Abstract
The brain renin-angiotensin system (RAS) has available the necessary functional components to produce the active ligands angiotensins II (AngII), angiotensin III, angiotensins (IV), angiotensin (1–7), and angiotensin (3–7). These ligands interact with several receptor proteins including AT1, AT2, AT4, and Mas distributed within the central and peripheral nervous systems as well as local RASs in several organs. This review first describes the enzymatic pathways in place to synthesize these ligands and the binding characteristics of these angiotensin receptor subtypes. We next discuss current hypotheses to explain the disorders of Alzheimer’s disease (AD) and Parkinson’s disease (PD), as well as research efforts focused on the use of angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), in their treatment. ACE inhibitors and ARBs are showing promise in the treatment of several neurodegenerative pathologies; however, there is a need for the development of analogs capable of penetrating the blood-brain barrier and acting as agonists or antagonists at these receptor sites. AngII and AngIV have been shown to play opposing roles regarding memory acquisition and consolidation in animal models. We discuss the development of efficacious AngIV analogs in the treatment of animal models of AD and PD. These AngIV analogs act via the AT4 receptor subtype which may coincide with the hepatocyte growth factor/c-Met receptor system. Finally, future research directions are described concerning new approaches to the treatment of these two neurological diseases.
Highlights
The brain renin-angiotensin system (RAS) has available the necessary functional components to produce the active ligands angiotensins II (AngII), angiotensin III, angiotensins (IV), angiotensin [1,2,3,4,5,6,7], and angiotensin [3,4,5,6,7]
Recent findings suggest that many of the memory enhancing effects initially attributed to AngII are likely due to the conversion of AngII to angiotensin IV (AngIV), and it is this peptide acting as an agonist at the AT4 receptor subtype, that is responsible for cognitive facilitation [20, 57, 58]
With the recognition that local tissue RASs exist has come research interest in additional physiological and pharmacological functions that permit better understanding of clinical dysfunctions such as inflammation, cellular proliferation, apoptosis, and fibrosis accompanied by an increased appreciation for the role of both the AT1 and AT2 receptor subtypes [reviewed in Ref. [170, 171]]
Summary
The brain renin-angiotensin system (RAS) has available the necessary functional components to produce the active ligands angiotensins II (AngII), angiotensin III, angiotensins (IV), angiotensin [1,2,3,4,5,6,7], and angiotensin [3,4,5,6,7]. Recent findings suggest that many of the memory enhancing effects initially attributed to AngII are likely due to the conversion of AngII to AngIV, and it is this peptide acting as an agonist at the AT4 receptor subtype, that is responsible for cognitive facilitation [20, 57, 58]. The likely mechanism underlying this ACE inhibitor-induced protection is a reduction in the synthesis of AngII acting at the AT1 receptor subtype [reviewed in Ref.
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