Leonurine Exerts Antidepressant-Like Effects in the Chronic Mild Stress-Induced Depression Model in Mice by Inhibiting Neuroinflammation

Jia, Miaomiao; Li, Chenxin; Zheng, Ying; Ding, Xin; Chen, Meng; Ding, Jingzhong; Du, Ren‐Hong; Lu, Ming; Hu, Gang

doi:10.1093/ijnp/pyx062

Cited by 45 publications

(34 citation statements)

References 44 publications

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“…The protocols for the Western blot and TEM assays have been reported previously ( Lu et al, 2014 ; Jia et al, 2017 ). Midbrain and cell protein lysates were quantified by Bradford assays (Bio-Rad, Hercules, CA, United States).…”

Section: Methodsmentioning

confidence: 99%

Plin4-Dependent Lipid Droplets Hamper Neuronal Mitophagy in the MPTP/p-Induced Mouse Model of Parkinson’s Disease

et al. 2018

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Epidemiological studies have shown that both lipid metabolism disorder and mitochondrial dysfunction are correlated with the pathogenesis of neurodegenerative diseases (NDDs), including Parkinson’s disease (PD). Emerging evidence suggests that deposition of intracellular lipid droplets (LDs) participates in lipotoxicity and precedes neurodegeneration. Perilipin family members were recognized to facilitate LD movement and cellular signaling interactions. However, the direct interaction between Perilipin-regulated LD deposition and mitochondrial dysfunction in dopaminergic (DA) neurons remains obscure. Here, we demonstrate a novel type of lipid dysregulation involved in PD progression as evidenced by upregulated expression of Plin4 (a coating protein and regulator of LDs), and increased intracellular LD deposition that correlated with the loss of TH-ir (Tyrosine hydroxylase-immunoreactive) neurons in the MPTP/p-induced PD model mouse mesencephalon. Further, in vitro experiments showed that inhibition of LD storage by downregulating Plin4 promoted survival of SH-SY5Y cells. Mechanistically, reduced LD storage restored autophagy, leading to alleviation of mitochondrial damage, which in turn promoted cell survival. Moreover, the parkin-poly-Ub-p62 pathway was involved in this Plin4/LD-induced inhibition of mitophagy. These findings were further confirmed in primary cultures of DA-nergic neurons, in which autophagy inhibitor treatment significantly countermanded the ameliorations conferred by Plin4 silencing. Collectively, these experiments demonstrate that a dysfunctional Plin4/LD/mitophagy axis is involved in PD pathology and suggest Plin4-LDs as a potential biomarker as well as therapeutic strategy for PD.

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Section: Methodsmentioning

confidence: 99%

Plin4-Dependent Lipid Droplets Hamper Neuronal Mitophagy in the MPTP/p-Induced Mouse Model of Parkinson’s Disease

et al. 2018

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“…Further, some cytokines such as interleukin- (IL-) 1 β , IL-6, and tumor necrosis factor- α (TNF- α ) were believed to be contributors of the onset and progression of depression [ 7 – 9 ] because these cytokines affected the neuron function and neuroactive molecule production which were associated with depression [ 10 – 12 ]. Meanwhile, some anti-inflammation medications could relieve symptoms of depression by reducing the overexpression of cytokines [ 7 , 13 – 15 ].…”

Section: Introductionmentioning

confidence: 99%

TLR4-NF-κB Signal Involved in Depressive-Like Behaviors and Cytokine Expression of Frontal Cortex and Hippocampus in Stressed C57BL/6 and ob/ob Mice

