Journal
SCHIZOPHRENIA BULLETIN
Volume 47, Issue 6, Pages 1782-1794Publisher
OXFORD UNIV PRESS
DOI: 10.1093/schbul/sbab066
Keywords
antioxidant; physical exercice; mechanism; brain development; early psychosis; cognition
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Funding
- Swiss-NationalScience-Foundation [320030_122419]
- National-Center-of-Competence-in-Research (NCCR)SYNAPSY-The-Synaptic-Bases-of-Mental Diseases [51AU40_125759]
- Damm-Etienne Foundation
- Alamaya Foundation
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Research on schizophrenia highlights the importance of new therapeutic approaches involving antioxidant/anti-inflammatory compounds and psycho-social therapy. Dysfunction of parvalbumin-expressing fast-spiking interneurons (PVI) in SZ can be rescued by a sequential combination of NAC+EE, which inhibits the MMP9/RAGE mechanism. Clinical trials show that NAC supplementation can improve cognition and symptoms in early psychosis patients, suggesting potential neuroprotective mechanisms through a combination of pharmacological and psycho-social therapy for individuals vulnerable to early-life insults.
Research in schizophrenia (SZ) emphasizes the need for new therapeutic approaches based on antioxidant/anti-inflammatory compounds and psycho-social therapy. A hallmark of SZ is a dysfunction of parvalbumin-expressing fast-spiking interneurons (PVI), which are essential for neuronal synchrony during sensory/cognitive processing. Oxidative stress and inflammation during early brain development, as observed in SZ, affect PVI maturation. We compared the efficacy of N-acetyl-cysteine (NAC) and/or environmental enrichment (EE) provided during juvenile and/or adolescent periods in rescuing PVI impairments induced by an additional oxidative insult during childhood in a transgenic mouse model with gluthation deficit (Gclm KO), relevant for SZ. We tested whether this rescue was promoted by the inhibition of MMP9/RAGE mechanism, both in the mouse model and in early psychosis (EP) patients, enrolled in a double-blind, randomized, placebo-controlled clinical trial of NAC supplementation for 6 months. We show that a sequential combination of NAC+EE applied after an early-life oxidative insult recovers integrity and function of PVI network in adult Gclm KO, via the inhibition of MMP9/RAGE. Six-month NAC treatment in EP patients reduces plasma sRAGE in association with increased prefrontal GABA, improvement of cognition and clinical symptoms, suggesting similar neuroprotective mechanisms. The sequential combination of NAC+EE reverses long-lasting effects of an early oxidative insult on PVI/perineuronal net (PNN) through the inhibition of MMP9/RAGE mechanism. In analogy, patients vulnerable to early-life insults could benefit from a combined pharmacological and psycho-social therapy.
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