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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adolescent
-
Adult
-
Animals
-
Brassica / chemistry
-
Child
-
Cognition Disorders / chemically induced
-
Cognition Disorders / diet therapy*
-
Cognition Disorders / pathology
-
Disease Models, Animal
-
Hippocampus / drug effects
-
Hippocampus / metabolism
-
Humans
-
Intracellular Signaling Peptides and Proteins / metabolism
-
Isothiocyanates / administration & dosage*
-
Isothiocyanates / chemistry
-
Kelch-Like ECH-Associated Protein 1
-
Mice
-
Middle Aged
-
NF-E2-Related Factor 2 / metabolism
-
Oxidative Stress / drug effects*
-
Phencyclidine / toxicity
-
Plant Extracts / administration & dosage*
-
Plant Extracts / chemistry
-
Prefrontal Cortex / drug effects
-
Prefrontal Cortex / metabolism
-
Schizophrenia / diet therapy*
-
Schizophrenia / pathology
-
Seedlings / chemistry
-
Sulfoxides
Substances
-
Intracellular Signaling Peptides and Proteins
-
Isothiocyanates
-
KEAP1 protein, human
-
Kelch-Like ECH-Associated Protein 1
-
NF-E2-Related Factor 2
-
NFE2L2 protein, human
-
Plant Extracts
-
Sulfoxides
-
sulforaphane
-
Phencyclidine
Grants and funding
This work was supported by a Grant-in-Aid for Scientific Research on Innovative Areas of the Ministry of Education, Culture, Sports, Science and Technology, Japan (to K. H., #24116006), and a Grant-in-Aid for Scientific Research on Innovative Areas (Comprehensive Brain Science Network) from the Ministry of Education, Science, Sports and Culture of Japan (to R. H. and K. H.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Kagome Co. Ltd. provided support in the form of salaries for authors HS and YS, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.