Potential role of nanopharmacology in reducing neuroinflammation associated with hypertension and metabolic disorders

Abstract

Hypertension disrupts cerebral blood flow, leading to endothelial dysfunction, breakdown of the blood-brain barrier (BBB), and inflammatory cell infiltration. This cascade triggers glial cell activation, increases oxidative stress, and causes pro-inflammatory cytokine release, creating a neurotoxic environment. In this context, we explore the intricate connection between hypertension, neuroinflammation, and neurodegeneration, as well as how hypertension interacts with other metabolic disorders, such as obesity and diabetes, to further worsen neuroinflammation. Additionally, we discuss the role of the renin-angiotensin-aldosterone system, the impact of the microbiome, and the potential contribution of chronic infections in exacerbating neuroinflammation. It is essential to emphasize the potential of nanotechnology to transform therapeutic approaches. Nanoparticle-based drug delivery systems can enhance the bioavailability and selectivity of antihypertensive drugs, antioxidants, and neuroprotective compounds, enabling targeted delivery across the BBB. By combining effective blood pressure management with nanotechnology-enabled therapies that modulate inflammation, oxidative stress, and protein aggregation, we can explore new avenues for preventing and treating hypertension and metabolic disorder-associated neurodegenerative conditions. Ultimately, hypertension significantly contributes to neuroinflammation and neurodegeneration by promoting neuronal cell death, primarily through impaired cerebral blood flow and disruption of the BBB. The interaction of hypertension with metabolic disorders exacerbates these effects. However, advancements in our understanding and new technologies reveal promising nanopharmacological approaches for targeted drug delivery to the brain, thereby improving treatment outcomes, enhancing adherence, and reducing side effects.

Key Words: Neuroinflammation; Nanotechnology/nanopharmacology; Blood-brain barrier; Oxidative stress; Neurodegeneration; Hypertension; Metabolic disorders

Core Tip: This mini-review unveils the intricate nexus between hypertension, metabolic disorders, and neurodegeneration, spotlighting neuroinflammation as a pivotal mediator. Compromised cerebral blood flow and blood-brain barrier (BBB) disruption initiate a cascade of oxidative stress and pro-inflammatory cytokine release, culminating in neuronal injury. We advocate for the transformative potential of nanopharmacology. Nanoparticle-mediated drug delivery offers a strategic avenue to enhance therapeutic bioavailability and selectivity, enabling targeted intervention across the BBB. By synergizing effective blood pressure management with nanotechnology-driven modulation of neuroinflammation, we pioneer novel strategies to mitigate neurodegenerative pathologies. This paradigm shift holds promise for revolutionizing therapeutic approaches, paving the way for improved patient outcomes in hypertension-associated neurological disorders.

INTRODUCTION

High blood pressure is one of the main cardiovascular risk factors. It affects a significant percentage of the world's population, increasing the risk of cerebrovascular events, cognitive impairment, and neurodegenerative diseases[1]. While the systemic consequences of hypertension on the heart, kidneys, and large blood vessels are well documented, it has become clear that it also exerts a profound impact on the brain[2,3]. Hypertension promotes microvascular alterations, endothelial dysfunction, reduced cerebral blood flow, glial cell activation, and proinflammatory mediator release, culminating in a chronic neuroinflammatory condition[4,5].

It is well known that high blood pressure is often associated with several or all the components of metabolic syndrome (abdominal obesity, hyperlipidemia, and elevated fasting blood glucose levels). The consequence of this association is lack of cardiovascular-renal-metabolic health[6]. Together with high blood pressure, these factors generate progressive, inflammatory-based changes in various tissues, including neuroinflammation[7].

Neuroinflammation is the persistent activation of astrocytes and microglia and the release of cytokines, chemokines, and reactive oxygen species (ROS), which creates a hostile environment for neurons[8,9]. This chronic inflammatory state facilitates the accumulation of pathological proteins, such as beta-amyloid or hyperphosphorylated tau, accelerates neuronal loss, and ultimately contributes to neurodegenerative disease pathogenesis, including Alzheimer's disease (AD), Parkinson's disease (PD), and other cognitive disorders[10,11].

