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Review
. 2025 Jul 18;26(14):6899.
doi: 10.3390/ijms26146899.

Novel Roles for Urokinase- and Tissue-Type Plasminogen Activators in the Pathogenesis of Mood Disorders

Amine Bahi  1   2 , Sinclair Steele  3
Affiliations
Review

Novel Roles for Urokinase- and Tissue-Type Plasminogen Activators in the Pathogenesis of Mood Disorders

Amine Bahi et al. Int J Mol Sci. .

Abstract

This narrative review explores the intricate relationship between the plasminogen activator system (PAS), comprising urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA), and a range of neuropsychiatric disorders, including depression and anxiety. By synthesizing existing preclinical and clinical evidence, we clarify the roles of uPA and tPA in the pathogenesis and potential treatments of these conditions. This narrative review emphasizes their involvement in modulating neuronal plasticity, synaptic remodeling, and neurotransmitter systems, which are pivotal in maintaining brain function and behavior. Additionally, this review highlights key mechanisms by which these activators influence the neurobiological processes underlying mood and cognitive dysfunction. Critical analysis identifies areas of consensus, such as the role of plasminogen activators in neuroinflammation and stress responses, while also addressing gaps and controversies in the literature. The findings underscore the therapeutic potential of targeting the uPA/tPA system for innovative interventions. By offering a nuanced understanding of their contributions to mood disorders, this review aims to inspire future research toward developing novel, mechanism-based treatment strategies that harness the PAS' capacity to restore neural homeostasis and improve patient outcomes.

Keywords: depression; mood disorders; neuronal plasticity; plasminogen activator system; therapeutic strategies; tissue-type plasminogen activator (tPA); urokinase-type plasminogen activator (uPA).

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
The plasminogen activating system. tPA: tissue-type plasminogen activator. uPA: urokinase-type plasminogen activator. FDP: fibrin degradation products.
Figure 2
Figure 2
The role of the plasminogen activating system and BDNF maturation in neuronal survival, neuroplasticity, and synaptogenesis.
Figure 3
Figure 3
Alteration of functional BDNF and depression. ↑ increase; ↓ decrease.
See this image and copyright information in PMC

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