced during a variety of biochemical reactions within the cell and within organelles such as mitochondria, peroxisomes, and endoplasmic reticulum. Mitochondria convert energy for the cell into a usable form, adenosine triphosphate.
Santiago Perez Lloret, MD, PhD is a neuroscientist and neurologist who currently works at the National Scientific and Technical Research Council in Argentina. He does research in neuropharmacology, epidemiology and neurobiology. He was a faculty member at the 5th World Parkinson Congress in Kyoto Japan as well as the 4th World Parkinson Congress in Portland, Oregon.
Ideas and opinions expressed in this post reflect that of the author(s) solely. They do not necessarily reflect the opinions of the World Parkinson Coalition®