Reducing blood pressure attenuates neuroinflammation. In fact, some anti-hypertension drugs, like renin-angiotensin system blockers and calcium antagonists, positively affect neural inflammation[12-14].

New treatments used to control metabolic syndrome and diabetes mellitus, like sodium glucose cotransporter 2 inhibitors and glucagon-like peptide-1 agonists, mildly reduce blood pressure. Chronic use of these treatments has attenuated neuroinflammation, dementia, and AD[15-18].

In addition to conventional antihypertensive and new metabolic drug interventions, recent research has begun to explore nanodrugs and nanoparticle delivery systems to improve the bioavailability, selectivity, and efficacy of compounds with neuroprotective and anti-inflammatory potential effects[19,20]. These approaches could help overcome biological barriers, such as the blood-brain barrier (BBB), and offer new therapeutic alternatives to mitigate neuroinflammation and neuronal damage associated with hypertension and some metabolic derangements.

This mini-review aims to integrate evidence from the last 5 years on the relationship between hypertension, neuroinflammation, and neurodegeneration. We will explore the vascular and molecular mechanisms that link high blood pressure with brain damage, address the key role of glia and inflammatory signaling pathways, and discuss emerging therapeutic implications, including the potential application of nanopharmaceuticals. In doing so, we will generate a comprehensive view to guide us toward new strategies for preventing and treating neurological deterioration associated with the previously described conditions.

IMPACT OF HYPERTENSION ON CEREBRAL VASCULATURE

Hypertension-induced vascular damage constitutes a fundamental starting point in the pathophysiological cascade that leads to neuroinflammation and neurodegeneration. Chronic hypertension alters arteriolar caliber, thickens vascular walls, and disrupts blood flow autoregulation. These changes facilitate endothelial dysfunction, increasing BBB permeability and allowing immune cell and inflammatory mediator infiltration into the brain parenchyma[21].

A notable example is the study that used mouse models deficient in the Collagen type XVIIIa1 gene to simulate early cerebral small vessel disease microvascular lesions[22]. These animals exhibited microvascular damage, extracellular matrix remodeling, neuroinflammation, and early glial activation, suggesting that hypertension contributes to a damaging environment for neurons from an early stage. Glial activation is accompanied by cytokine, chemokine, and growth factor release that perpetuates the inflammatory state[8].

The retina is a neurosensory tissue with vasculature like the brain, acting as an accessible model to understand the effects of hypertension. Studies in ocular hypertension provide evidence analogous to that in the brain. Yu et al[23] found that increased intraocular pressure induced retinal neurodegeneration through activation of p38/mitogen-activated protein kinases (MAPK) pathways, promoting ganglion cell death and neuroinflammation. Similarly, Shi et al[9] revealed that pathologically high intraocular pressure leads to reactive glial proliferation, impaired blood-retinal barrier, and activation of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX2)/endothelin-1/extracellular regulated kinase 1/2 (ERK1/2) pathway, contributing to inflammation and neuronal damage.

These retinal models reflect processes like those observed in the brain, reinforcing that hypertension triggers an inflammatory cascade capable of damaging nervous tissue, regardless of region. Thus, the retina can be considered a model to study the early detection of vascular and neuroinflammatory changes in the brain.

MOLECULAR AND CELLULAR MECHANISMS OF NEUROINFLAMMATION

Neuroinflammation associated with hypertensive and metabolic diseases is a complex phenomenon involving multiple molecular pathways. Oxidative stress plays a key role, with NOX2 inducing ROS generation[24]. These reactive species trigger lipid, protein, and genomic damage and activate proinflammatory signaling pathways, including p38/MAPK and ERK1/2[25].

Recent studies have elucidated how these pathways contribute to glial cell inflammation. Yang et al[8] highlighted a role for the cellular FLICE-like inhibitory protein in regulating astroglial inflammation in an experimental model of glaucoma, indicating that ocular hypertension relies on intracellular mediators to orchestrate the inflammatory response in glia.

