<i>SELENOM</i> Knockout Induces Synaptic Deficits and Cognitive Dysfunction by Influencing Brain Glucose Metabolism

Lin, Shujing; Chen, Chen; Ouyang, Pei; Cai, Zhiyu; Liu, Xibei; Abdurahman, Anwar; Peng, Jia-Ying; Liu, Yu; Zhang, Zhong-Hao; Song, Guo-Li

doi:10.1021/acs.jafc.2c07491

Cited by 5 publications

(1 citation statement)

References 49 publications

(77 reference statements)

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“…More generally, calcium/calmodulin-dependent kinases (CAMKs) are closely tied to synaptic plasticity, learning and memory processes ( Bayer and Schulman, 2019 ). Selenom is reported to affect synaptic plasticity and cognitive function ( Lin et al, 2023 ). Nfil3 is a transcription factor that regulates expression of synaptic plasticity genes and is implicated in the regulation of inhibitory long-term potentiation (iLTP) and depression (iLTD) ( Chapman et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Methylone is a rapid-acting neuroplastogen with less off-target activity than MDMA

Warner-Schmidt,

Stogniew,

Mandell

et al. 2024

Front. Neurosci.

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BackgroundPost-traumatic stress disorder (PTSD) is a highly prevalent psychiatric disorder that can become chronic and debilitating when left untreated. Available pharmacotherapies are limited, take weeks to show modest benefit and remain ineffective for up to 40% of patients. Methylone is currently in clinical development for the treatment of PTSD. Preclinical studies show rapid, robust and long-lasting antidepressant-like and anxiolytic effects. The mechanism of action underlying these effects is not yet fully understood. This study investigated the downstream gene expression changes and signaling pathways affected by methylone in key brain areas linked to PTSD and MDD. It also sought to determine whether neuroplasticity-related genes were involved. We compared effects of methylone with MDMA to explore similarities and differences in their brain effects because MDMA-assisted psychotherapy has recently shown benefit in clinical trials for PTSD and methylone is a structural analog of MDMA.MethodsMonoamine binding, uptake and release studies were performed and a high-throughput-screen evaluated agonist/antagonist activities at 168 GPCRs in vitro. We used RNA sequencing (RNA-seq) to probe drug-induced gene expression changes in the amygdala and frontal cortex, two brain areas responsible for emotional learning that are affected by PTSD and MDD. Rats were treated with methylone or MDMA (both 10 mg/kg, IP), and their responses were compared with controls. We performed functional enrichment analysis to identify which pathways were regulated by methylone and/or MDMA. We confirmed changes in gene expression using immunohistochemistry.ResultsMethylone, a monoamine uptake inhibitor and releaser, demonstrated no off-target effects at 168 GPCRs, unlike MDMA, which showed activity at 5HT2A and 5HT2C receptors. RNA-seq results revealed significant regulation of myelin-related genes in the amygdala, confirmed by immunohistochemistry. In the frontal cortex, methylone significantly upregulated genes implicated in neuroplasticity.ConclusionResults suggest that (1) methylone is a rapid-acting neuroplastogen that affects key brain substrates for PTSD and MDD and that (2) methylone appears to exhibit higher specificity and fewer off-target effects than MDMA. Together, these results are consistent with the reported clinical experiences of methylone and MDMA and bolster the potential use of methylone in the treatment of PTSD and, potentially, other neuropsychiatric disorders.

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Section: Discussionmentioning

confidence: 99%

Methylone is a rapid-acting neuroplastogen with less off-target activity than MDMA

Warner-Schmidt,

Stogniew,

Mandell

et al. 2024

Front. Neurosci.

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Transcriptomic Profiles Associated with Experimental Placebo Effects in Chronic Pain

Colloca,

Mocci,

Wang

et al. 2024

Clin Pharma and Therapeutics

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Gene expression networks associated with placebo effects are understudied; in this study, we identified transcriptomic profiles associated with placebo responsivity. Participants suffering from chronic pain underwent a verbal suggestion and conditioning paradigm with individually tailored thermal painful stimulations to elicit conditioned placebo effects. Participants reported pain intensity on a visual analog scale (VAS) anchored from zero = no pain to 100 = maximum imaginable pain. RNA was extracted from venous blood and RNA sequencing and validation tests were performed to identify differentially expressed genes (DEGs) associated with placebo effects, controlling for sex and level of pain. Unbiased enrichment analyses were performed to identify biological processes associated with placebo effects. Of the 10,700 protein‐coding genes that passed quality control filters, 667 were found to be associated with placebo effects (FDR <0.05). Most genes (97%) upregulated were associated with larger placebo effects. The 17 top transcriptome‐wide significant genes were further validated via RT‐qPCR in an independent cohort of chronic pain participants. Six of them (CCDC85B, FBXL15, HAGH, PI3, SELENOM, and TNFRSF4) showed positive and significant (P < 0.05) correlation with placebo effects in the cohort. The overall DEGs were highly enriched in regulation of expression of SLITs and ROBOs (R‐HSA‐9010553, FDR = 1.26e−33), metabolism of RNA (R‐HSA‐8953854, FDR = 1.34e−30), Huntington's disease (hsa05016, FDR = 9.84e−31), and ribosome biogenesis (GO:0042254, FDR = 2.67e−15); alternations in these pathways might jeopardize the proneness to elicit placebo effects. Future studies are needed to replicate this finding and better understand the unique molecular dynamics of people who are more or less affected by pain and placebo.

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Do selenium-enriched foods provide cognitive benefit?

Bai

Zhang

2023

Metab Brain Dis

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SELENOM Knockout Induces Synaptic Deficits and Cognitive Dysfunction by Influencing Brain Glucose Metabolism

Cited by 5 publications

References 49 publications

Methylone is a rapid-acting neuroplastogen with less off-target activity than MDMA

Methylone is a rapid-acting neuroplastogen with less off-target activity than MDMA

Transcriptomic Profiles Associated with Experimental Placebo Effects in Chronic Pain

Do selenium-enriched foods provide cognitive benefit?

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