Renin-angiotensin system blockade attenuates brain mitochondrial dysfunction, oxidative stress, and neuroinflammation associated with hypertension, metabolic disorders, and aging

Abstract

Although aging is an inherent part of life, it represents a process of progressive dysfunction rather than a fixed biological outcome. Consequently, highly prevalent conditions such as cardiorenal-metabolic syndrome-which encompasses obesity, hypertension (HTN), and metabolic disorders-can accelerate age-related changes. The renin-angiotensin system (RAS) plays a critical role in pathophysiology and affects multiple organs, including the brain. The central nervous system contains both RAS branches: The ACE/Ang II/AT1 and AT2 receptor axis, as well as the ACE2/Ang-(1-7)/Mas receptor axis. Neuroinflammation is a chronic process characterized by glial cell activation triggered by increased production of reactive oxygen and nitrogen species, resulting in oxidative stress. Mitochondria are the primary cellular sites where these processes occur. Under conditions such as metabolic disorders, obesity, HTN, and aging, these reactions are markedly accelerated. Associated mechanisms include insulin resistance, elevated levels of advanced glycation end-products, and disruption of the blood-brain barrier. The consequences of these alterations may include brain dysfunction, cognitive decline, Parkinson’s disease, and neurodegenerative conditions such as Alzheimer’s disease. This review focuses on the primary effects of therapeutic interventions on mitochondrial function, with particular attention to the modulation of oxidative stress, chronic neuroinflammation, and glial dysregulation. We highlight the strategic use of angiotensin receptor blockers and ACE2 activators as promising tools that may redefine the prevention and treatment of vascular dementia and other neurodegenerative diseases of inflammatory origin.

Key Words: Renin-angiotensin system blockade; Oxidative stress; Central nervous system inflammation; Neurodegeneration; Hypertension; Metabolic disorders; Mitochondria; Aging

Core Tip: This study highlights renin-angiotensin system blockade as a promising strategy for preventing brain damage associated with hypertension, metabolic disorders, and aging. These conditions accelerate mitochondrial dysfunction, oxidative stress, and neuroinflammation. Our work focuses on the strategic use of angiotensin receptor blockers and ACE2 activators, demonstrating their potential to mitigate these pathological processes and offering a novel avenue for the prevention and treatment of vascular dementia and other neurodegenerative diseases.

INTRODUCTION

The present article is a narrative review of the empirical integrative type. Literature searches were conducted using PubMed, Scopus, ScienceDirect, and Google Scholar databases. Search terms included: Neuroinflammation and oxidative stress; renin angiotensin system update; renin-angiotensin system (RAS) and neuroinflammation; RAS and aging; nervous system vulnerability to oxidative stress; glial cells and reactive oxygen species (ROS); and mitochondria and neuroinflammation.

The RAS has historically been recognized for its role in regulating blood pressure (BP), water-salt balance, and extracellular fluid volume. Over recent decades, compelling evidence has demonstrated the existence of a functional RAS within the central nervous system (CNS)-referred to as the brain RAS-which operates independently of the peripheral system[1]. The brain RAS participates in processes such as regulation of sympathetic tone, energy metabolism, and modulation of neuroinflammation. It contains all components required for local function, including renin, angiotensinogen, ACE, Ang II, its receptors AT1 and AT2 (AT1R and AT2R), and the counter-regulatory ACE2/Ang-(1-7)/Mas receptor pathway.

Neuroinflammation is characterized by activation of glial cells-primarily microglia and astrocytes-and the release of proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6, which disrupt neuronal homeostasis and contribute to the progression of various neurological diseases[2]. Although this response may be protective in acute phases, chronic persistence is associated with neuronal damage, synaptic dysfunction, and cognitive decline[3].

This review synthesizes recent advances demonstrating how RAS dysregulation contributes to mitochondrial dysfunction, oxidative stress, neuroinflammation, immune alterations, and glial pathology in brain aging, injury, and neurodegeneration. Based on this evidence, we propose that RAS inhibition represents a viable therapeutic strategy to attenuate neuroinflammatory processes associated with chronic conditions such as hypertension (HTN), metabolic disorders, and aging, all of which are linked to persistent systemic and cerebral inflammation.

RAS AND NEUROINFLAMMATION: PATHOPHYSIOLOGICAL FOUNDATIONS

The brain RAS is increasingly recognized as a major modulator of cerebral homeostasis and disease. Beyond its classical systemic roles, the RAS influences mitochondrial function, oxidative stress, neuroinflammation, immune responses, glial activity, blood-brain barrier (BBB) integrity, and synaptic plasticity.

Activation of the ACE/Ang II/AT1R axis has been associated with the promotion of neuroinflammation through the induction of ROS, activation of M1 proinflammatory phenotype microglia, release of cytokines such as IL-1β, TNF-α, and IL-6, and disruption of BBB integrity[4]. This pathological imbalance has been described in HTN, vascular dementia, and other clinical conditions including obesity, metabolic disorders, and aging.

In contrast, the ACE2/Ang-(1-7)/MasR axis exhibits anti-inflammatory properties[5,6]. These effects are mediated through inhibition of the TRAF6/NF-κB signaling pathway, reduction of ROS generation, and improvement of mitochondrial function in HTN models. In a rat model of HTN, pharmacological activation of ACE2 using diminazene aceturate prevented glial activation and enhanced hippocampal neurogenesis, even in the absence of significant BP reduction[7]. Another study from the same group demonstrated that experimental ACE2 activation also attenuates platelet-induced neuroinflammation in HTN by reducing CD40/CD40 L signaling, improving endothelial function, and inhibiting the NLRP3/NF-κB inflammatory pathway in microglia[8].

Together, these findings underscore the dual role of the brain RAS in regulating CNS inflammation. While the ACE/Ang II/AT1R axis promotes a proinflammatory and pro-oxidative environment, the ACE2/Ang-(1-7)/MasR axis emerges as a critical neuroprotective pathway. Targeted modulation of these RAS components therefore represents a promising therapeutic strategy for mitigating neuroinflammation accross a wide spectrum of CNS pathologies, including aging.

NEUROINFLAMMATION ASSOCIATED WITH HTN

Arterial HTN is associated with chronic activation of the brain RAS, triggering oxidative stress, BBB dysfunction, and a sustained proinflammatory glial response. These processes contribute to cognitive decline and increased vulnerability to neurodegeneration. Elevated BP and obesity-particularly when present in midlife-are among the most significant risk factors for dementia[9].