However, hypertension does not act in isolation; it is integrated into an adverse cardiometabolic environment where obesity, diabetes, and dyslipidemia converge. Patel and Edison[1] analyzed how hyperinsulinemia and insulin resistance potentiate vascular dysfunction by impairing nitric oxide signaling, exacerbating renin-angiotensin-aldosterone system (RAAS) overactivation. This environment sensitizes glial cells to inflammatory triggers and enhances BBB permeability, amplifying central nervous system (CNS) vulnerability and favoring neuroinflammatory cascades that drive cognitive decline[1].

In parallel, elevated levels of free fatty acids (FFAs), commonly present in obesity and metabolic syndromes, activate toll-like receptors (TLRs), particularly TLR4, on microglia and endothelial cells. This leads to upregulation of nuclear factor-kappa B signaling and downstream inflammatory mediators, further aggravating the hypertensive milieu[26]. FFAs also increase mitochondrial dysfunction and contribute to dysregulated phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling, reducing neuroprotective pathway activation and exacerbating oxidative neuronal injury[27].

Emerging evidence also underscores a role for gut dysbiosis in this process. Disruptions in gut microbiota composition reduce neuroprotective short-chain fatty acid production, while increasing circulating endotoxins like lipopolysaccharides (LPS)[28]. These microbial-derived products can translocate into the bloodstream, particularly under hypertensive conditions that impair gut barrier integrity. Once in circulation, they activate systemic inflammation and penetrate the brain through a compromised BBB, enhancing glial reactivity and cytokine production. This "gut–brain axis" represents a potent amplifier of neuroinflammation, especially when intertwined with hypertension-induced vascular vulnerability[29].

On the other hand, Kountouras et al[2] addressed the impact of Helicobacter pylori and metabolic syndrome on mast cell activation and neurodegenerative pathophysiology, showing that hypertension is part of a broader network of systemic inflammatory factors.

RAAS is another critical axis; Tiwari et al[3] showed that angiotensin-converting enzyme 2 modulation in hypertensive models promotes neurogenesis and attenuated the inflammatory impact in the hippocampus through Wnt/β-catenin signaling. Likewise, Gouveia et al[4] found that intranasal administration of irbesartan, an angiotensin II receptor antagonist, reverses cognitive impairment and neuroinflammation in mice with LPS-induced inflammation, activating the PI3K/AKT pathway.

In addition to vascular and metabolic factors, there are other interaction routes. Li et al[30] suggested that chronic oral infection by periodontal pathogens can trigger an oral-brain axis, favoring neuroinflammation and increasing the risk of AD. Hypertension can potentially alter protective barriers, making the CNS more vulnerable to infectious insults and enhancing their harmful effect. The molecular and cellular mechanisms of neuroinflammation in the hypertension context are summarized in Table 1.

Table 1 Interplay between hypertension, molecular pathways, and neuroinflammation.

Stage	Pathway/factor	Role/mechanism	Crosstalk	Neuroinflammatory outcome
Hypertension		Initiates vascular injury, oxidative stress, and endothelial dysfunction	Triggers activation of RAAS, NADPH oxidase, and other stress-response pathways	Compromised blood-brain barrier, vascular leakage
Vascular damage	RAAS	Angiotensin II vasoconstriction, oxidative stress, proinflammatory signaling	Activates NADPH oxidase, p38/MAPK, suppresses ACE2	Endothelial dysfunction, proinflammatory environment
Oxidative stress	NADPH oxidase	Produces ROS in response to angiotensin II and inflammation	ROS activates p38/MAPK, ERK1/2; contributes to Wnt/β-catenin and PI3K/AKT dysregulation	Promotes inflammation, cell damage
Inflammatory signal transduction	p38/MAPK	Induces cytokine release (e.g., interleukin-6, tumor necrosis factor-alpha), microglial activation	Interacts with ERK1/2 and Wnt/β-catenin; enhanced by ROS	Neuroinflammation, synaptic dysfunction
	ERK1/2	Regulates gene expression under oxidative and inflammatory stress	Crosstalk with p38/MAPK and PI3K/AKT	Glial activation, neurotoxicity
	PI3K/AKT	Normally protective (anti-apoptotic); dysregulated under chronic stress	Interacts with ERK1/2, influenced by oxidative stress	Loss of neuroprotection, increased cell vulnerability
Anti-inflammatory counteraction	ACE2	Converts angiotensin II to angiotensin-(1-7), countering RAAS effects	Opposes RAAS; downregulated in hypertension	Loss of balance sustained inflammation
Cellular remodeling	Wnt/β-catenin	Controls cell survival, synaptic plasticity; dysregulated in neuroinflammation	Activated by MAPK/ROS; contributes to chronic glial activation	Synaptic loss, glial scarring
Cumulative effect	Integrated pathways	Chronic activation of RAAS, MAPK, NADPH oxidase, Wnt, and ERK1/2	Synergistic feedback loops worsen endothelial and neuronal stress	Sustained neuroinflammation, cognitive decline, neurodegeneration

