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Review
. 2025 Aug 25;7(5):fcaf310.
doi: 10.1093/braincomms/fcaf310. eCollection 2025.

Noradrenergic therapies in neurodegenerative disease: from symptomatic to disease modifying therapy?

Robert Durcan  1 , Claire O'Callaghan  2 , James B Rowe  1   3
Affiliations
Review

Noradrenergic therapies in neurodegenerative disease: from symptomatic to disease modifying therapy?

Robert Durcan et al. Brain Commun. .

Abstract

A feature shared by many different neurodegenerative diseases is early pathology and degeneration of the pontine locus coeruleus. The human locus coeruleus contains about 50 000 neurons and is the primary source of the neurotransmitter noradrenaline. We propose the hypothesis that noradrenergic drugs can have broad, transdiagnostic benefit in slowing or preventing the progression of neurodegenerative diseases. There are direct noradrenergic anti-inflammatory effects in vivo, with microglia and astrocytes regulated by adrenoreceptors, and noradrenergic influences on glymphatics. Noradrenaline loss is associated with a pro-inflammatory state, promoting further neurodegeneration. Noradrenergic neuron loss is associated with worsening of both amyloid and tau deposition in animal models. There may be indirect survival benefits arising from alleviating the prognostically detrimental features of apathy and impulsivity, and noradrenergic influences on other neurotransmitters. The evidence base we set out supports the need for clinical trials of noradrenergic treatments for disease-modification.

Keywords: locus coeruleus; neurodegeneration; noradrenaline.

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Conflict of interest statement

The authors report no competing interests.

Figures

Graphical Abstract
Graphical Abstract
Figure 1
Figure 1
Action of noradrenergic drugs: (A) Potential disease-modifying actions of noradrenergic therapy may arise at multiple points in the pathogenesis of neurodegenerative diseases and their consequences. (B) There are multiple sites of action of noradrenergic treatments. NRI = Noradrenaline reuptake inhibitor, SNRI = Serotonin / Noradrenaline reuptake inhibitor, TCA = Tricyclic antidepressant, NDRI = Noradrenaline / Dopamine reuptake inhibitor. Created in BioRender. Durcan, R. (2025) https://BioRender.com/j93pbpn.
Figure 2
Figure 2
Locus coeruleus projections: (A): Sagittal view of the brain, illustrating the widespread cortical projections from the locus coeruleus (LC), (B, C) Magnetic resonance images using a magnetisation transfer sequence, showing coronal and axial views of locus coeruleus respectively. Created in BioRender. Durcan, R. (2025) https://BioRender.com/6q5x99s.
Figure 3
Figure 3
Mechanisms of potential disease modification: Summary of the multifaceted mechanisms through which noradrenergic treatments can enact a meaningful modifying force on neurodegenerative disease. Created in BioRender. Durcan, R. (2025) https://BioRender.com/7cwlt6f.
See this image and copyright information in PMC

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