Autophagy inhibition plays a protective role against 3, 4-methylenedioxymethamphetamine (MDMA)-induced loss of serotonin transporters and depressive-like behaviors in rats

Shih, Jui‐Hu; Chiu, Chuang-Hsin; Ma, Kuo‐Hsing; Huang, Yuahn-Sieh; Shiue, Chyng‐Yann; Yeh, Ting-Yin; Lin, Yansong; Li, I‐Hsun

doi:10.1016/j.phrs.2019.02.026

Cited by 20 publications

(15 citation statements)

References 54 publications

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“…Autophagy inhibition by 3-MA with dosage of 15 mg/kg/d i.p. is consistent with studies in the rat models 60,61 . The sham group was injected with an equal volume of saline as a control.…”

Section: Animals and Treatmentsupporting

confidence: 92%

Delayed treatment with an autophagy inhibitor 3-MA alleviates the progression of hyperuricemic nephropathy

Shi

Tao

et al. 2020

Cell Death Dis

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Autophagy is a cell self-renewal process that relies on the degradation of the cytoplasmic proteins or organelles of lysosomes and is associated with development of numerous diseases. However, the therapeutic effect of autophagy inhibition on hyperuricemic nephropathy (HN) and the underlying mechanisms are still unknown. Here, we investigated the effect of delayed treatment with 3-methyladenine (3-MA), a specific autophagy inhibitor, on the development of HN in a rat model. Administration of 3-MA at 21 days following after uric acid injury protected kidney from hyperuricemic-related injuries, as demonstrated by improving renal dysfunction and architecture damage, blocking Beclin-1 and LC3II/I and decreasing the number of autophagic vacuoles. Late treatment with 3-MA was also effective in attenuating renal fibrosis as evidenced by reducing ECM protein deposition, blocking epithelial-tomesenchymal transition (EMT) and decreasing the number of renal epithelial cells arrested at the G2/M phase of cell cycle. Injury to the kidney resulted in increased expression of TGFβ receptor I, and phosphorylation of Smad3, 3-MA significantly abrogated all these responses. Moreover, inhibition of autophagy suppressed mitochondrial fission, downregulated the expression of Dynamin-related protein 1 (Drp-1), Cofilin and F-actin, and alleviated cell apoptosis. Finally, 3-MA effectively blocked STAT3 and NF-κB phosphorylation and suppressed infiltration of macrophages and lymphocytes as well as release of multiple profibrogenic cytokines/chemokines in the injured kidney. Taken together, these findings indicate that hyperuricemia-induced autophagy is critically involved in the activation of renal fibroblasts, EMT, mitochondrial fission and apoptosis of tubular epithelial cells and development of renal fibrosis. Thus, this study provides evidence for autophagy inhibitors as the treatment of HN patients.

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“…Autophagy inhibition by 3-MA with dosage of 15 mg/kg/d i.p. is consistent with studies in the rat models 60,61 . The sham group was injected with an equal volume of saline as a control.…”

Section: Animals and Treatmentsupporting

confidence: 92%

Delayed treatment with an autophagy inhibitor 3-MA alleviates the progression of hyperuricemic nephropathy

Shi

Tao

et al. 2020

Cell Death Dis

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“…Prenatal stress induces cognitive impairment and depressive-like behavior through autophagy (12). Previous study reported that inhibition of autophagy prevents depressive-like behavior induced by ecstasy in rats (13).…”

Section: Introductionmentioning

confidence: 98%

Sinisan Protects Primary Hippocampal Neurons Against Corticosterone by Inhibiting Autophagy via the PI3K/Akt/mTOR Pathway