The importance of central RAS activation has been corroborated in spontaneous HTN models. Neuromedin B is a neuropeptide involved in an broad range of biological activities that include BP elevation. Chronic blockade of neuromedin B receptors within the paraventricular nucleus of the hypothalamus-a critical autonomic control center for autoα, IL-6, and restoring anti-inflammatory cytokines (IL-10, IL-4)-translated into reduced sympathetic tone and sustained BP reduction[10]. This study illustrates how RAS-ROS-cytokine convergence within neurovegetative centers drives hypertensive neuroinflammation and how interruption of this axis reverses both inflammatory and cardiovascular components. These findings confirm that brain inflammation associated with HTN can be modulated by targeting specific RAS elements beyond BP modulation.

Preclinical evidence aligns with recent clinical observations. In a cross-sectional study of hypertensive adults, predominant use of ACE inhibitors (ACEIs) and AT1R blockers angiotensin receptor blockers (ARBs) was associated with differential effects on cognitive processing speed. Patients treated with ACEIs showed a modest decline in scores, whereas those receiving ARBs demonstrated a neutral or even favorable cognitive improvement profile[11]. These findings suggest that the neurological impact of each class depends not only on BP reduction but also on direct modulation of the brain RAS.

Whether the neuroprotective effects of ACEIs and ARBs are primarily attributable to their antihypertensive action or to direct intracellular antioxidant and anti-inflammatory mechanisms remains unresolved. Numerous studies and meta-analyses that sustained BP reduction has neuroprotective effects on cognitive activity[12,13]. A persistent decrease of 10 mmHg in systolic BP over more than four years reduces dementia risk by 13%[14]. Overall, pharmacological antihypertensive therapy may help mitigate cognitive decline associated with elevated BP[15,16].

Nevertheless, several systematic reviews and meta-analyses have yielded discrepant conclusions[17,18]. As noted by the authors, conflicting data likely arise from heterogeneity in antihypertensive drug classes. In addition, the majority of those large studies were not originally designed to focus on cognitive status. Therefore, neuropsychological assessments lacked adequate sensitivity to identify alterations in different aspects of cognition. In addition, discrepancies among studies may stem from the inclusion of both midlife and late-life participants within the same trials, despite evidence that the relationship between BP and cognitive function differs between these two age groups. Discrepancies may also result from a lack of standardization in cognitive decline assessments and statistical methodologies. Finally, the conclusions of the available meta-analyses are limited by heterogeneity among the included trials, particularly regarding duration of antihypertensive drug exposure, baseline systolic BP, length of follow-up, analytical comparisons between groups (e.g., each antihypertensive drug class vs untreated participants or vs other antihypertensive therapies), and sex distribution, among other confounders.

Of note, when participants from different studies were regrouped to minimize the above-mentioned confounders, a beneficial effect of antihypertensive therapy on cognitive decline emerged[18].

Additionally, the degree of neuroprotection is not uniform across antihypertensive drug classes, suggesting that protective effects may depend, at least in part, on the type of agent used. Drugs that block the RAS-particularly ARBs-demonstrated a protective advantage. In a recent meta-analysis encompassing four databases from different regions worldwide and involving nearly two million new users of antihypertensive medications, with a mean follow-up ranging from 5.6 to 8.4 years, ARB use was associated with a lower risk of incident all-cause dementia compared with other antihypertensive therapies, including ACEIs[19].

The intriguing divergence between the effects of ARBs and ACEIs may be explained by differences in Ang II availability under each treatment. ACEIs are known to reduce Ang II levels, whereas ARBs, by selectively blocking the AT1R, can indirectly promote Ang II production. This elevation in Ang II leads to overstimulation of the AT2R, which, as discussed earlier, contributes to AT2R-mediated neuroprotective effects. This concept is further supported by a critical review published in 2025. The review concluded that although both ACEIs and ARBs cross the BBB and exert neuroprotective effects, ARBs appear to confer greater benefits. By selectively blocking AT1R while preserving compensatory AT2R and MasR signaling, ARBs were associated with improved brain structural integrity, reduced amyloid burden, and lower dementia risk. These benefits were particularly evident when treatment was initiated during the early stages of HTN[20].

Innovative therapeutic approaches have explored the interaction between the RAS and the endocannabinoid system. Among recently proposed strategies, nano-formulated anandamide (nf-AEA) has demonstrated both central and peripheral benefits in experimental models of spontaneous HTN. In spontaneously hypertensive rats, weekly administration of nf-AEA not only significantly reduced systolic BP but also decreased inflammatory and oxidative stress markers in both brain tissue and serum, even reversing abnormal behavioral patterns characteristic of the hypertensive phenotype. These effects were associated with modulation of the AT1R/iNOS/Hsp70 signaling pathway and a neuroprotective profile without central adverse effects, highlighting nf-AEA as a potential therapeutic alternative for controlling HTN-associated neuroinflammation[21].

Moreover, accumulating evidence indicates that chronic vitamin D (Vit D) deficiency enhances RAS activation and exacerbates neuroinflammatory processes linked to HTN. Vit D deficiency increases renin expression and promotes an imbalance between the Ang II/AT1R axis and the ACE2/Ang-(1-7)/MasR axis, thereby intensifying inflammatory responses and oxidative damage within the CNS. This functional connection between hypovitaminosis D, RAS dysregulation, and neuroinflammation suggests that modulation of RAS activity though optimization of Vit D status may represent a preventive or complementary therapeutic strategy in hypertensive patients at risk of cognitive decline[22].

NEUROINFLAMMATION IN METABOLIC DISORDERS: METABOLIC SYNDROME, OBESITY, TYPE 2 DIABETES

Metabolic syndrome (MetS) encompasses abdominal obesity, HTN, dyslipidemia, and insulin resistance. MetS, oxidative stress, inflammation, and RAS are tightly interconnected, largely through the central role of mitochondrial dysfunction in these disorders[23-27]. In rodent models of MetS induced by high-fructose corn syrup intake, widespread oxidative stress and inflammatory responses develop across multiple organs, leading to tissue injury, associated RAS activation, mitochondrial DNA alterations, and brain disturbances[28-30].