Wang

Liu

et al. 2018

Neural Plasticity

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Studies found that elevated levels of cytokines such as interleukin- (IL-) 1β, IL-6, and tumor necrosis factor-α (TNF-α) are closely associated with the pathogenesis of depression. Obesity providing a low-grade inflammation state was proposed to be implicated in susceptibility to depression in obesity. However, the alterations of cytokines and the TLR4-NF-κB signal in the brain of normal-weight and obese mice under stress have not been fully elucidated. This study used chronic unpredictable mild stress (CUMS) to induce a depressive-like behavior in an animal model and examine depressive-like behaviors, memory changes, and serum corticosterone levels, as well as the expressions of cytokines and NF-κB in the frontal cortex and hippocampus. We aimed to observe the role of neuroinflammation in susceptibility to depression in obesity under CUMS. In addition, we investigated the protective effect of inhibiting the TLR4-NF-κB signal. Our results demonstrated that CUMS induced depressive-like behavior and spatial memory damage, higher level of serum corticosterone, and overexpression of cytokines and NF-κB in the frontal cortex and hippocampus in both C57BL/6 and ob/ob mice. ob/ob mice displayed serious behavioral disorder and higher levels of IL-1β, IL-6, TNF-α, and NF-κB. Our results concluded that a hyperactive TLR4-NF-κB signal and higher level of cytokines are involved in susceptibility to depression in stressed obese mice.

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“…Leonurine has been shown to impart antiapoptosis effects in ischemic stroke mice by upregulating B‐cell lymphoma/leukemia‐2 (Bcl‐2) and downregulating Bcl‐2‐associated X protein (Bax) expression . Leonurine has also been reported to exert antidepressant effects by improving monoamine neurotransmitters in depression model of mice . Leonurine plays an antineuroinflammatory role by inhibiting microglial overactivation in Alzheimer's disease Sprague Dawley (SD) rats .…”

Section: Discussionmentioning

confidence: 99%

Protective effects of leonurine against ischemic stroke in mice by activating nuclear factor erythroid 2‐related factor 2 pathway

Xie

Zhang

et al. 2019

CNS Neurosci Ther

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Aims Leonurine has been shown to trigger antioxidant responses during ischemic stroke, and nuclear factor erythroid 2‐related factor 2 (Nrf‐2) imparts protective effects against oxidative injury. The present study has determined that leonurine prevents ischemic injury of brain tissues via Nrf‐2 pathway activation. Methods Male ICR mice and Nrf‐2−/− mice were subjected to permanent middle cerebral artery occlusion (pMCAO) and received leonurine treatment at 2 hours after pMCAO by intraperitoneal injection. Neurological deficit scores as well as infarct volume were assessed to determine the neuroprotective role of leonurine. Nrf‐2 was investigated using Western blotting and real‐time polymerase chain reaction (RT‐PCR) analysis to elucidate the neuroprotective mechanism of leonurine. Commercial kits were employed to determine reactive oxygen species (ROS), superoxide (SOD), catalase (CAT), glutathione peroxidase (GSH‐Px), malonaldehyde (MDA), and glutathione (GSH). Vascular endothelial growth factor (VEGF) was evaluated by Western blotting and RT‐PCR analysis, and VEGF was localized using immunofluorescence. Results The application of leonurine on ICR mice resulted in an improvement in neurological deficit scores and a reduction in infarct volume. Leonurine upregulated nuclear Nrf‐2 protein and increased total Nrf‐2 protein expression and mRNA levels. Leonurine regulated SOD, MDA, CAT, GSH, and GSH‐Px, and it significantly inhibited ROS production in ICR mice. Leonurine improved VEGF expression and increased VEGF expression in neurons, astrocytes, and endothelial cells. However, leonurine had no obvious beneficial effects on Nrf‐2−/− mice. Conclusions Leonurine exerted neuroprotective effects, promoted antioxidant responses, and upregulated VEGF expression by activating the Nrf‐2 pathway.

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Leonurine Exerts Antidepressant-Like Effects in the Chronic Mild Stress-Induced Depression Model in Mice by Inhibiting Neuroinflammation

Cited by 45 publications

References 44 publications

Plin4-Dependent Lipid Droplets Hamper Neuronal Mitophagy in the MPTP/p-Induced Mouse Model of Parkinson’s Disease

Plin4-Dependent Lipid Droplets Hamper Neuronal Mitophagy in the MPTP/p-Induced Mouse Model of Parkinson’s Disease

TLR4-NF-κB Signal Involved in Depressive-Like Behaviors and Cytokine Expression of Frontal Cortex and Hippocampus in Stressed C57BL/6 and ob/ob Mice

Protective effects of leonurine against ischemic stroke in mice by activating nuclear factor erythroid 2‐related factor 2 pathway

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