The brain is particularly vulnerable to oxidative damage because of its high rate of oxygen consumption, abundant
lipid content, and relative paucity of
antioxidant enzymes compared with other organs. It has been well established that oxidative stress (OS) is involved in the pathogenesis of age-associated
neurodegenerative disorders such as
Alzheimer's disease (AD). Indeed, a large number of genetic and environmental factors of
neurodegenerative disorders are associated with OS. Of note, studies on the levels of oxidative damage in patients with the
prodromal stage of AD, transgenic animal models of AD, and induced pluripotent stem (iPS) cells derived from AD patients support the early-stage involvement of OS in the pathological cascade of the disorder. Recently, a growing body of evidence suggests that a considerable number of genetic and environmental factors of
psychiatric disorders such as
schizophrenia (SZ),
bipolar disorders, and depression are associated with OS. Not only genetic polymorphisms in genes encoding
antioxidant enzymes but also several known susceptible genes for
psychiatric disorders, i. e., Disrupted-in-Schizophrenia-1 (DISC1),
Neuregulin 1 (NRG1),
proline dehydrogenase (PRODH), and G72, are all associated with increased levels of OS or decreased
antioxidant capacities. Moreover, environmental factors such as
infection,
hypoxia,
malnutrition, illicit
substance use, and psychosocial stress are possibly associated with OS. In fact, increased levels of oxidized
nucleic acids,
proteins, and
lipids have been described in the postmortem brains of patients with SZ and
bipolar disorders, and decreased
antioxidant capacities have been described in blood samples obtained from patients with first-episode
psychosis. In concordance, iPS cells from SZ patients show an increased level of OS. Of particular interest is a conditional gene knockout mouse model of SZ with the functional elimination of
NMDA receptors specifically from cortical interneurons. The
NMDA receptor knockout mouse shows behavioral phenotypes resembling symptoms of human SZ. Importantly, a marked increase of OS, particularly in the cortical
parvalbumin-positive interneurons, is rapidly exacerbated by post-weaning social isolation, but treatment with
antioxidants abolishes OS and partially alleviates the SZ-like behavioral phenotypes. Therefore, it is suggested that OS is a convergence point for genetic and environmental susceptibilities to not only neurodegenerative but also
psychiatric disorders. In other words, OS potentially plays a central role in the pathomechanisms that integrate gene-environment interactions in neuropsychiatric disorders. Further investigations into the development of useful OS
biomarkers and efficacious OS-targeting interventions may shed light on a promising approach for establishing preemptive strategies against neuropsychiatric disorders.