ACE2: Angiotensin-converting enzyme 2; AKT: Protein kinase B; ERK1/2: Extracellular regulated kinase 1/2; MAPK: Mitogen-activated protein kinases; NADPH: Nicotinamide adenine dinucleotide phosphate; PI3K: Phosphatidylinositol 3-kinase; RAAS: Renin-angiotensin-aldosterone system; ROS: Reactive oxygen species.

CONVERGING PATHWAYS IN INFLAMMATION AND NEURODEGENERATION:

Long-term inflammation creates a neurotoxic environment that is permissible for neurodegeneration. Chronic activation of astrocytes and microglia, continuous release of proinflammatory cytokines, such as interleukin-1β and tumor necrosis factor-alpha, and oxidative stress contribute to synaptic dysfunction, neuronal loss, and accumulation of aberrant proteins such as hyperphosphorylated tau. These alterations are standard pathological features in various neurodegenerative diseases[31].

El-Desouky et al[10] highlighted the relevance of intervening on the inflammatory axis and protein aggregation. Compound RF26 is a new phosphodiesterase type 5 (PDE5) inhibitor that improves memory and reduces tau aggregation in a tauopathy model. These findings suggest that modulating inflammatory and vascular pathways can attenuate or reverse some aspects of neurodegenerative deterioration[10].

At the clinical level, hypertension is one of several factors that converge in neurodegeneration. Khalil et al[11] addressed cardiovascular dysautonomia in PD, demonstrating that vascular and autonomic alterations may contribute to cognitive decline. In AD, Patel and Edison[1] highlight the relationship between hypertension, obesity, diabetes, and amyloid protein accumulation, reinforcing the concept that cardiometabolic conditions generate an inflammatory microenvironment that precipitates or accelerates neurodegeneration.

Interaction with pathogens or the microbiome adds complexity[30][2]. These factors can ignite or perpetuate inflammation in a brain already vulnerable from hypertension.

THERAPEUTIC INTERVENTIONS AND FUTURE PERSPECTIVES

In addition to blood pressure control, therapeutic approaches should be aimed at interrupting the inflammatory and oxidative cascades that mediate brain damage. In this regard, nanotechnology-based drug delivery systems[20] have emerged as a promising strategy to improve the efficacy and selectivity of antihypertensive and neuroprotective therapies[32-36].

In this sense, inhibition of prooxidative and proinflammatory pathways, such as in the combination of NADPH and N-acetylcysteine, attenuates neurodegeneration and neuroinflammation[23]. Additionally, including phytochemicals or antioxidant molecules in nanoparticles could improve their bioavailability and effectively target damaged nervous tissue[19,37,38].

