Table 1.
Demographic information for patients with schizophrenia and healthy controls.
Fig 1.
Prophylactic effect of SFN on PCP-induced cognitive deficits.
(A): Schedule of PCP treatment, novel object recognition test (NORT), and Golgi staining. (B): On days 15 and 16, NORT was performed. Pretreatment with SFN significantly attenuated PCP-induced cognitive deficit in mice. The data show the mean ± S.E.M. (n = 11 or 12). (C): Brain regions of medial prefrontal cortex (mPFC), CA1, CA3, and dentate gyrus (DG) of hippocampus, striatum, Nucleus accumbens (NAc) shell and core, ventral tegmental area (VTA) were shown. (D): On day 15, brains of all groups were collected, and Golgi staining of all brain samples was performed. Repeated PCP administration significantly decreased the density of spine in the mPFC and CA1, but not CA3, DG, striatum, NAc shell and core, and VTA. Pretreatment with SFN significantly attenuated PCP-induced reduction of spine density in the mPFC and CA1. The data show the mean ± SEM (n = 7 or 8). ***P < 0.001, N.S. not significant.
Fig 2.
Prophylactic effect of SFN on PCP-induced alterations in 8-oxo-dG immunostaining and PV-positive immunostaining in the brain.
(A): Treatment schedule and immunohistochemistry. On day 15, all mice were perfused. Then immunohistochemistry was performed. (B): Brain regions of medial prefrontal cortex (mPFC), CA1, CA3, and dentate gyrus (DG) of hippocampus, were shown. (C): Repeated PCP administration significantly increased 8-oxo-dG immunostaining in the mPFC and CA1, but not CA3 and DG. Pretreatment with SFN significantly attenuated PCP-induced increases of 8-oxo-dG immunostaining in the mPFC and CA1. The data show the mean ± SEM (n = 6 or 7). (C): Repeated PCP administration significantly decreased PV-positive immunostaining in the mPFC and CA1, but not CA3 and DG. Pretreatment with SFN significantly attenuated PCP-induced decreases of PV-positive immunostaining in the mPFC and CA1. The data show the mean ± SEM (n = 6 or 7). **P < 0.01, ***P < 0.001, N.S. not significant.
Fig 3.
Therapeutic effect of SFN on PCP-induced cognitive deficits in mice.
(A): Schedule of treatment and NORT. From days 1–5 and 8–12, saline (10 ml/kg/day) or PCP (10 mg/kg/day) was administered into mice. Subsequently, vehicle (10 ml/kg/day) or SFN (30 mg/kg/day) was administered from days 15–28. On day 29 and 30, NORT was performed. (B): PCP-induced cognitive deficit in mice were significantly improved by subsequent subchronic administration of SFN. The data show the mean ± S.E.M. (n = 8–11). ***P < 0.001, N.S. not significant.
Fig 4.
Prophylactic effect of dietary GF food during juvenile and adolescence on PCP-induced cognitive deficits in mice at adulthood.
(A): Chemical structure of glucoraphanine (GF) and sulforaphane (SFN). Glucoraphanine (GF) is metabolized to SFN in the body. (B): Schedule of treatment and NORT. From days 1 (4-week olds)– 28 (8-week olds), normal food (NF) or 0.1% GF food (GF) was administered into mice. From days 29 (8-week olds), normal food was administered to all mice. Subsequently, saline (10 ml/kg/day) or PCP (10 mg/kg/day) was administered from days 29–33 and days 36–40. On day 43 and 44, NORT was performed. (C): Dietary 0.1% GF food during days 1–28 significantly attenuated PCP-induced cognitive deficit in mice at adulthood (10-week olds). The data show the mean ± S.E.M. (n = 10–12). ***P < 0.001, N.S. not significant.
Fig 5.
Prophylactic effect of dietary GF food during juvenile and adolescence on PCP-induced oxidative stress and reduction of PV-positive cells in the brain at adulthood.
(A): Schedule of treatment, and immunohistochemistry. From days 1 (4-week olds)– 28 (8-week olds), normal food (NF) or 0.1% glucoraphanine food (GF) was administered into mice. From days 29 (8-week olds), normal food was administered to all mice. Subsequently, saline (10 ml/kg/day) or PCP (10 mg/kg/day) was administered from days 29–33 and days 36–40. On day 43, all mice were perfused. (B): Brain regions of mPFC, CA1, CA3, and dentate gyrus (DG) of hippocampus, were shown. (C): Repeated PCP administration significantly increased 8-oxo-dG immunostaining in the mPFC and CA1, but not CA3 and DG. Dietary intake of 0.1% GF from 4-week old to 8-week olds significantly attenuated PCP-induced increases of 8-oxo-dG immunostaining in the mPFC and CA1 at 10-week olds. The data show the mean ± SEM (n = 5–7). (D): Repeated PCP administration significantly decreased PV-positive immunostaining in the mPFC and CA1, but not CA3 and DG. Dietary intake of 0.1% GF from 4-week old to 8-week olds significantly attenuated PCP-induced decreases of PV-positive immunostaining in the mPFC and CA1 at 10-week olds. The data show the mean ± SEM (n = 5–7). **P < 0.01, ***P < 0.001, N.S. not significant.
Fig 6.
Interaction between NRF2 gene variant and KEAP1 gene variants on intellectual ability in patients with schizophrenia.
(A): There was a significant (P = 0.0036) epistatic effect of NRF2 gene (rs10930781) and KEAP1 gene variant (rs1048290) on working memory in patients with schizophrenia, but not controls (S1 Table). On the other hand, a significant (P = 0.0035) effect of these variants on processing speed was due to the NRF2 gene variant. (B): There was a significant (P = 0.012) epistatic effect of NRF2 gene (rs10930781) and KEAP1 gene variant (rs11545829) on working memory in schizophrenia, but not controls (S2 Table). On the other hand, a significant effect (P = 0.0024) of these variants on processing speed in schizophrenia was due to the NRF2 gene variant (S2 Table).