Caught in vicious circles: a perspective on dynamic feed-forward loops driving oxidative stress in schizophrenia

Abstract

A growing body of evidence has emerged demonstrating a pathological link between oxidative stress and schizophrenia. This evidence identifies oxidative stress as a convergence point or "central hub" for schizophrenia genetic and environmental risk factors. Here we review the existing experimental and translational research pinpointing the complex dynamics of oxidative stress mechanisms and their modulation in relation to schizophrenia pathophysiology. We focus on evidence supporting the crucial role of either redox dysregulation, N-methyl-D-aspartate receptor hypofunction, neuroinflammation or mitochondria bioenergetics dysfunction, initiating "vicious circles" centered on oxidative stress during neurodevelopment. These processes would amplify one another in positive feed-forward loops, leading to persistent impairments of the maturation and function of local parvalbumin-GABAergic neurons microcircuits and myelinated fibers of long-range macrocircuitry. This is at the basis of neural circuit synchronization impairments and cognitive, emotional, social and sensory deficits characteristic of schizophrenia. Potential therapeutic approaches that aim at breaking these different vicious circles represent promising strategies for timely and safe interventions. In order to improve early detection and increase the signal-to-noise ratio for adjunctive trials of antioxidant, anti-inflammatory and NMDAR modulator drugs, a reverse translation of validated circuitry approach is needed. The above presented processes allow to identify mechanism based biomarkers guiding stratification of homogenous patients groups and target engagement required for successful clinical trials, paving the way towards precision medicine in psychiatry.

Fig. 1. Schematic representation of the concept proposed in this paper, showing the reciprocal interaction between mitochondria, NMDAR, neuro-immune system, dopamine on one hand and the complex redox regulation/oxidative stress (OxS) on the other.

Irrespectively of which is the primary affected system via genetic or environmental factors, this will trigger during development subsequent vicious circles of OxS that can feed on one another and drive durably parvalbumin (PV) neurons and myelin impairments that culminate in the neural synchronization and cognitive deficits characteristic of schizophrenia.

Fig. 2. Potential points of action of various molecules capable of interrupting the diverse vicious circles.

a Treatments with compounds such as NAC, sulforaphane or omega-3 type polyunsaturated fatty acids (PUFAS)—which possess both anti-oxidative and anti-inflammatory properties with mild side-effect profiles [, –221] are known to exert their effects through the redox system thus representing good candidates for preventive interventions targeting individuals at high-risk for schizophrenia. Sulforaphane works through the NRF2 system to trigger the anti-oxidant defence system [222]. b MitoQ and other mitochondria-targeted antioxidants could support compromised energy metabolism and mitochondria function [116]. c For NMDAR hypofunction, several strategies using compounds (e.g., D-serine, sarcosine, glycine transporter inhibitor and benzoate) that modulate NMDAR activity have been tried in schizophrenia patients with mixed success [, –229]. d In terms of neuro-inflammation, estrogens, minocycline and NAC showed efficacy, with greater beneficial results on symptom severity in first-episode psychosis patients or during early-phase of schizophrenia [216].