Metabolic disorders and the brain RAS converge on a shared pathological axis, characterized by chronic activation of inflammatory pathways. This state promotes oxidative stress, BBB dysfunction, and M1-type glial responses, collectively increasing vulnerability to neurodegeneration. Consistent with this concept, patients with MetS exhibit a fourfold higher risk of developing neurodegenerative diseases and dementia[31]. In a diet-induced MetS model, Pedrosa and colleagues identified elevated levels of agonistic autoantibodies against the AT1R (AT1-AA) in both serum and cerebrospinal fluid. These autoantibodies cross the BBB, amplify Ang II/AT1R signaling in the substantia nigra, and trigger the release of TNF-α, IL-6, and ROS, thereby accelerating dopaminergic neuron loss[32]. Importantly, treatment with ARBs abolished these alterations, underscoring RAS overactivation as a critical link between peripheral inflammation in MetS and central neuroinflammation.

Visceral obesity further contributes to a systemic proinflammatory environment characterized by leptin and resistin resistance, elevated IL-1β/IL-6 levels, and NF-κB activation. As reviewed by Al-Kuraishy et al[33], this microenvironment upregulates brain AT1R expression and NADPH oxidase activity while supressing the counter-regulatory ACE2/Ang-(1-7)/MasR axis, thereby disrupting redox and inflammatory homeostasis. The downstream consequences include increased amyloid deposition, tau hyperphosphorylation, and synaptic dysfunction in the hippocampus and cortex, linking obesity to a heightened risk of Alzheimer’s disease (AD).

Insulin resistance in MetS also impairs cerebral insulin signaling, leading to reduced glucose transport, activation of apoptosis pathways, and decreased ATP production, all of which contribute to cognitive decline, dementia, and AD[34]. In parallel, insulin resistance promotes endothelial dysfunction, microvascular flow disturbances, and adverse changes in glucose and lipid metabolism. As a result, ROS and nitrogen species increase, leading to a decline in nitric oxide production[35].

Sustained hyperglycemia and insulin resistance in type 2 diabetes (T2D) affect the CNS through multiple converging mechanisms. Cerebral insulin resistance disrupts IRS-1/Akt signaling, promotes glycogen synthase kinase 3β hyperactivity, and accelerates tau hyperphosphorylation and Aβ accumulation. These processes are further exacerbated by mitochondrial dysfunction and excessive ROS production. Elevated glucose levels enhance free radical generation, which activates microglia and stimulates the Ang II/AT1R pathway, thereby closing a loop of oxidative stress and inflammation[36].

RAS inhibition improves insulin sensitivity and pancreatic β-cell function, leading to better glucose tolerance[37]. These metabolic benefits extend to the brain, attenuating MetS-associated neuroinflammatory changes. Moreover, increased Ang II availability secondary to AT1R blockade-along with activation of AT2R by Ang-(1-7) or its analogs acting on MasR-exerts additional neuroprotective effects, mediated at least in part by local metabolic improvements[38].

AGEs further contribute to BBB disruption by upregulating AT1R expression, downregulating ACE2, and increasing endothelial permeability. This facilitates the entry of peripheral cytokines into the CNS, thus amplifying neuroinflammation[33]. In parallel, gut dysbiosis associated with metabolic derangements has emerged as a major amplifier of neuroinflammatory signaling. Altered microbiota composition favors lipopolysaccharide translocation into the bloodstream, especially under hypertensive or hyperglycemic conditions that compromise intestinal barrier integrity. These microbial products reach the brain through a permeabilized BBB, activate microglia, and stimulate proinflammatory cytokine release via the gut-brain axis[39].

Recent data confirm that metabolic alterations drive neuroinflammation through Ang II/AT1R axis activation, production of AT1-AA autoantibodies, and suppression of the protective ACE2/Ang-(1-7)/MasR pathway. Interventions aimed at restoring this balance-including ARBs, ACE2 activators, strict weight and glycemic control-emerge as promising approaches to reduce neural inflammation and lower the risk of cognitive decline in MetS, obesity, and T2D. In this context, the natural compound allicin, derived from garlic, is particularly useful as a complementary treatment in metabolic disorders because of its anti-inflammatory, antioxidant, and RAS-modulating properties. Recent studies indicate that allicin attenuates RAS activation, improves mitochondrial function through induction of proteins such as HSP70 and NRF2, and promotes mitochondrial fusion. By interrupting the vicious cycle linking cardiovascular dysfunction and neuroinflammation, allicin may represent a promising therapeutic alternative in the comprehensive management of MetS and its neurological complications[40].

NEUROINFLAMMATION AND AGING

Brain aging is characterized by a state of low-grade, chronic inflammation-commonly termed inflammaging-in which RAS dysregulation, oxidative stress, inflammasome activation, and, more recently, ferroptosis converge. Recent findings identify mitochondria as a central hub integrating oxidative and inflammatory signals during brain aging. Within this framework, RAS blockers, Vit D supplementation, and compounds such as melatonin and cannabinoids-known to act on mitochondrial receptors and modulate RAS signaling-have demonstrated the capacity to reduce inflammation and oxidative damage, thereby exerting neuroprotective effects. The effects of RAS blockade and Vit D supplementation will be discussed later. Notably, melatonin and cannabinoids interact through shared intracellular pathways and exhibit synergistic properties that could be harnessed in future therapeutic strategies targeting age-related neurodegenerative diseases[41].

In the substantia nigra of C57BL/6 mice, AT2R mRNA expression progressively declines with age, while AT1R expression increases in parallel with pro-oxidative markers (such as NADPH oxidase) and proinflammatory cytokines (IL-1β, TNF-α). Genetic deletion of AT2R in young animals reproduces the proinflammatory phenotype typically observed in aged animals, indicating that the loss of AT2R signaling represents an early trigger of age-related neuroinflammation. Conversely, pharmacological activation of AT2R suppresses AT1R overexpression and cytokine production in both microglia and dopaminergic neurons through the activation of the AT2R/NO/cGMP pathway and downregulation of the transcription factor Sp1[42].

Additionally, the NLRP3 inflammasome is upregulated in the substantia nigra of aged rodents and during early stages of dopaminergic degeneration. AT1R blockade with candesartan inhibits the transcription of NLRP3, pro-IL-1β, and pro-IL-18 and reduces the levels of mature IL-1β and IL-18, both in vivo and in mesencephalic cultures. These findings identify the Ang II/AT1R axis as a direct modulator of inflammasome activation during aging[43].

MacLachlan and colleagues further linked the ACE1/ACE2 imbalance to normal aging and early AD. In the human frontal and temporal cortex, ACE1 and Ang II protein levels increase with age, while ACE1 enzymatic activity declines. In early AD (Braak stages III-IV), ACE1 activity rises beyond levels observed in normal aging, without equivalent changes in ACE2 activity, indicating a pronounced shift toward a proinflammatory RAS profile during the prodomal phases of the disease[44].

