DNA methylation of the GC box in the promoter region mediates isolation rearing-induced suppression of srd5a1 transcription in the prefrontal cortex

Araki, Ryoko; Nishida, Shoji; Hiraki, Yosuke; Matsumoto, Kinzo; Yabe, Takeshi

doi:10.1016/j.neulet.2015.08.031

Cited by 18 publications

(10 citation statements)

References 39 publications

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“…A possible hypothesis for the persistent side effects may be epigenetic modifications occurring in PFS patients. Indeed, downregulation and hypermethylation of 5α-R were observed in the rodent nervous system and associated with inflammation and depression (29, 30), features that, as mentioned earlier, have been also observed in PFS model (28). In this setting, the evaluation of the methylation pattern remains challenging since it could change during adulthood and with ageing (31).…”

Section: Introductionsupporting

confidence: 55%

Altered methylation pattern of the SRD5A2 gene in the cerebrospinal fluid of post-finasteride patients: a pilot study

Melcangi

Casarini

Marino

et al. 2019

Endocrine Connections

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Context Post-finasteride syndrome (PFS) occurs in patients with androgenic alopecia after suspension of the finasteride treatment, leading to a large variety of persistent side effects. Despite the severity of the clinical picture, the mechanism underlying the PFS symptoms onset and persistence is still unclear. Objective To study whether epigenetic modifications occur in PFS patients. Methods Retrospective analysis of a multicentric, prospective, longitudinal, case–control clinical trial, enrolling 16 PFS patients, compared to 20 age-matched healthy men. Main outcomes were methylation pattern of SRD5A1 and SRD5A2 promoters and concentration of 11 neuroactive steroids, measured by liquid chromatography-tandem mass spectrometry, in blood and cerebrospinal fluid (CSF) samples. Results SRD5A1 and SRD5A2 methylation analysis was performed in all blood samples (n = 16 PFS patients and n = 20 controls), in 16 CSF samples from PFS patients and in 13 CSF samples from controls. The SRD5A2 promoter was more frequently methylated in CSF of PFS patients compared to controls (56.3 vs 7.7%). No promoter methylation was detected in blood samples in both groups. No methylation occurred in the SRD5A1 promoter of both groups. Unmethylated controls compared to unmethylated SRD5A2 patients showed higher pregnenolone, dihydrotestosterone and dihydroprogesterone, together with lower testosterone CSF levels. Andrological and neurological assessments did not differ between methylated and unmethylated subjects. Conclusions For the first time, we demonstrate a tissue-specific methylation pattern of SRD5A2 promoter in PFS patients. Although we cannot conclude whether this pattern is prenatally established or induced by finasteride treatment, it could represent an important mechanism of neuroactive steroid levels and behavioural disturbances previously described in PFS.

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Section: Introductionsupporting

confidence: 55%

Altered methylation pattern of the SRD5A2 gene in the cerebrospinal fluid of post-finasteride patients: a pilot study

Melcangi

Casarini

Marino

et al. 2019

Endocrine Connections

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“…However, considering the fact that when administration of KST was conducted for almost a same period by the therapeutic procedure, KST did not affect ISO-induced behavioral abnormalities, it is very likely that KST may be able to block processes including epigenetic alteration, which is triggered early after starting ISO. Recent findings reported by Araki et al have demonstrated that ISO induces epigenetic changes in promoter coding regions of the GABA B1a receptor [40] and srd5a1 [41], a gene coding for the biosynthetic enzyme neurosteroid allopregnanolone, which is down-regulated by ISO [16, 42]. Moreover, our preliminary study indicated that inhibition of allopregnanolone biosynthesis in the brain caused impairment of sociability behavior in mice in a manner reversible by systemic administration of allopregnanolone (unpublished data).…”

Section: Discussionmentioning

confidence: 99%

Daily administration of yokukansan and keishito prevents social isolation-induced behavioral abnormalities and down-regulation of phosphorylation of neuroplasticity-related signaling molecules in mice