Zhang

Sun

et al. 2021

Front. Psychiatry

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Objective: Corticosterone causes significant neurotoxicity in primary hippocampal neurons which is associated with depression. Dysfunctional autophagy is implicated in cognitive impairment and depressive-like behavior. The traditional Chinese medicine Sinisan (SNS) is highly effective in clinical treatment of depression. However, the molecular mechanisms underlying therapeutic effects of SNS are unknown.Purpose: The aim of this study was to elucidate the protective effect of SNS and the underlying mechanisms against corticosterone-induced neuronal damage.Study Design: The effects of serum derived from rats containing SNS (or untreated controls) on the expression of autophagy-related molecules in primary rat hippocampal neurons exposed to different concentrations of corticosterone for different intervals were explored.Methods: CCK-8 assay, LDH assay were used to analyze cell viability and LDH activity. Western blot, qRT-PCR, and immunofluorescence assays were used to determine protein and mRNA expression levels of molecules such as LC3, p62, Beclin1, ULK1, PI3K, p-PI3K, Akt p-Akt, mTOR, p-mTOR, p70S6, p-p70S6, 4ebp1 and p-4ebp1.Results: Corticosterone induced a dose- and time-dependent reduction in cellular viability. Moreover, corticosterone (100–400 μM) treatment for 24 h increased LC3-II/LC3-I protein ratio, increased Beclin1 and ULK1 protein expression levels, and decreased p62, PI3K, p-PI3K, p-Akt, p-mTOR, p-p70S6, and p-4ebp1 protein expression levels. Notably, SNS-containing serum reversed corticosterone-induced reduction of neuronal viability, and increased p62, PI3K, p-Akt, p-mTOR, p-p70S6, and p-4ebp1 protein and mRNA expression levels. In addition, SNS-containing serum decreased LC3-II/LC3-I protein ratio, and downregulated Beclin1, and ULK1 protein and mRNA expression in primary hippocampal neurons.Conclusion: SNS protects primary hippocampal neurons against corticosterone-induced neurotoxicity by preventing excessive autophagy through activation of PI3K/AKT/mTOR pathway.

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“…8A). Before investigating the effects of Ori on in ammatory response of BV2 cells induced by LPS, we rst assayed LPS activity and cytotoxicity by treating BV2 cells with Ori at various concentrations respectively (5,10,20, and 40 umol/L). As shown in Fig.…”

Section: Ori Dose-dependently Blocked the Interaction Between Nlrp3 And Nek7mentioning

confidence: 99%

Oridonin relieves depressive-like behaviors by inhibiting neuroinflammation and autophagy impairment in rats subjected to chronic unpredictable mild stress

Liang¹,

Wang²,

Wang³

et al. 2021

Preprint

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Background: Major depressive disorder (MDD) is a common, chronic, and severe life-threatening disorder with increasing prevalence. Although neuroinflammation is associated with the etiology of depression, the mechanistic interplay between depression, neuroinflammation, and autophagy is yet to be demonstrated. This study investigated the effect of Oridonin on CUMS-induced neuroinflammation, depression, and autophagy impairment. Methods: Male 4-week-old Sprague-Dawley rats were subjected to chronic unpredictable mild stress (CUMS) for 4 and 6 weeks respectively, some of which were injected with Oridonin, fluoxetine (FLX) or their combination at different durations of CUMS. After CUMS procedure, sucrose preference test and Forced swim test were used to evaluate depressive-like behaviors. Concomitant neuroinflammation changes and autophagy impairments were examined in the hippocampus.Reults: In this study, we found that chronic stress resulted in depressive-like behaviors and caused neuroinflammation and autophagy impairment. In particular, CUMS treatment significantly increased the levels of cytokines (IL-1β, IL-18 and Caspase-1), reduced autophagy-related protein levels (Beclin-1, p62, Atg5 and LC3B), caused microglia cells activation. Oridonin treatment can prevent and reverse the depressive-like behavior induced by CUMS in prophylactic and therapeutic administration, but there is ceiling effect in the treatment process. Furthermore, 10mg/kg dose of Ori has a stronger and longer lasting antidepressant effect than the 10mg/kg dose of fluoxetine. And the antidepressant effect of Ori in combination with fluoxetine was greater than that of high-dose fluoxetine alone. In addition, Ori treatment significantly normalized autophagy-related protein levels, and reduced levels of cytokines via blocking the interaction between NLRP3 and NEK7. Further, we investigated the role of autophagy in LPS-activated BV2 cells and levels of cytokines. Similarly, Oridonin treatment abolished and reversed levels of cytokines and autophagy-related protein levels.Conclusions: All these results supported our hypothesis that Ori possesses potent anti-depressive action, which might be mediated via inhibition of neuroinflammation and autophagy impairment through blocking the interaction between NLRP3 and NEK7.

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Autophagy inhibition plays a protective role against 3, 4-methylenedioxymethamphetamine (MDMA)-induced loss of serotonin transporters and depressive-like behaviors in rats

Cited by 20 publications

References 54 publications

Delayed treatment with an autophagy inhibitor 3-MA alleviates the progression of hyperuricemic nephropathy

Delayed treatment with an autophagy inhibitor 3-MA alleviates the progression of hyperuricemic nephropathy

Sinisan Protects Primary Hippocampal Neurons Against Corticosterone by Inhibiting Autophagy via the PI3K/Akt/mTOR Pathway

Oridonin relieves depressive-like behaviors by inhibiting neuroinflammation and autophagy impairment in rats subjected to chronic unpredictable mild stress

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