Accelerated brain aging has also been described in post-coronavirus disease (COVID) syndrome, a condition characterized by persistent neuroinflammation, RAS disruption, iron dyshomeostasis, and ferroptosis-mediated cell death. In this context, melatonin has emerged as a promising therapeutic candidate due to its proposed role as a ferroptosis inhibitor. Its combined anti-inflammatory, iron-chelating, antioxidant, and Ang II-antagonist properties position melatonin as a potential intervention to mitigate post-infection brain aging[45].

With respect to vascular aging and metabolic comorbidities, accelerated vascular senescence associated with diabetes and chronic kidney disease involves cellular senescence, oxidative stress, and reduced levels of the anti-aging hormone Klotho. Dysregulation of RAS/aldosterone signaling and decreased sirtuin expression further contribute to systemic and brain inflammation. In this setting, SGLT-2 inhibitors, GLP-1 receptor agonists, and RAS blockers emerge as multifactorial therapeutic strategies to curb both vascular and cerebral frailty[46].

Overall, aging is associated with a shift in the brain RAS from its protective arm toward Ang II/AT1R predominance. The age-related decline in AT2R signaling within the substantia nigra facilitates AT1R overexpression, promoting ROS generation and sustained release of IL-1β and IL-6. This pro-oxidative environment activates the NLRP3 inflammasome, amplifies M1-type microglial responses, and accelerates dopaminergic neuronal vulnerability. In the human cortex, these processes are compounded by enzymatic imbalance: ACE1 and Ang II accumulate with age, with their activity peaking in the prodromal phase of AD, while ACE2 remains insufficient to counterbalance this shift, thereby amplifying the proinflammatory bias. Interestingly, candesartan has been shown to reverse NLRP3 inflammasome activation.

In summary, conditions that accelerate biological aging-such as long COVID, diabetes, and chronic kidney disease-exacerbate the Ang II/AT1R axis. RAS dysregulation, iron-dependent ferroptosis, Klotho deficiency, and vascular senescence fuel sustained systemic and brain inflammation. Restoring RAS balance through selective AT1R blockade, ACE2 potentiation, or AT2R activation, in combination with anti-ferroptotic and cardiometabolic therapies, emerges as a key strategy to mitigate inflammaging and delay the onset of age-associated neurodegenerative processes[45,47].

OXIDATIVE STRESS AND NEUROINFLAMMATION: LESIONAL MECHANISMS

As a consequence of normal metabolism, living organisms continuously generate oxidizing species, including ROS and reactive nitrogen species (RNS). When not adequately controlled, these molecules can induce cellular injury and death by promoting the oxidation of proteins, lipids, carbohydrates, and nucleic acids. In addition to endogenous metabolic processes, ROS and RNS can be excessively generated by exogenous factors such as environmental pollution, ionizing or ultraviolet radiation, cigarette smoke, and excessive calorie intake, among others.

To counterbalance reactive species-induced damage, aerobic organisms possess protective strategies involving both enzymatic antioxidants-such as superoxide dismutase, catalase, glutathione (GSH) peroxidase-and non-enzymatic antioxidants, including GSH, vitamin E, and ascorbic acid. Together, these systems help maintain redox balance. Under physiological conditions, when this balance is preserved, ROS and RNS do not exert deleterious effects but instead function as intracellular signals that regulate cellular metabolism and contribute to the maintenance of homeostasis[48,49]. In addition, they play essential roles in host defense mechanisms and in the modulation of inflammatory responses[50].

Nevertheless, when redox homeostasis is chronically disrupted tissue levels of ROS and RNS rise substantially, overwhelming antioxidant defenses and generating a pathological condition known as oxidative stress. In this scenario, excessive ROS and RNS induce cellular and tissue injury, disrupt cell signaling, and thereby contribute to the pathogenesis of various diseases.

The derangement of cell signaling during oxidative stress promotes the secretion of proinflammatory agents, the generation of neoepitopes-immunogenic molecular domains recognized by T lymphocytes-and the release of damage-associated molecular patterns (DAMPs) from damaged or dying cells[51]. In summary, this oxidative stress-induced response promotes a proinflammatory environment which, when occurring within the CNS, leads to neuroinflammation.

NERVOUS SYSTEM SUSCEPTIBILITY TO OXIDATIVE DAMAGE

The nervous system is particularly susceptible to oxidative stress-induced injury for several interrelated reasons[52-54].

Elevated cerebral O₂ utilization

The brain relies heavily on mitochondrial oxidative phosphorylation to meet its high energy demands, during which molecular oxygen is reduced to form water. Accordingly, this organ exhibits high oxygen consumption to generate the large amounts of ATP required to sustain its elevated activity, including the maintenance of neuronal membrane potentials, ion channel function, and the storage and release of neurotransmitters, among other processes. However, despite the high efficiency of the mitochondrial electron transport chain, some electrons leak directly to molecular oxygen, producing the superoxide anion (O₂) free radical rather than being forwarded to the next electron carrier in the chain. Thus, mitochondria are considered the main cellular sources of oxygen-derived reactive species. It has been estimated that 1%-2% of the oxygen consumed per day is converted to O₂, which is enzymatically dismutated to H₂O₂ and to the highly reactive hydroxyl radical (HO^-)[55].

Abundance of polyunsaturated fatty acids in nerve cell membranes

Lipids in neuronal membranes are rich in polyunsaturated fatty acids (PUFAs), which are easily oxidized by ROS due to their high double-bond content[56]. In this context, it should be noted that neurons with long axons display a high membrane surface-to-volume ratio, which facilitates rapid signal transmission but increases cellular PUFA content.

Prolonged activation of glutamate receptors leading to neuronal toxicity

In the mammalian CNS, glutamate and related excitatory amino acids are the main synaptic activators. Under physiological conditions, binding of these neurotransmitters to ionotropic receptors promotes superoxide production that functions as an intercellular signal. However, severe neuronal energy deficits or cell death can cause excessive glutamate release, followed by sustained receptor activation, leading to increased O₂^-, formation, oxidative stress, pathological elevations of intracellular Ca²⁺, and cell injury[57]. In addition, oxidative stress-induced neuronal damage can stimulate further release of excitatory neurotransmitters, creating a vicious cycle that contributes to the progression of neuroinflammation.

Limited antioxidant defenses in the brain and nervous system

Compared with other organs, antioxidant defenses in the brain are relatively limited. In particular, catalase levels are low in most brain regions[58]. GSH peroxidase and vitamin E are also present in reduced amounts. In contrast, ascorbic acid levels are high both in gray and white matter; however, ascorbic acid can function either as an antioxidant or as a pro-oxidant (see below).

