Brain RAS in CNS Diseases: Beneficial Effects of Small Molecule Agonists and Inhibitors

Review Article

Ann Hematol Oncol. 2022; 9(1): 1388.

Brain RAS in CNS Diseases: Beneficial Effects of Small Molecule Agonists and Inhibitors

Wright JW* and Harding JW

Department of Psychology, Department of Integrative Physiology and Neuroscience and Program in Biotechnology, Washington State University, Pullman, WA USA

*Corresponding author: John W Wright, Department of Psychology, Washington State University, P.O. Box 644820, Pullman, WA 99164-4820, USA

Received: January 11, 2022; Accepted: March 04, 2022; Published: March 11, 2022


Neurodegenerative diseases are unrelenting, unforgiving and cruel given the long duration of patient suffering due to the impact of progressive damage within specific brain locations. In the case of dementias, there is a direct impact on memory and cognitive processing, and the loss of personal dignity and worth. Ultimately, the patient loses the ability to maintain basic hygiene placing attentional responsibilities on family members and support staff. With respect to neurodegenerative diseases of the eye, the patient must deal with progressive deleterious changes in vision resulting from retinal damage. This review discusses the role of the Renin-Angiotensin System (RAS) in cardiovascular disease, Alzheimer’s and Parkinson’s diseases, Type 2-induced dementia, depression, glaucoma, macular degeneration and diabetic retinopathy. We conclude with a consideration of the challenges posed regarding the development of new drugs designed to treat dementias, depression, and neurodegenerative diseases of the eye. The use of small molecule agonist and antagonist analogs of RAS components is discussed. These analogs can be configured to pass the blood-brain barrier and target relevant receptor proteins in specific brain structures or they can be applied topically to the eye to discourage increases in intraocular pressure, decreased retinal microvascular blood flow, tissue inflammation and oxidative stress as well as the accumulation of extracellular material (drusen) that can disrupt normal vision. Along with suggested drug development strategies, several important drug targets are identified in an effort to focus attention, and facilitate research efforts, to improve drug efficacy and thus provide better clinical outcomes for these patients.

Keywords: Renin-angiotensin system; Angiotensin receptors; Angiotensin receptor blockers; Dementias; Glaucoma; Macular degeneration


Aβ: Amyloid-Beta Peptide; ACE: Angiotensin Converting Enzyme; ACEi: Angiotensin Converting Enzyme Inhibitor; AD: Alzheimer’s Disease; AH: Aqueous Humor; AMD: Age-Related Macular Degeneration; AP: Area Postrema; APA: Aminopeptidase A; APN: Aminopeptidase N; AngII: Angiotensin II; AngIII: Angiotensin III; AngIV: Angiotensin IV; ARB: Angiotensin Receptor Blocker; AT1: Angiotensin Receptor 1; AT2: Angiotensin Receptor 2; BBB: Blood-Brain Barrier; BDNF: Brain-Derived Neurotrophic Factor; Carb-P: Carboxypeptidase P; CBF: Cerebral Blood Flow; CVOs: Circumventricular Organs; DA: Dopaminergic ; DR: Diabetic Retinopathy; HGF: Hepatocyte Growth Factor; IGF-1: Insulin-Like Growth Factor; IOP: Intra-Ocular Pressure; IRAP: Insulin-Regulated Aminopeptidase; L-DOPA: Levodopa; LTP: Long-Term Potentiation; Mas: MAS1 Oncogene; MCI: Mild Cognitive Impairment; Met: N-Methyl-N’-Nitro-N-Nitrosoguanidine; MDD: Major Depressive Disorder; MPP+: MPTP Metabolite; MPTP: 1-Methyl-4-Phenyl- 1,2,3,6-Tetrahydropyridine; MRI: Magnetic Resonance Imaging; NGF: Nerve Growth Factor; NADPH: Nicotinamide Adenine Dinucleotide Phosphate; NO: Nitric Oxide; NTS: Nucleus of the Solitary Tract; PD: Parkinson’s Disease ; PAI-1: Plasminogen Activator Inhibitor 1; PO: Propyl Oligopeptidase; RAS: Renin-Angiotensin System; RPE: Retinal Pigment Epithelial Complex; SFO: Subfornical Organ; T2D: Type 2 Diabetes; VEGF: Vascular Endothelial Growth Factor


