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Hypothesis

AT1 Receptor Blockade as a Neuroprotective Strategy in ADHD: A Hypothesis on the Role of Neuroinflammation and the Renin-Angiotensin System

This version is not peer-reviewed.

Submitted:

03 February 2025

Posted:

05 February 2025

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Abstract
Attention deficit hyperactivity disorder (ADHD) is a neuropsychiatric condition that affects a significant percentage of the child and adult population. Although it has traditionally been associated with dysfunctions in the dopaminergic and noradrenergic systems, emerging evidence suggests that neuroinflammation and activation of the renin-angiotensin-aldosterone system (RAAS) could play crucial roles in its pathophysiology. Chronic activation of the AT1 receptor by an excess of angiotensin II (Ang II), mediated by a low-grade inflammatory state associated with ADHD and potentiated by the use of psychostimulants such as methylphenidate, may contribute to the neurocognitive dysfunction seen in ADHD. It is proposed that AT1 receptor antagonists (ARA-II) may act as neuroprotectors, reducing neuroinflammation, modulating dopaminergic neurotransmission and improving executive function in these patients. Activation of the AT1 receptor increases neuroinflammation through the activation of microglia and the release of proinflammatory cytokines such as interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α). This generates oxidative stress, mitochondrial dysfunction and alterations in dopaminergic neurotransmission in the prefrontal cortex and basal ganglia. Blocking the AT1 receptor with ARA-II would divert Ang II towards the production of angiotensin-(1-7), favouring the activation of the MasR receptor with anti-inflammatory and neuroprotective effects. If this hypothesis is confirmed, the use of ARBs could represent an innovative approach in the treatment of ADHD, not only reducing the cardiovascular side effects of psychostimulants but also improving cognitive function through modulation of RAAS and reducing neuroinflammation. Preclinical studies and controlled clinical trials are required to evaluate this possibility.
Keywords: 
Attention Deficit Disorder with Hyperactivity; Neuroinflammation; Angiotensin II Type 1 Receptor Blockers; Dopamine; Renin-Angiotensin System
Subject: 
Medicine and Pharmacology  -   Neuroscience and Neurology
Copyright: This open access article is published under a Creative Commons CC BY 4.0 license, which permit the free download, distribution, and reuse, provided that the author and preprint are cited in any reuse.

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