Andrographolide Exerts Significant Antidepressant-Like Effects Involving the Hippocampal BDNF System in Mice

Zhang, Jingjing; Gao, Tingting; Wang, Yuan; Wang, Jinliang; Guan, Wei; Wang, Yingjie; Wang, Chengniu; Liu, Jianfeng; Jiang, Bo

doi:10.1093/ijnp/pyz032

Cited by 43 publications

(32 citation statements)

References 64 publications

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“…CUMS was done as previously described ( Ren et al, 2017 ; Ni et al, 2018 ; Xu et al, 2018 ; Jiang et al, 2019 ; Zhang et al, 2019 ). In brief, the experimental C57BL/6J mice were housed individually and subjected daily to 8 weeks of CUMS exposure which consisted of a random combination of eight stressors, including food or water deprivation (23 h), damp sawdust (12 h), restraint (2 h), cage rotation (30 min), inversion of light/dark cycle, 45°C cage tilting in empty cage (12 h) and cold (4°C for 1 h).…”

Section: Methodsmentioning

confidence: 99%

“…This test was conducted as previously used ( Jiang et al, 2017 ; Ren et al, 2017 ; Wang et al, 2017 ; Ni et al, 2018 ; Song et al, 2018 ; Xu et al, 2018 ; Jiang et al, 2019 ; Zhang et al, 2019 ; Wang et al, 2020 ). In brief, the experimental C57BL/6J mice were habituated to two bottles (one with 1% sucrose solution and the other with fresh water) for 48 h, and the bottle positions were counterbalanced across days (every 6 h).…”

Section: Methodsmentioning

confidence: 99%

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The Selective SIK2 Inhibitor ARN-3236 Produces Strong Antidepressant-Like Efficacy in Mice via the Hippocampal CRTC1-CREB-BDNF Pathway

Liu

Tang

et al. 2021

Front. Pharmacol.

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Depression is a widespread chronic medical illness affecting thoughts, mood, and physical health. However, the limited and delayed therapeutic efficacy of monoaminergic drugs has led to intensive research efforts to develop novel antidepressants. ARN-3236 is the first potent and selective inhibitor of salt-inducible kinase 2 (SIK2). In this study, a multidisciplinary approach was used to explore the antidepressant-like actions of ARN-3236 in mice. Chronic social defeat stress (CSDS) and chronic unpredictable mild stress (CUMS) models of depression, various behavioral tests, high performance liquid chromatography-tandem mass spectrometry, stereotactic infusion, viral-mediated gene transfer, western blotting, co-immunoprecipitation and immunofluorescence were used together. It was found that ARN-3236 could penetrate the blood-brain barrier. Repeated ARN-3236 administration induced significant antidepressant-like effects in both the CSDS and CUMS models of depression, accompanied with fully preventing the stress-enhanced SIK2 expression and cytoplasmic translocation of cyclic adenosine monophosphate response element binding protein (CREB)-regulated transcription coactivator 1 (CRTC1) in the hippocampus. ARN-3236 treatment also completely reversed the down-regulating effects of CSDS and CUMS on the hippocampal brain-derived neurotrophic factor (BDNF) system and neurogenesis. Moreover, we demonstrated that the hippocampal CRTC1-CREB-BDNF pathway mediated the antidepressant-like efficacy of ARN-3236. Collectively, ARN-3236 possesses strong protecting effects against chronic stress, and could be a novel antidepressant beyond monoaminergic drugs.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

The Selective SIK2 Inhibitor ARN-3236 Produces Strong Antidepressant-Like Efficacy in Mice via the Hippocampal CRTC1-CREB-BDNF Pathway

Liu

Tang

et al. 2021

Front. Pharmacol.

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“…T0450L) were purchased from Targetmol (Boston, MA). The doses for LIMKi 3 (100 or 200 μM/mouse) and fluoxetine (20 mg/kg) were chosen based on previous reports ( Lunardi et al, 2018 ; Song et al, 2018 ; Zhang et al, 2019 ). LIMKi 3 was stereotaxically given into the mPFC region of C57BL/6J mice, and the vehicle used was artificial cerebral spinal fluid containing 1% dimethyl sulfoxide.…”

Section: Methodsmentioning

confidence: 99%

LIMK1/2 in the mPFC Plays a Role in Chronic Stress-Induced Depressive-Like Effects in Mice

