Dietary Intake of Sulforaphane-Rich Broccoli Sprout Extracts during Juvenile and Adolescence Can Prevent Phencyclidine-Induced Cognitive Deficits at Adulthood.

Yumi Shirai,Yusuke Ushida,Yuko Fujita,Kazutaka Ohi,Ryota Hashimoto,Tamaki Ishima,Hiroyuki Suganuma,Kenji Hashimoto,Yuka Yasuda,Masatoshi Takeda,Hidenaga Yamamori

doi:10.1371/journal.pone.0127244

Yumi Shirai, Yusuke Ushida + Show 9 more

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https://doi.org/10.1371/journal.pone.0127244

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Abstract

Oxidative stress and inflammation play a role in cognitive impairment, which is a core symptom of schizophrenia. Furthermore, a hallmark of the pathophysiology of this disease is the dysfunction of cortical inhibitory γ-aminobutyric acid (GABA) neurons expressing parvalbumin (PV), which is also involved in cognitive impairment. Sulforaphane (SFN), an isothiocyanate derived from broccoli, is a potent activator of the transcription factor Nrf2, which plays a central role in the inducible expressions of many cytoprotective genes in response to oxidative stress. Keap1 is a cytoplasmic protein that is essential for the regulation of Nrf2 activity. Here, we found that pretreatment with SFN attenuated cognitive deficits, the increase in 8-oxo-dG-positive cells, and the decrease in PV-positive cells in the medial prefrontal cortex and hippocampus after repeated administration of phencyclidine (PCP). Furthermore, PCP-induced cognitive deficits were improved by the subsequent subchronic administration of SFN. Interestingly, the dietary intake of glucoraphanin (a glucosinolate precursor of SFN) during the juvenile and adolescence prevented the onset of PCP-induced cognitive deficits as well as the increase in 8-oxo-dG-positive cells and the decrease in PV-positive cells in the brain at adulthood. Moreover, the NRF2 gene and the KEAP1 gene had an epistatic effect on cognitive impairment (e.g., working memory and processing speed) in patients with schizophrenia. These findings suggest that SFN may have prophylactic and therapeutic effects on cognitive impairment in schizophrenia. Therefore, the dietary intake of SFN-rich broccoli sprouts during the juvenile and adolescence may prevent the onset of psychosis at adulthood.

Highlights

Cognitive impairment is observed in patients with a number of psychiatric diseases, including schizophrenia, major depressive disorder, bipolar disorder, generalized anxiety disorder, panic disorder, post-traumatic stress disorder, obsessive compulsive disorder, attention deficit hyperactivity disorder, and autism spectrum disorder [1]
We examined whether SFN affected alterations in the dendritic spines of the medial prefrontal cortex, CA1, CA3, dentate gyrus (DG) of the hippocampus, striatum, nucleus accumbens (NAc), or ventral tegmental area (VTA) after the repeated administration of PCP
Pretreatment with SFN was able to prevent the onset of PCP-induced cognitive deficits in mice, suggesting that dietary SFN may prevent cognitive impairment associated with environmental events in humans

Summary

Introduction

Cognitive impairment is observed in patients with a number of psychiatric diseases, including schizophrenia, major depressive disorder, bipolar disorder, generalized anxiety disorder, panic disorder, post-traumatic stress disorder, obsessive compulsive disorder, attention deficit hyperactivity disorder, and autism spectrum disorder [1]. We reported that SFN could prevent behavioral abnormalities and dopaminergic neurotoxicity in mice after the administration of the psychostimulant methamphetamine [22]. We reported that SFN could attenuate behavioral abnormalities in mice after the administration of the N-methyl-D-aspartate (NMDA) receptor antagonist phencyclidine (PCP)[23], since a PCP model of schizophrenia has been accepted throughout the world. These findings suggest that SFN could be a potential therapeutic natural compound for neuropsychiatric diseases, including substance abuse and schizophrenia [7, 22, 23]

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