- Brain RAS, via Ang II acting on AT1Rs, drives NOX-mediated oxidative stress and NF-κB neuroinflammation, impairing synaptic plasticity, neurogenesis, BBB integrity, and HPA regulation.
- Counter-regulatory RAS components, AT2Rs and the ACE2/Ang-(1-7)/MasR axis, confer neuroprotection and oppose AT1R-driven oxidative and inflammatory cascades.
- Pharmacological RAS modulation with ACE inhibitors and ARBs offers a precision medicine approach targeting core molecular drivers of depression, anxiety, schizophrenia and bipolar disorder.
Horm Behav. 2026 Oct 2;186:106003. doi: 10.1016/j.yhbeh.2026.106003. Online ahead of print.
ABSTRACT
The renin-angiotensin system (RAS), traditionally recognized for cardiovascular and renal regulation, has emerged as a critical mechanistic player in neuropsychiatric pathophysiology. The brain possesses its own independent RAS with components located throughout limbic regions, cortical areas, and monoaminergic circuits that are essential for mood, cognition, and behavior. Within this framework, angiotensin II (Ang II), acts primarily through angiotensin II type 1 receptors (AT1Rs), orchestrates pathological cascades including nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX)-mediated oxidative stress and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-driven neuroinflammation which converge to disrupt synaptic plasticity, impair neurogenesis, compromise blood-brain barrier (BBB) integrity, and dysregulate hypothalamic-pituitary-adrenal axis (HPA) axis- all contributing to major depression, anxiety disorders, schizophrenia, and bipolar disorder. However, the brain also contains protective RAS pathways, including angiotensin II Type 2 receptors (AT2Rs) and the angiotensin-converting enzyme 2/ Angiotensin-(1-7)/ Mas receptor (ACE2/Ang-(1-7)/MasR) axis, which offer neuroprotective effects that counterbalance these damaging processes. Therefore, targeting the RAS may represent a paradigm shift in neuropsychiatric treatment, as medications that modulate this system- including angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs)- show significant promise by addressing the fundamental molecular mechanisms driving mental illness rather than merely managing symptoms. Ultimately, this approach bridges peripheral physiological dysregulation with central nervous system (CNS) dysfunction, offering a precision medicine strategy that targets the root biological causes of neuropsychiatric disorders and opens new therapeutic avenues for patients who may not respond adequately to conventional treatments.
PMID:42826581 | DOI:10.1016/j.yhbeh.2026.106003
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