Brain iron content

Iron is widely distributed throughout the brain, and several brain regions exhibit particularly high iron concentrations. Following brain injury, free iron is rapidly released; under these conditions, ascorbic acid mainly acts as a pro-oxidant by reducing Fe³⁺ to Fe²⁺, which reacts with H₂O₂ to form the highly reactive hydroxyl radical. This process enhances oxidative damage to biomolecules, including proteins, DNA, lipids, and carbohydrates[59,60]. Furthermore, the highly reactive iron released following injury can persist in brain tissue because cerebrospinal fluid either lacks, or has very limited, iron-binding capacity[61].

Neurotransmitter autooxidation

Some neurotransmitters, including serotonin, dopamine and its precursor L-3,4-dihydroxyphenylalanine, as well as norepinephrine, are susceptible to oxidation; namely, they can react with O₂ to produce O₂^-, H₂O₂, and the oxidizing agents quinones and semiquinones, which consume reduced GSH and covalently bind to sulfhydryl (-SH) groups in proteins, thereby altering their function[62,63].

Dopamine oxidation by monoamine oxidases

The oxidative degradation of dopamine by mitochondrial monoamine oxidases (MAOs) is a major source of H₂O₂ in the brain[64,65]. Both MAO isoforms-MAO-A and MAO-B-are expressed in glial cells and are capable of oxidizing dopamine[66].

Oxidative damage to the BBB

The BBB is a protective membranous structure that selectively limits the access of molecules and leukocytes from circulation to the CNS. In this way, the BBB prevents the entry of potentially harmful substances into the brain, allowing normal neural function. However, abundant evidence identifies ROS as key contributors to BBB disruption and increased permeability. This may occur, for example, through the activation of matrix metalloproteinases that degrade essential matrix components, thereby altering BBB selective permeability, or through direct oxidative damage to the molecular constituents of cellular tight junctions. Several mechanisms have been proposed to explain ROS-mediated BBB injury, including: (1) Bradykinin binding to B2 receptors in the CNS, which activates phospholipase A2 and promotes the release of membrane arachidonic acid, whose metabolism is associated with ROS generation; (2) Excessive production of excitatory amino acids; and (3) Recruitment and activation of neutrophils and macrophages following brain injury[67].

Glial cells can promote oxidative injury

Glial cells constitute the major cellular components of the brain, providing structural support to neurons and performing other essential functions. Among CNS glial cells, astrocytes play a central role in maintaining the BBB, providing metabolic support to neurons, and regulating neurotransmitter levels. Additionally, microglia-the resident macrophage-like immune cells of the CNS-are responsible for clearing injured cells, debris, and pathogens.

Nevertheless, accumulating evidence indicates that neuroinflammation is primarily mediated by microglia and astrocytes[68]. Under pathological conditions-such as exposure to toxins, infection, oxidative stress, trauma, or inflammation-astrocytes may become major sources of injurious ROS and RNS, which can subsequently activate microglia or directly damage nerve cells[69,70]. Upon activation, microglia produce both ROS and inflammatory cytokines; these mediators can further stimulate microglial ROS and RNS production, establishing a self-amplifying cycle of neuroinflammation and oxidative stress[68,71].

At the same time, glial cells have also been shown to participate in the regulation of CNS oxidative stress. Neurons are particularly vulnerable cells to excessive ROS and RNS, and their survival partially depends on the antioxidant support provided by neighboring astrocytes[70].

Notably, astrocytes play a dual role in regulating the balance between oxidants and antioxidants. They contain high intracellular levels of antioxidants that protect both themselves and adjacent cells from oxidative damage following CNS injury[72]. In this context, activation of the Nrf2-ARE pathway (nuclear factor erythroid 2-related factor 2-antioxidant response element pathway) represents the principal antioxidant mechanism monitoring redox homeostasis in both glial cells and neurons[73].

Finally, microglia can undergo phenotypic polarization in response to diverse stimuli, adopting either an M1 (proinflammatory) or M2 (anti-inflammatory) phenotype. Through this plasticity, microglia play a pivotal role in the regulation of tissue injury and repair[74]. The below presents evidence that RAS blockade-using ARBs or ACEIs-exerts anti-inflammatory and immunomodulatory effects that counteract the detrimental consequences of glial activation.

Hemoglobin neurotoxicity

Hemoglobin, the most abundant blood protein, is normally confined within erythrocytes; however, during cerebral injury, hemoglobin can be released from disintegrated erythrocytes, followed by heme degradation and the liberation of oxidizing free iron ions. As a consequence, neurons-remarkably vulnerable to Fe²⁺ mediated injury-are damaged. Ferrous iron readily reacts with H₂O₂ to generate the hydroxyl radical, which is considered the most deleterious ROS[75-77]. Furthermore, free heme itself is a potent inducer of lipid peroxidation[78]. In addition, cell-free hemoglobin can react with H₂O₂ or other peroxides to generate highly oxidizing species that promote lipid peroxidation, and it can also scavenge nitric oxide, resulting in irreversible NO consumption and vasoconstriction[76].

Oxidative stress, neuroinflammation, and CD4⁺ T lymphocytes

Neuroinflammation is associated with the infiltration of T cells into the CNS[79]. To combat infections, CD4⁺ lymphocytes (T-helper cells) contribute to the activation of other immune cells. Upon activation, CD4⁺ lymphocytes differentiate into T-helper 1 (Th1), Th2 or Th17 phenotypes, primarily depending on the cytokine environment to which they are exposed[80]. Th1 cells promote the elimination of intracellular pathogens, whereas Th2 cells are mainly involved in responses against extracellular parasites. Importantly, once pathogen clearance is achieved, Th2 lymphocytes secrete IL-10, which inhibits the inflammatory responses mediated by Th1 cells and other components of the innate immune system. Th17 lymphocytes, in turn, contribute to inflammatory immune responses against extracellular bacteria and fungi by stimulating the release of proinflammatory cytokines[81].

In summary, Th1 and Th17 represent inflammatory phenotypes that can promote neuroinflammation. Although the Th2 phenotype also participates in inflammatory immune responses, it may attenuate neuroinflammatory changes[82].

CD4⁺ cells orchestrate the interplay between innate and adaptive immune responses ensuring an effective defense against pathogenic challenges and highlighting their critical role in cell survival.