Gao

Wang

Liu

et al. 2020

International Journal of Neuropsychopharmacology

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Background Depression is one of the most common forms of mental illness and also a leading cause of disability worldwide. Developing novel antidepressant targets beyond the monoaminergic systems is now popular and necessary. LIM kinases, including LIM domain kinase 1 and 2 (LIMK1/2), play a key role in actin and microtubules dynamics through phosphorylating cofilin. Since depression is associated with atrophy of neurons and reduced connectivity, here we speculate that LIMK1/2 may play a role in the pathogenesis of depression. Methods In this study, the chronic unpredictable mild stress (CUMS), chronic restraint stress (CRS) and chronic social defeat stress (CSDS) models of depression, various behavioral tests, stereotactic injection, western blotting and immunofluorescence methods were adopted. Results It was found that CUMS, CRS and CSDS all significantly enhanced the phosphorylation levels of LIMK1 and LIMK2 in the medial prefrontal cortex (mPFC) but not the hippocampus of mice. Administration of fluoxetine, a most commonly used SSRI in clinical practice, fully reversed the effects of CUMS, CRS and CSDS on LIMK1 and LIMK2 in the mPFC. Moreover, pharmacological inhibition of LIMK1 and LIMK2 in the mPFC by LIMKi 3 infusions notably prevented the pro-depressant effects of CUMS, CRS and CSDS in mice. Conclusions In summary, these results suggest that LIMK1/2 in the mPFC has a role in chronic stress-induced depressive-like effects in mice, and could be a novel pharmacological target for developing antidepressants. Significance Statement It is now popular and necessary to develop novel antidepressant targets beyond the monoaminergic systems. LIMK1/2 plays a key role in actin and microtubules dynamics through phosphorylating cofilin. This study mainly investigated the correlation between the LIMK-Cofilin system in the mPFC and depression. It was found that both chronic stress and fluoxetine were able to significantly regulate the phosphorylation of LIMK1, LIMK2 and cofilin in the mPFC but not the hippocampus, and inhibiting LIMK1/2 in the mPFC led to antidepressant-like effects in mice. Therefore, LIMK1/2 in the mPFC is a potential participant underlying the pathophysiology of depression and could be a novel antidepressant target. Moreover, this study provides support for the potential use of LIMKi 3 treatment strategies against chronic stress-related mental disorders.

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“…Andrographolide can cross the blood-brain barrier and concentrate in the brain (Li et al, 2012;Lu, 1995), where it ameliorated oxidative injury through suppressing PI3K/Akt and NF-κB pathways to protect neurons in ischaemic stroke models (Chan, Wong, Wong, & Bian, 2010;Chern et al, 2011), and promoted hippocampal BDNF signalling cascade to reverse depressant-like effects (Zhang et al, 2019). It can also attenuate cognitive impairment in the mouse model of Alzheimer's disease (Geng et al, 2018;Rivera et al, 2016;Serrano et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Andrographolide alleviates Parkinsonism in MPTP‐PD mice via targeting mitochondrial fission mediated by dynamin‐related protein 1

Geng

Gao

et al. 2019

British J Pharmacology

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Background and Purpose: Accumulating evidence indicates that mitochondrial dynamics play an important role in the progressive deterioration of dopaminergic neurons. Andrographolide has been found to exert neuroprotective effects in several models of neurological diseases. However, the mechanism of how andrographolide protects neurons in Parkinson's disease (PD) remains not fully understood. Experimental Approach: Behavioural experiments were performed to examine the effect of andrographolide in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-PD mice. Mitochondrial mass and morphology were visualized using transmission electron microscopy (TEM). SH-SY5Y cells and primary mouse neurons were exposed to rotenone to mimic PD in vitro. Western blotting, co-immunoprecipitation and immunofluorescence were performed. The target protein of andrographolide was identified by biotin-andrographolide pulldown assay as well as drug affinity responsive target stability (DARTS), cellular thermal shift (CETSA), and surface plasmon resonance (SPR) assays. Key Results: Andrographolide administration improved behavioural deficits and attenuated loss of dopaminergic neurons in MPTP-exposed mice and reduced cell death induced by rotenone in vitro. An increased mitochondrial mass, and decreased surface area were found in the striatum from MPTP-PD mice, as well as in rotenonetreated primary neurons and SH-SY5Y cells, while andrographolide treatment preserved mitochondrial mass and morphology. Dynamin-related protein 1 (DRP1) was identified as a target protein of andrographolide. Andrographolide bound to DRP1 and inhibited its GTPase activity, thereby preventing excessive mitochondria fission and neuronal damage in PD. Conclusions and Implications: Our findings suggest that andrographolide may protect neurons against rotenone-or MPTP-induced damage in vitro and in vivo through inhibiting mitochondrial fission.

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Andrographolide Exerts Significant Antidepressant-Like Effects Involving the Hippocampal BDNF System in Mice

Cited by 43 publications

References 64 publications

The Selective SIK2 Inhibitor ARN-3236 Produces Strong Antidepressant-Like Efficacy in Mice via the Hippocampal CRTC1-CREB-BDNF Pathway

The Selective SIK2 Inhibitor ARN-3236 Produces Strong Antidepressant-Like Efficacy in Mice via the Hippocampal CRTC1-CREB-BDNF Pathway

LIMK1/2 in the mPFC Plays a Role in Chronic Stress-Induced Depressive-Like Effects in Mice

Andrographolide alleviates Parkinsonism in MPTP‐PD mice via targeting mitochondrial fission mediated by dynamin‐related protein 1

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