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Mechanisms affecting brain remodeling in depression: do all roads lead to impaired fibrinolysis?

Abstract

Fibrinolysis occurs when plasminogen activators, such as tissue plasminogen activator (tPA), convert plasminogen to plasmin, which dissolves the fibrin clot. The proteolytic activity of tPA and plasmin is not restricted to fibrin degradation. In the extravascular space, these two proteases modify a variety of substrates other than fibrin, playing a crucial role in physiological and pathological tissue remodeling. In the brain, for example, tPA and plasmin mediate the conversion of brain-derived neurotrophic factor precursor (proBDNF) to mature brain-derived neurotrophic factor precursor (BDNF). Thus, the fibrinolytic system influences processes reported to be dysfunctional in depression, including neurogenesis, synaptic plasticity, and reward processing. The hypothesis that decreased fibrinolytic activity is an important element in the pathogenesis of depression is supported by the association between depression and increased levels of plasminogen activator inhibitor (PAI)−1, the main inhibitor of tPA. Also, various biochemical markers of depression induce PAI-1 synthesis, including hypercortisolism, hyperinsulinemia, hyperleptinemia, increased levels of cytokines, and hyperhomocysteinemia. Moreover, hypofibrinolysis provides a link between depression and emotional eating, binge eating, vegetarianism, and veganism. This paper discusses the role of reduced fibrinolytic activity in the bidirectional interplay between depression and its somatic manifestations and complications. It also reviews evidence that abnormal fibrinolysis links heterogeneous conditions associated with treatment-resistant depression. Understanding the role of hypofibrinolysis in depression may open new avenues for its treatment.

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Fig. 1: Multiple roles of tPA and plasmin in brain remodeling.
Fig. 2: The food-mood connection.

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Acknowledgements

The author is deeply grateful to Dr. Jacqueline A. Menezes, Professor Olavo Bohrer Amaral, Dr. Sylvio S. Neves Provenzano, and Professor Ian A. Greer for their invaluable suggestions.

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Hoirisch-Clapauch, S. Mechanisms affecting brain remodeling in depression: do all roads lead to impaired fibrinolysis?. Mol Psychiatry (2021). https://doi.org/10.1038/s41380-021-01264-1

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