In this context, it is noteworthy that oxidative stress and redox imbalance alters CD4⁺ T-cell differentiation and function[83], enhances T-cell apoptosis and necrosis[84], and intensifies the proinflammatory activity of Th1 and Th17 subsets, thereby contributing to the progression of neuroinflammation.

MITOCHONDRIA AND NEUROINFLAMMATION

Abundant evidence indicates that mitochondrial dysfunction precedes neuroinflammation and contributes to its progression[85]. However, the relationship between altered mitochondrial function and neuroinflammation is complex: Mitochondrial dysfunction can promote neuroinflammation, while inflammatory mediators released from activated glial cells can, in turn, impair mitochondrial function. Notably, because neurons are highly energy-demanding cells, they are particularly susceptible to mitochondrial dysfunction[86].

To understand the relationship between mitochondria and inflammation, it is necessary to consider that, in multicellular organisms, the immune system can detect tissue injury, pathogenic microorganisms, and cellular or metabolic stress through pattern recognition receptors (PRR). Upon activation-particularly in the case of extensive cell or tissue damage-PRRs can initiate an acute inflammatory response aimed at eliminating the harmful insult and promoting tissue repair[87].

PRRs are expressed by cells of the innate immune system-although they have also been described in B lymphocytes and epithelial cells-and survey both intracellular and extracellular compartments for danger signals. These signals include molecular structures derived from invading microorganisms, known as pathogen-associated molecular patterns (PAMPs), as well as endogenous molecular motifs released by damaged or dying cells, referred to as DAMP.

Among the four recognized PRR families-namely Toll-like receptors, RIG-I-like receptors, C-type lectin receptors, and NOD-like receptors-NLRs are intracellular PRRs capable of identifying both PAMPs and DAMPs.

Upon binding to their specific ligands, NLRs activate signaling cascades that elicit diverse immune responses. Once activated, some NLR family members participate in the assembly of cytosolic multiprotein complexes known as inflammasomes, which promote the release of inflammatory cytokines and can trigger pyroptosis-a form of inflammatory cell death that contributes to pathogen clearance.

The NLRP3 inflammasome is among the most extensively studied inflammasome complexes, as its deregulation has been implicated in numerous inflammatory conditions, including atherosclerosis, and MetS[88].

NLRP3 can be activated by a remarkably broad range of stimuli, including pathogenic viruses, bacteria, fungi, and protozoa, as well as extracellular ATP, toxins, and particulate matter such as asbestos, uric acid crystals, silica, and cholesterol crystals[89,90]. Research aimed at clarifying how NLRP3 responds to such diverse signals have led to the proposal that it does not directly recognize each stimuli, but rather senses a common downstream cellular signal generated by these activators. Notably, all known NLRP3 activators induce ROS production[91], and accumulating evidence suggests that mitochondria are the primary source of ROS (mtROS) involved in inflammasome activation. Therefore, through mtROS generation, mitochondria appear to provide a unifying signal that promotes NLRP3 inflammasome activation in response to diverse insults. Additional mitochondria-dependent mechanisms have been proposed, including the release of mitochondrial DNA or cardiolipin, mitophagy, and mitochondrial fission. Although the role of mitochondria in regulating NLRP3 inflammasome has been debated[92], recent studies demonstrate that mtROS-mediated NLRP3 inflammasome activation contributes to renal damage induced by hyperlipidemia[93]. Other proposed mechanisms underlying NLRP3 activation by different stimuli include disassembly of the trans-Golgi network[94], induction of ionic fluxe[88], and lysosomal damage[95].

MITOCHONDRIA, INFLAMMATION, AND THE RAS

As discussed above, mitochondrial dysfunction can promote inflammation; however, mitochondria are also major sources of ROS and direct targets of ROS-mediated damage[96]. This damage can further impair mitochondrial function, giving rise to a vicious cycle linking mitochondrial dysfunction and inflammation. In this context, cells possess several protective strategies that limit mitochondria-driven inflammatory responses[97]. Nevertheless, when the capacity of these protective systems is exceeded, mitochondria-induced inflammation becomes maladaptive and contributes to disease pathogenesis.

Evidence indicating that both mitochondrial dysfunction and RAS dysregulation are major contributors to neuroinflammation[98] has prompted investigations into the interaction between RAS and mitochondrial function. In vitro studies in dopaminergic neurons have shown that activation of the pro-inflammatory and pro-oxidant branch of the RAS alters mitochondrial dynamics-specifically fusion and fission processes that regulate mitochondrial function[99]-promoting mitochondrial fission. These effects were counteracted by activation of the anti-inflammatory and antioxidant branch of the RAS. Similarly, AT1R activation in microglial cells disrupted mitochondrial dynamics and enhanced superoxide generation, whereas these responses were prevented by Ang-(1-7) administration. The effects of RAS components on brain mitochondrial function and dynamics were confirmed in vivo in rodent models[98].

In addition to plasma membrane AT1R and AT2R, brain cells express both Ang II receptors within mitochondria, particularly in dopaminergic neurons. Activation of mitochondrial AT1R by Ang II stimulates superoxide production through mitochondrial NADPH oxidase-4 and increases mitochondrial respiratory activity. In contrast, mitochondrial AT2R activation supresses respiratory activity by stimulating nitric oxide production[100]. Together, these findings indicate that mitochondrial AT1R and AT2R exert opposing effects on Ang II-induced oxidant production.

ANGIOTENSIN AND OXIDATIVE STRESS

Under physiological conditions, RAS activation leads to the production of ROS, which, by participating in redox signaling cascades, regulate a variety of RAS functions.

However, overactivation of AT1R by Ang II promotes excessive generation of superoxide anions through NADPH oxidases, mitochondria, NOS uncoupling, and xanthine oxidase[101], leading to aberrant redox signaling, cell damage, and tissue dysfunction. In this scenario, superoxide release is a major contributing factor to Ang II-induced pathophysiologic changes. In addition, effector peptides from the proinflammatory and prooxidant axis of the RAS are key players in the promotion and maintenance of inflammation[27,102,103].

RAS, PERIPHERAL INFLAMMATION, AND NEUROINFLAMMATION DIALOGUE

Peripheral inflammation is known to elicit neuroinflammation through the activation of microglia and astrocytes by peripherally generated proinflammatory factors that can cross the BBB and reach brain tissue[104,105]. Thus, under conditions of peripheral AT1R overactivation, it is important to consider that, owing to the crosstalk between peripheral inflammation and neuroinflammation, blockade of the circulating RAS may not only protect its target organs but also exert beneficial effects on brain function.