The Renin-Angiotensin System (RAS) is recognized as one of the oldest hormone systems best known for its roles in regulating blood pressure and body water balance. In 1891 Robert Tiegerstedt and his student Per Bergan identified a pressor agent extracted from rabbit kidney tissues that they called “renin” [1]. Fifty years later, this finding led to the discovery of a vasoconstrictor agent isolated from ischemic kidneys of Goldblatt hypertensive dogs [2]. Page and Helmer [3] independently found the same molecule after injecting renin into intact animals. They also identified a “renin activator” later reported to be angiotensinogen [4]. This vasoconstrictor agent was eventually determined to be an octapeptide variously called, “renin substrate”, “hypertension” and “angiotensin”, ultimately termed Angiotensin II (AngII) [5-7].

This review initially describes the presently identified angiotensin ligands and their respective receptor subtypes. Angiotensin 1 and 2 (AT1 and AT2) subtypes have been well characterized and the AngII/ AT1 system is particularly important in the etiology of cardiovascular diseases [4,8,9]. The AT3 subtype was first isolated in mouse neuroblastoma cell cultures [10,11], but a separate gene has thus far not been sequenced in humans. The identity of the AT4 subtype has been controversial and will be discussed. Next, we will focus on the role of the brain Ang IV/AT4 receptor system in several neurodegenerative diseases. Additional diseases of the eye are identified as important targets requiring much additional research attention regarding the RAS and its relevance. Finally, recommendations are offered concerning drug development approaches in order to penetrate the blood-brain barrier and influence the brain RAS. Target diseases include dementias associated with Alzheimer’s and Parkinson’s diseases, Type II diabetes, as well as depression/neuroinflammation and diseases impacting the retina of the eye.

The Renin-Angiotensin System

The RAS is responsible for mediating several classic physiologies such as the regulation of systemic blood pressure and body water/ electrolyte balance, as well as a number of novel physiologies and behaviors including influences on sexual reproduction and behavior, Cerebral Blood Flow (CBF) and cerebroprotection, seizures, stress, depression, and memory [12,13]. AngII binds at the G-protein coupled AT1 receptor subtype [14-16]. Over the years the AngII/AT1 receptor system has been a major focus regarding the development of antihypertensive drugs and its role in promoting inflammation, oxidative stress and tissue remodeling [17,18]. These processes contribute to the “neuronal inflammation response” a key factor in the development of neurodegenerative diseases including Alzheimer’s Disease (AD) [19-21]. The biologically active angiotensin peptides are derived from the protein angiotensinogen (255 amino acids) via a cascade of enzymatic activity and include AngII (Asp- Arg-Val-Tyr-Ile-His-Pro-Phe), AngIII (Arg-Val-Tyr-Ile-His-Pro- Phe), Angiotensin IV (AngIV: Val-Tyr-Ile-His-Pro-Phe), Ang (1-7) (Asp-Arg-Val-Tyr-Ile-His-Pro) and Ang (3-7) (Val-Tyr-Ile-His-Pro) (Figure 1) [22-25]. Specifically, the decapeptide angiotensin I (AngI: Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu) is formed by renin (EC acting upon the N-terminal of angiotensinogen. AngI serves as a substrate for angiotensin Converting Enzyme (EC which is responsible for hydrolyzing the carboxy terminal dipeptide His-Leu to form AngII. AngII is converted to the heptapeptide AngIII by glutamyl aminopeptidase A (APA; EC cleavage of the Asp residue at the N-terminal [26-28]. AngIII is acted upon by membrane alanyl aminopeptidase N (APN; EC resulting in the cleavage of Arg to form the hexapeptide AngIV. AngIV can be further converted to Ang (3-7) by Carboxypeptidase P (Carb-P) and Propyl Oligopeptidase (PO) cleavage of the Pro-Phe bond. Angiotensin (1-7) is formed from AngII via Carb-P cleavage of Phe [29], by the monopeptidase ACE2 [30,31], and by ACE cleavage of the dipeptide Phe- His from Ang (1-9) [32].