MMP9/RAGE pathway overactivation mediates redox dysregulation and neuroinflammation, leading to inhibitory/excitatory imbalance: a reverse translation study in schizophrenia patients.

Details

Serval ID
serval:BIB_6531CBA55607
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
MMP9/RAGE pathway overactivation mediates redox dysregulation and neuroinflammation, leading to inhibitory/excitatory imbalance: a reverse translation study in schizophrenia patients.
Journal
Molecular psychiatry
Author(s)
Dwir D., Giangreco B., Xin L., Tenenbaum L., Cabungcal J.H., Steullet P., Goupil A., Cleusix M., Jenni R., Chtarto A., Baumann P.S., Klauser P., Conus P., Tirouvanziam R., Cuenod M., Do K.Q.
ISSN
1476-5578 (Electronic)
ISSN-L
1359-4184
Publication state
Published
Issued date
25/03/2019
Peer-reviewed
Oui
Language
english
Notes
Publication types: Journal Article
Publication Status: aheadofprint
Abstract
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 <sup>-/-</sup> ), 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.
Pubmed
Open Access
Yes
Create date
04/04/2019 9:03
Last modification date
03/05/2020 6:02
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