Conversely, the local brain RAS contributes to the regulation of cardiovascular, renal, and metabolic functions and is also involved in memory and learning processes[106,107]. Consequently, exaggerated brain AT1R activation leads to sympathetic stimulation, HTN, and neuroinflammation, which further exacerbate BP elevation. Moreover, excessive brain AT1R activity is associated with heart failure, aberrant stress responses, reduced cerebral blood flow, and disruption of the BBB[108].

Therefore, beyond their direct effects on peripheral Ang II receptors, blockade of the brain RAS using BBB-crossing ACEIs or ARBs is expected to benefit not only the brain itself but also a range of centrally modulated physiological functions under RAS control.

PRECLINICAL AND CLINICAL STUDIES ON RAS INHIBITORS AND NEUROINFLAMMATION

Considering the evidence described above, the inhibition of the RAS has garnered increasing interest as a therapeutic strategy to mitigate neuroinflammation and cognitive decline associated with aging and neurodegenerative diseases. Below is a summary of the most relevant findings from recent preclinical and clinical studies.

Preclinical and mechanistic studies

Captopril and complement system-mediated neuroprotection: Dong et al[109] demonstrated, in a kainate-induced epilepsy model, that treatment with captopril-an ACEI-not only reduced seizure frequency and duration but also improved cognitive performance in spatial memory tests. These benefits were attributed to attenuation of glial activation and inhibition of complement C3-C3aR-mediated synaptic phagocytosis, a key mechanism underlying neuroinflammation in the hippocampus. Intranasal administration of C3a partially blocked these effects, confirming the involvement of the complement system in captopril’s neuroprotective action.

Telmisartan and lipopolysaccharides-induced microglial activation: In a comparative study of eight ARBs, Affram et al[110] identified telmisartan as the most effective compound in reducing microglial activation induced by lipopolysaccharides (LPS). Telmisartan reduced nitric oxide and ROS production in both primary microglial cultures and BV2 cell lines. Unlike other ARBs, telmisartan dose-dependently activated AMPK, inhibited mTOR, and promoted microglial autophagy via the AMPK-mTOR axis. Its anti-inflammatory effect was not dependent on PPARγ but was partially blocked by the AMPK inhibitor compound C, confirming its unique mechanism of action. Additionally, telmisartan induced microglial apoptosis at high concentrations, possibly through autophagy hyperactivation.

Telmisartan and inhibition of neurotoxic A1 astrocyte conversion: In a recent study, Quan et al[111] showed that telmisartan, beyond its antihypertensive action, exerts immunomodulatory effects on astrocytes exposed to conditioned media from activated microglia. This microenvironment induces a biphasic astrocyte response, characterized by a transient neuroprotective A2 phenotype followed by sustained conversion to a neurotoxic A1 phenotype, commonly associated with AD and Parkinson’s diseases (PD). Telmisartan inhibited this shift by reducing NF-κB/p65 phosphorylation and expression through a PPARγ-dependent mechanism. These effects were not replicated by losartan or AT1R blockade, suggesting a RAS-independent action in astrocytes. The anti-inflammatory response was reversed by PPARγ or proteasome inhibition, confirming that PPARγ-mediated p65 degradation is central to telmisartan’s mechanism of action.

RAS modulation and microglial activation in PD: Liu et al[112] investigated the ACE2/Ang-(1-7)/MasR axis in PD-related neuroinflammation using mouse models and cell cultures. In ACE2 knockout mice, motor deficits worsened, α-synuclein expression increased, and microglial activation intensified, accompanied by elevated ROS production and inflammation in the substantia nigra and striatum. In BV2 cells exposed to LPS, activation of the ACE2/MasR pathway significantly reduced Iba1 expression, promoted an anti-inflammatory microglial phenotype, and enhanced antioxidant capacity. Transcriptomic data (GSE10867 and GSE26532) support these findings, indicating that RAS modulation directly influences microglial activation. Together, these results confirm that RAS dysregulation-particularly ACE2 loss-potentiates neuroinflammation, while its restoration represents a promising therapeutic target in PD.

Nanopharmacology and RAS modulation: Nanopharmacology has emerged as a promising strategy to enhance the bioavailability, selectivity, and efficacy of neuroprotective compounds. Nanoparticulate delivery systems capable of crossing the BBB and directly targeting neuroinflammatory pathways have been developed. These approaches not only potentiate the effects of antihypertensive and antioxidant drugs but also enable the simultaneous modulation of the RAS, oxidative stress, and inflammatory signaling. As such, they offer a comprehensive therapeutic framework against neurodegeneration induced by HTN and MetS[39].

Human clinical trials

Candesartan vs lisinopril in mild cognitive impairment: A randomized clinical trial compared the effects of candesartan (an ARB) and lisinopril (an ACEI) in older patients with mild executive-type cognitive impairment. After 12 months of treatment, participants receiving candesartan showed significant improvements in executive function and memory compared with those treated with lisinopril, suggesting a neuroprotective effect of ARBs independent of BP control[113].

ACEIs in systemic lupus erythematosus and cognitive dysfunction: The Hospital for Special Surgery is conducting a clinical trial to evaluate the impact of ACEIs on brain function in patients with systemic lupus erythematosus (SLE). The study compares the effects of lisinopril, which crosses the BBB, vs benazepril, a peripherally acting ACEI, on biomarkers of cerebral hypermetabolism and cognitive performance. The underlying hypothesis is that central RAS blockade could mitigate neuroinflammation, which contributes to cognitive dysfunction in SLE (IRB No. 2020-0226; available from: https://www.hss.edu/clinical-trials_lupus-ace-inibition-SLE.asp). However, robust published results are still lacking.

Prolonged use of ARBs and AD risk: A large-scale cohort study reported that long-term use of ARBs capable of crossing the BBB-such as telmisartan and candesartan-was associated with a significantly lower risk of developing AD compared to ACEIs or ARBs that do not cross the barrier. This protective association was more pronounced with longer treatment durations and higher cumulative doses[114].

Table 1 summarizes key preclinical and clinical studies on RAS inhibition and its effects on neuroinflammation. Figure 1 provides a schematic representation of the mechanisms through which the brain RAS integrates mitochondrial dysfunction, ROS production, and neuroinflammation under conditions of HTN, obesity, insulin resistance, and aging. Pharmacological interventions and potential protective pathways are also illustrated.

