Impact of the Renin-Angiotensin System on the Pathogeny and Pharmacotherapeutics of Neurodegenerative Diseases

Abstract

Brain neurodegenerative diseases (BND) are debilitating conditions that are especially characteristic of a certain period of life and considered major threats to human health. Current treatments are limited, meaning that there is a challenge in developing new options that can efficiently tackle the different components and pathophysiological processes of these conditions. The renin-angiotensin-aldosterone system (RAS) is an endocrine axis with important peripheral physiological functions such as blood pressure and cardiovascular homeostasis, as well as water and sodium balance and systemic vascular resistance—functions which are well-documented. However, recent work has highlighted the paracrine and autocrine functions of RAS in different tissues, including the central nervous system (CNS). It is known that RAS hyperactivation has pro-inflammatory and pro-oxidant effects, thus suggesting that its pharmacological modulation could be used in the management of these conditions. The present paper underlines the involvement of RAS and its components in the pathophysiology of BNDs such as Parkinson’s disease (PD), Alzheimer’s disease (AD), multiple sclerosis (MS), Huntington’s disease (HD), motor neuron disease (MND), and prion disease (PRD), as well as the identification of drugs and pharmacologically active substances that act upon RAS, which could alleviate their symptomatology or evolution, and thus, contribute to novel therapeutic approaches.

Role of brain renin–angiotensin system in depression: A new perspective

“…62,63 Moreover, over-activity of RAS is correlated with disease severity in different neurodegenerative disorders, including dementia, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, stroke, and traumatic brain injury. 64,65 Furthermore, dysregulation of brain RAS is also implicated in different mental and psychiatric disorders, such as bipolar disorder. 66 Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that each last from days to weeks.…”

“…Similarly, ACEIs and ARBs are effective against Alzheimer's disease (AD) neuropathology by inhibiting inflammation and oxidative stress‐induced neuronal injury 62,63 . Moreover, over‐activity of RAS is correlated with disease severity in different neurodegenerative disorders, including dementia, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, stroke, and traumatic brain injury 64,65 …”

“… 62 , 63 Moreover, over‐activity of RAS is correlated with disease severity in different neurodegenerative disorders, including dementia, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, stroke, and traumatic brain injury. 64 , 65 …”

The potential role of brain renin‐angiotensin system in the neuropathology of Parkinson disease: Friend, foe or turncoat?

“…It has been reported that exaggerated of brain RAS is linked with the development and progression of different neurodegenerative diseases such as Alzheimer diseases (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and other neurological disorders including traumatic brain injury and stroke. 49 …”

Structural Features Influencing the Bioactive Conformation of Angiotensin II and Angiotensin A: Relationship between Receptor Desensitization, Addiction, and the Blood–Brain Barrier

“…To combat cardiovascular pathologies (e.g., atherosclerosis, coronary artery disease and hypertension), important pharmaceuticals have been developed which either inhibit its synthesis (i.e., angiotensin-converting enzyme inhibitors) or block its receptor (i.e., AngII receptor blockers (ARBs)) [ 26 ]. Additionally, AngII acts on T cell receptors [ 51 ], modulating the immune and inflammatory responses that result in autoimmune diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis) [ 52 ], diseases arising from chronic hyper-inflammation (e.g., atherosclerosis, coronary artery disease and chronic kidney disease) [ 53 , 54 ] and neurodegenerative disorders (e.g., Alzheimer’s disease, multiple sclerosis and motor neuron disease) [ 55 , 56 ]. More recently, sartans (non-peptide ARBs) have proven effective in combating COVID-19, not only by inhibiting the infective process [ 57 ] but also by blocking AngII-mediated inflammatory responses (i.e., cytokine storm) [ 58 ].…”