Another possible alternative is modulation of the RAAS and associated pathways. Nanoparticles can improve the delivery of RAAS inhibitors, increasing their stability and ability to cross the BBB[27]. For example, nanoparticles targeting smooth muscle cells in the pulmonary vasculature have alleviated hypoxic vasoconstriction[39]. Similarly, encapsulating anti-hypertensive compounds in nanometric systems like polyethylene glycol-poly lactic acid-co-glycolic acid (PEG-PLGA) nanocarriers can enhance their efficacy and reduce doses and side effects[40]. Indeed, pharmacokinetic results for PEG-PLGA nanoparticles loaded with isoliensinine have shown promising results, demonstrating enhanced stability, sustained release, and improved bioavailability compared to free isoliensinine in an in vivo model of hypertension (angiotensin II-induced mice). This nanoparticle system significantly increased drug cellular uptake and targeted delivery, particularly in vascular smooth muscle cells, leading to greater efficacy in reducing angiotensin II-induced hypertension[40]. While there was no report of toxicity and the delivery system shows potential in clinical applications, further studies are necessary to confirm long-term safety, scalability, and efficacy across diverse patient populations.

This approach is also being evaluated for its utility in inhibiting protein aggregation and related metabolic pathways. In addition to compounds such as RF26 (a novel PDE5 inhibitor)[10], co-administration of nanoparticles with anti-inflammatory drugs, antioxidants, or vitamin D analogues can block key inflammatory and metabolic pathways[33-36,41] to prevent neurodegeneration[42].

Therapeutic and phytotherapeutic combinations are interesting approaches. Nanodrugs that release natural compounds (phytochemicals, antioxidants) or hormones, such as melatonin or anandamide (AEA), could offer synergistic effects. For example, AEA encapsulated in polymeric micelles has shown beneficial renal effects in hypertension[35], improving the pharmacokinetic profile of AEA, targeting to renal cells and prolonged anti-hypertensive effects in spontaneously hypertensive rats. The nanomicelles enhanced AEA bioavailability and induced sustained natriuretic and diuretic responses compared to free AEA, which lost efficacy over time. Nevertheless, the limited sample size and the absence of long-term safety data present key limitations, emphasizing the need for further studies to validate clinical relevance and optimize organ-specific delivery strategies. Likewise, thymoquinone or indole-3-carbinol could potentially enhance AEA’s anti-inflammatory and antioxidant actions[43,44].

These interventions suggest the need for a multifactorial approach. Nanotechnology offers tools to achieve targeted release, improve the permeability of biological barriers, and reduce systemic drug toxicity. Despite the promising therapeutic potential of pharmaceutical nanoformulations for hypertension and neuroinflammation, several barriers hinder their clinical adoption. Key challenges include concerns about long-term toxicity, limited scalability of manufacturing processes, and complex regulatory pathways due to the novelty and variability of nanocarriers. Additionally, the lack of extensive clinical trials—many still in preclinical or early-phase stages—restricts comprehensive safety and efficacy data. To address these issues, rigorous biocompatibility testing, standardized manufacturing protocols, and adaptive regulatory frameworks are essential. Incorporating personalized dosing strategies based on patient-specific pharmacokinetics and biomarker profiles may further enhance treatment outcomes and minimize adverse effects, paving the way for safer, more targeted nano-based therapies.

CONCLUSION

Taken together, it is clear that hypertension damages the peripheral cardiovascular system and exerts a direct and multifaceted impact on the central nervous system. Elevated blood pressure causes microvascular alterations, endothelial dysfunction, and breakdown of protective barriers, which sets a favorable scenario for glial activation, oxidative stress, and proinflammatory cytokine release. This chronic inflammatory environment promotes neuronal degeneration, facilitating the onset and progression of neurodegenerative diseases.

Multiple molecular pathways participate in this cascade, including p38/MAPK, ERK1/2, NOX2, RAAS, and Wnt/β-catenin, in addition to contributions by metabolic, infectious, and microbiome factors. Nanotechnology has emerged as a promising tool to improve the efficacy of therapies, facilitate the targeted delivery of anti-inflammatory, antioxidant, or neuroprotective drugs, and potentially reverse or slow hypertension-associated neurodegeneration.

Emerging therapeutic strategies suggest that tight blood pressure control combined with anti-inflammatory, antioxidant, metabolic pathway modulating and nanopharmaceutical-based interventions may open new routes towards preventing and treating cognitive decline. Future research should focus on validating these approaches in clinical trials, optimizing nanometric formulations and developing biomarkers to guide personalized therapies to improve the quality of life of affected individuals.