Genipin normalizes depression-like behavior induced by prenatal stress through inhibiting DNMT1

Ye, Di; Zhang, Li; Fan, Weidong; Zhang, Xianquan; Dong, Erbao

doi:10.1080/15592294.2018.1450033

Cited by 28 publications

(16 citation statements)

References 45 publications

(101 reference statements)

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“…However, the sex-specific expression patterns of GR protein in PS offspring suggest that additional mechanisms are involved. Specific DNMTs or demethylase were found to be involved in anxiety-like behavior in adult rodents; it was suggested that these enzymes exert their effects by modifying GR expression in the hippocampus (Cheng et al, 2018;Ye et al, 2018). In support of this possibility, we showed that PS exposure increased DNMT3a expression in the hippocampus of adolescent female rats while decreasing that of Tet-2 in males.…”

Section: Discussionsupporting

confidence: 65%

Differences in DNA Methylation Reprogramming Underlie the Sexual Dimorphism of Behavioral Disorder Caused by Prenatal Stress in Rats

Lei

et al. 2020

Front. Neurosci.

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Prenatal stress (PS) can lead to neuroendocrine and emotional disorders later in adolescence. Sexual dimorphism in these neurodevelopmental outcomes have been observed; however, the underlying mechanisms are not fully understood. To address this issue, we investigated whether there are sex differences in epigenetic reprogramming in rats exposed to PS. Pregnant female rats were subjected to chronic restraint stress from gestational day (G)12 to G18. From postnatal day (P)38 to P45, subgroups of offspring including both males and females were subjected to behavioral testing and brain tissue specimens were analyzed by DNA pyrosequencing, western blotting, and Golgi staining to assess changes in methylation pattern of glucocorticoid receptor (GR) gene, expression of DNA methyltransferase (DNMT) and DNA demethylase, and dendrite morphology, respectively. The DNA methyltransferase inhibitor decitabine was administered to rats prior to PS to further evaluate the role of methylation in the sexually dimorphic effects of PS. The results showed that PS increased anxiety-like behavior in offspring, especially in females, while depression-like behavior was increased in male offspring compared to control littermates. The methylation pattern in the promoter region of the GR gene differed between males and females. Sex-specific changes in the expression of DNMTs (DNMT1 and DNMT3a) and DNA demethylase (Tet methylcytosine dioxygenase 2) were also observed. Interestingly, decitabine alleviated the behavioral disorder caused by PS and restored dendrite density and morphology in female but not male rats. These findings suggest that different change patterns of DNMT and demethylase in the two sexes after PS are responsible for the sexually dimorphism, which could have implications for the clinical management of stress-related disorders.

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Section: Discussionsupporting

confidence: 65%

Differences in DNA Methylation Reprogramming Underlie the Sexual Dimorphism of Behavioral Disorder Caused by Prenatal Stress in Rats

Lei

et al. 2020

Front. Neurosci.

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“…Melas et al discovered that treating depressive rats with escitalopram could down-regulate the expression of Dnmt1 in prefrontal cortex ( 31 ). And in hippocampus, genipin reduced despair-like traits (assessed via TST and FST) by inhibiting the expression of Dnmt1 and normalizing the expression of BDNF ( 53 ). Additionally, Wright et al found that the expression of Dnmt1 was increased in the central nucleus of amygdala in the depression mouse model established by chronic social failure stress (assessed via a social interaction test (SIT)), but only in the female mice ( 54 ).…”

Section: Dna Methyltransferases In Depressionmentioning

confidence: 99%

DNA Methyltransferases in Depression: An Update

Duan

2020

Front. Psychiatry

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Depression is one of the most common psychiatric disorders affecting public health. Studies over the past years suggest that the methylations of some specific genes such as BDNF, SLC6A4, and NR3C1 play an important role in the development of depression. Recently, epigenetic evidences suggest that the expression levels of DNA methyltransferases differ in several brain areas including the prefrontal cortex, hippocampus, amygdala, and nucleus accumbens in depression patients and animal models, but the potential link between the expression levels of DNA methylatransferases and the methylations of specific genes needs further investigation to clarify the pathogenesis of depression.

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“…In this context, it is important to note that in human prostate, methylation of SRD5A2 is regulated by DNA methyltransferase 1 (DNMT1) (44) and that, as demonstrated in animal models, forebrain deletion of DNMT1 (45) or its pharmacological inhibition (44, 46) had antidepressant-like properties.…”

Section: Discussionmentioning

confidence: 99%

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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Genipin normalizes depression-like behavior induced by prenatal stress through inhibiting DNMT1

Cited by 28 publications

References 45 publications

Differences in DNA Methylation Reprogramming Underlie the Sexual Dimorphism of Behavioral Disorder Caused by Prenatal Stress in Rats

Differences in DNA Methylation Reprogramming Underlie the Sexual Dimorphism of Behavioral Disorder Caused by Prenatal Stress in Rats

DNA Methyltransferases in Depression: An Update

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

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