Figure 1 Schematic representation of the mechanisms by which the renin-angiotensin system in the brain integrates mitochondrial dysfunction, reactive oxygen species, and neuroinflammation under conditions of hypertension, obesity, insulin resistance, and aging. Activation of the Ang II → AT1R pathway promotes overproduction of reactive oxygen species (ROS), alterations in mitochondrial complexes I and III, release of damage-associated molecular patterns (DAMPs), and pro-inflammatory glial activation [microglia M1 with ↑ interleukin (IL)-1β, tumor necrosis factor-α, IL-6, ionized calcium-binding adaptor molecule-1; reactive astrocytes glial fibrillary acidic protein], contributing to blood-brain barrier disruption, neurodegeneration, and cognitive impairment. DAMPs amplify inflammation through NLRP3 and other damage sensors, reinforcing the ROS-mitochondria-inflammation loop. Enzymatic antioxidant systems superoxide dismutase, catalase, and glutathione peroxidase attenuate ROS overload. Interventions such as allicin, diminazene aceturate, and vitamin D activate the protective ACE2 → Ang (1-7) → MasR axis, inducing HSP70, NRF1, NRF2, and peroxisome proliferator-activated receptor gamma coactivator 1-alpha, thereby improving mitochondrial bioenergetics, endothelial function, glial balance, and hippocampal neurogenesis. AT1R blockade by angiotensin receptor blockers reduces deleterious signaling and allows compensatory activation of AT2R, while nanoformulated anandamide modulates the AT1R/iNOS/HSP70 pathway, favoring mitochondrial recovery. Orange arrows indicate inhibition, whereas blue arrows indicate stimulation. RAS: Renin-angiotensin system; IROS: Reactive oxygen species; DAMPs: Damage-associated molecular patterns; GFAP: Glial fibrillary acidic protein; Iba-1: Ionized calcium-binding adaptor molecule-1; IL: Interleukin; TNF-α: Tumor necrosis factor-α; SOD: Superoxide dismutase; CAT: Catalase; GPx: Glutathione peroxidase; BBB: Blood-brain barrier; ARBs: Angiotensin receptor blockers; DIZE: Diminazene aceturate; Vit D: Vitamin D; nf-AEA: Nanoformulated anandamide.

Table 1 A summary of preclinical and clinical studies on renin-angiotensin system inhibition and neuroinflammation.

Ref.	Model	Active intervention	Effects
Dong et al[109]	Epilepsia	Captopril	Attenuation of glial activation and inhibition of complement C3-C3a receptor
Affram et al[110]	Microglial activation by lipopolysaccharides	Telmisartan	Attenuation of glial activation
Quan et al[111]	Microglia-induced neurotoxic A1 astrocyte conversion associated with Alzheimer’s and Parkinson’s disease	Telmisartan	Reduction of NF-κB/p65 phosphorylation and expression via a PPARγ-dependent mechanism
Liu et al[112]	Mouse models of Parkinson's disease	ACE2 knockout mice and cell cultures	Activating the ACE2/MasR pathway reduces inflammation in microglial cells
Martín Giménez et al[39]	Nanopharmacology and RAS modulation	Nanoparticulate delivery systems designed for crossing the BBB	Enhance the bioavailability, selectivity, and effectiveness of compounds
Hajjar et al[113]	Older patients with mild cognitive impairment, characterized by executive dysfunction	Comparison of candesartan and lisinopril	Improvements in executive function and memory in the candesartan group after 12 months of treatment
Lee et al[114]	The incidence of AD in patients with coronary disease	Comparison of RAS inhibition users and non-users	ARBs significantly reduced the risk of AD, while ACEIs were not significantly associated with the risk of AD

ACEIs: Angiotensin-converting-enzyme inhibitors; ARBs: Angiotensin receptor blockers; AD: Alzheimer’s disease; BBB: Blood-brain barrier; RAS: Renin-angiotensin system.

CONCLUSION

The brain RAS plays a pivotal role in neuroimmune regulation, and its imbalance toward the proinflammatory Ang II/AT1R axis has been consistently associated with endothelial dysfunction, glial activation, and progressive cognitive impairment. The evidence reviewed demonstrates that chronic RAS activation not only exacerbates neuroinflammation in HTN, aging, and metabolic disorders but also acts as a central modulator of oxidative stress, mitochondrial dysfunction, and NLRP3 inflammasome activation.

In contrast, reinforcement of the alternative ACE2/Ang-(1-7)/MasR axis, together with the use of AT1R antagonists, ACEI, and immunomodulatory molecules such as ARBs, as well as others strategies that regulate both branches of RAS-including allicin, Vit D, melatonin, and nanoformulated agents such as nf-AEA-has shown neuroprotective and anti-inflammatory effects in both experimental models and clinical studies. These approaches not only attenuate neuroinflammation but also preserve cognitive and behavioral functions in conditions associated with cerebral vascular damage.

In light of these findings, it is reasonable to consider whether pharmacological RAS blockade could serve as a preventive tool against vascular dementia. Although preliminary preclinical and clinical evidence suggests that long-term AT1R blockade may reduce the risk of cognitive decline, longitudinal studies and controlled trials are still required to confirm this potential. Nonetheless, the role of the RAS as a convergence node linking hemodynamic, metabolic, and immunological factors makes it an attractive target for the design of comprehensive therapeutic strategies. Collectively, these findings support the strategic use of ARBs and ACE2 activators as promising tools to mitigate HTN-associated neuroinflammation and preserve cognitive function.

In conclusion, the RAS not only represents a fundamental pathway in the pathophysiology of neuroinflammation but also offers a concrete therapeutic opportunity to slow down the progression of neurovascular pathologies. Its rational modulation-combined with antioxidant, anti-inflammatory, and mitochondria-targeted approaches-could redefine the prevention and treatment of vascular dementia and other neurodegenerative diseases of inflammatory origin. The following graphical overview (Figure 2) provides a clear and concise illustration of the RAS balance as a central axis linking peripheral organ dysfunction and brain health.

Figure 2 The renin-angiotensin system balance as an integrative axis between peripheral organs and brain health. The functional state of the renin-angiotensin system (RAS), largely regulated by the heart and kidneys, directly influences blood pressure and determines brain trajectories toward either health or disease. RAS dysregulation promotes hypertension, mitochondrial dysfunction, and pathological microglial activation, contributing to blood-brain barrier disruption, neuroinflammation, and cognitive decline. In contrast, a balanced RAS helps maintain normal blood pressure, preserve mitochondrial function, and support a neuroprotective environment that safeguards cognitive function. RAS: Renin-angiotensin system; BBB: Blood-brain barrier.