Fujiwara

Han

Awale

et al. 2017

BMC Complement Altern Med

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BackgroundOur previous studies demonstrated that post-weaning social isolation (ISO) in mice induces behavior abnormalities such as deficits of sociability- and attention-like behaviors. These deficits can be attenuated by methylphenidate (MPH), a drug used for attention deficit hyperactivity disorder (ADHD), suggesting that ISO mice offer a potential animal model of comorbid developmental disorder with ADHD and autism spectrum disorder symptoms. This study investigated the effects of Kampo formulae, yokukansan (YKS) and keishito (KST), on the neuropsychiatric symptoms of ISO mice to clarify the therapeutic or preventive/delaying potential of these formulae for the treatment of neurodevelopmental disorders.MethodsThree-to-4-week old male ICR mice were socially isolated during an experimental period and YKS and KST (1523.6 and 2031.8 mg/kg, p.o.) was administered starting from week 2 and week 0 after starting ISO for the analysis of their therapeutic and preventive/delaying potentials, respectively. Sociability, attention-related behavior and fear memory were elucidated by a 3 chamber test, a water-finding test and fear conditioning test, respectively. Moreover, the phosphorylation of neuroplasticity-related signaling molecules in mice hippocampus was analyzed using western blotting.ResultsIn a therapeutic procedure, YKS ameliorated ISO-induced impairments of attention-like behavior and context-dependent fear memory, but not of sociability, whereas KST had no beneficial effects in ISO mice. In experiments to analyze the preventive/delaying potentials of these treatments, both YKS and KST improved sociability, attention, and context-dependent fear memory deficits. The improvement of sociability in mice by YKS and KST was not inhibited by a dopamine D1 receptor antagonist, suggesting that YKS and KST improved the ISO-induced sociability deficit by other mechanisms besides activation of the dopaminergic system. On the other hand, the beneficial effects of YKS and KST on attention-like behavior were inhibited by a muscarinic antagonist, suggesting that YKS and KST ameliorated ISO-induced attention-like behavior through a cholinergic mechanism. Moreover, the phosphorylated forms of CaMKII and CREB were down-regulated by ISO stress and restored by YKS and KST administration.ConclusionsThese findings suggest that YKS and KST may be useful for the improvement of neurodevelopmental disorders.Electronic supplementary materialThe online version of this article (doi:10.1186/s12906-017-1710-7) contains supplementary material, which is available to authorized users.

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“…Moreover, Egr-1 also increases by epigenetic regulation in rat hippocampal neurons. 43 , 44 Moreover, Egr-1 also increases by epigenetic regulation in rat hippocampal neuron. 45 However, it is still unknown how SST regulates the Egr-1 expression in our present study.…”

Section: Discussionmentioning

confidence: 93%

Sansoninto, a traditional herbal medicine, ameliorates behavioral abnormalities and down-regulation of early growth response-1 expression in mice exposed to social isolation stress

Fujiwara

Tsushima

Okada

et al. 2018

Journal of Traditional and Complementary Medicine

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Social isolation (SI) mice exhibit behavioral abnormalities such as impairments of sociability- and attention-like behaviors, offering an animal model of neurodevelopmental disorders such as attention-deficit/hyperactivity disorder (ADHD). This study aimed to identify the effects of Sansoninto (SST; 酸棗仁湯 suān zǎo rén tāng) on the psychiatric symptoms related to ADHD using SI mice. Four-week-old mice were socially isolated during the experimental period, and SST administration (800 or 2400 mg/kg, p.o.) was started at 2 weeks after starting SI. SST ameliorated SI-induced impairments of sociability- and attention-like behaviors in a dose-dependent manner, and tended to ameliorate contextual- and auditory-dependent fear memory deficit. Moreover, the expression level of Egr-1 was down-regulated by SI stress, and was restored by a high dose of SST. These findings suggest that SST is useful for improvement of psychiatric disorders such as ADHD.

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DNA methylation of the GC box in the promoter region mediates isolation rearing-induced suppression of srd5a1 transcription in the prefrontal cortex

Cited by 18 publications

References 39 publications

Altered methylation pattern of the SRD5A2 gene in the cerebrospinal fluid of post-finasteride patients: a pilot study

Altered methylation pattern of the SRD5A2 gene in the cerebrospinal fluid of post-finasteride patients: a pilot study

Daily administration of yokukansan and keishito prevents social isolation-induced behavioral abnormalities and down-regulation of phosphorylation of neuroplasticity-related signaling molecules in mice

Sansoninto, a traditional herbal medicine, ameliorates behavioral abnormalities and down-regulation of early growth response-1 expression in mice exposed to social isolation stress

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