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

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.