MMP9/RAGE pathway overactivation mediates redox dysregulation and neuroinflammation, leading to inhibitory/excitatory imbalance: a reverse translation study in schizophrenia patients
Autor: | Rabindra Tirouvanziam, Abdelwahed Chtarto, Kim Q. Do, Lijing Xin, Philippe Conus, Martine Cleusix, Audrey Goupil, Daniella Dwir, Paul Klauser, Liliane Tenenbaum, Raoul Jenni, Michel Cuenod, Jan Harry Cabungcal, Philipp S. Baumann, Basilio Giangreco, Pascal Steullet |
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Rok vydání: | 2019 |
Předmět: |
CIBM-AIT
First episode Microglia business.industry Glutamate receptor Généralités medicine.disease_cause Article RAGE (receptor) Cellular and Molecular Neuroscience Psychiatry and Mental health medicine.anatomical_structure Dopamine Adult Animals Disease Models Animal Female Humans Inflammation/metabolism Male Matrix Metalloproteinase 9/metabolism Mice Neuroimmunomodulation Oxidation-Reduction Oxidative Stress Receptor for Advanced Glycation End Products/metabolism Schizophrenia/metabolism Medicine NMDA receptor business Molecular Biology Neuroscience Neuroinflammation Oxidative stress medicine.drug |
Zdroj: | Molecular psychiatry, vol. 25, no. 11, pp. 2889-2904 Molecular psychiatry, 25 (11 Molecular Psychiatry |
ISSN: | 1476-5578 1359-4184 |
Popis: | Various mechanisms involved in schizophrenia pathophysiology, such as dopamine dysregulation, glutamate/NMDA receptor dysfunction, neuroinflammation or redox imbalance, all appear to converge towards an oxidative stress “hub” affecting parvalbumine interneurones (PVI) and their perineuronal nets (PNN) (Lancet Psychiatry. 2015;2:258–70); (Nat Rev Neurosci. 2016;17:125–34). We aim to investigate underlying mechanisms linking oxidative stress with neuroinflammatory and their long-lasting harmful consequences. In a transgenic mouse of redox dysregulation carrying a permanent deficit of glutathione synthesis (gclm−/−), the anterior cingulate cortex presented early in the development increased oxidative stress which was prevented by the antioxidant N-acetylcysteine (Eur J Neurosci. 2000;12:3721–8). This oxidative stress induced microglia activation and redox-sensitive matrix metalloproteinase 9 (MMP9) stimulation, leading to the receptor for advanced glycation end-products (RAGE) shedding into soluble and nuclear forms, and subsequently to nuclear factor-kB (NF-kB) activation and secretion of various cytokines. Blocking MMP9 activation prevented this sequence of alterations and rescued the normal maturation of PVI/PNN, even if performed after an additional insult that exacerbated the long term PVI/PNN impairments. MMP9 inhibition thus appears to be able to interrupt the vicious circle that maintains the long-lasting deleterious effects of the reciprocal interaction between oxidative stress and neuroinflammation, impacting on PVI/PNN integrity. Translation of these experimental findings to first episode patients revealed an increase in plasma soluble RAGE relative to healthy controls. This increase was associated with low prefrontal GABA levels, potentially predicting a central inhibitory/excitatory imbalance linked to RAGE shedding. This study paves the way for mechanistically related biomarkers needed for early intervention and MMP9/RAGE pathway modulation may lead to promising drug targets. SCOPUS: ar.j info:eu-repo/semantics/published |
Databáze: | OpenAIRE |
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