Astrocytic mobilization of glutathione peroxidase-1 contributes to the protective potential against cocaine kindling behaviors in mice via activation of JAK2/STAT3 signaling

Nhu, Huynh; Nguyen, Lan Thuy Ty; Shin, Eun Joo; Kim, Dae Joong; Jeong, Ji Hoon; Chung, Yoon Hee; Lei, Xin Gen; Sharma, Naveen; Jang, Choon‐Gon; Nabeshima, Toshitaka; Kim, Hyoung Chun

doi:10.1016/j.freeradbiomed.2018.12.027

Cited by 20 publications

(9 citation statements)

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“…Lcn2 secreted by activated microglia and astrocytes can further enhance the activation of M1 and A1 [39,40], and the activation of the JAK2-STAT3 pathway is also necessary in neuroin ammation involving the participation of microglia and astrocytes. Inhibiting the JAK2-STAT3 pathway can also reduce the reactivity of glial cells [41][42][43]. Therefore, combined with the in vivo experimental results, we hypothesize that there may be a connection between the Lcn2 and JAK2-STAT3 pathways in the activation of M1 and A1 after SCI.…”

Section: Discussionmentioning

confidence: 74%

Photobiomodulation Inhibits the Activation of Neurotoxic Microglia and Astrocytes Through Inhibiting the Crosstalk of Lcn2/JAK2-STAT3 after Spinal Cord Injury in Rats

Wang

Zuo

et al. 2021

Preprint

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BackgroundIn situ microglia and astrocytes begin to activate and participate in neuroinflammation after spinal cord injury (SCI), and the high expression of lipocalin 2 (Lcn2) and the activation of the Janus kinase-2 (JAK2)-signal transducer and activator of transcription-3 (STAT3) pathway promote the polarization of activated microglia and astrocytes towards the neurotoxic phenotype (M1 microglia and A1 astrocytes). We previously reported that photobiomodulation (PBM) can promote functional recovery by reducing neuroinflammation after SCI, but the mechanism of PBM on the microglia and astrocytes involved is still unclear. Therefore, the purpose of this study was to explore the role of the Lcn2 and JAK2-STAT3 pathways in the activation of M1 and A1 and the mechanism by which PBM may play a therapeutic role.MethodsPBM intervention was performed every day after the SCI model was established, and the activation of microglia and astrocytes was observed at different time points post injury (1, 3, 7, 14, 28 dpi). The level of tissue apoptosis, the number of surviving neurons, the recovery of motor function, the level of Lcn2 and the activation of JAK2-STAT3 were evaluated in the PBM group and the vehicle group. M1 and A1 cells were irradiated with PBM in vitro, and the JAK2-STAT3 pathway inhibitor cucurbitacin I, adenovirus transfection and recombinant Lcn2 protein were cotreated with PBM to explore the mechanism of the activation of M1 and A1 and the underlying effect of PBM.ResultsPBM inhibited the activation of neurotoxic microglia and astrocytes, decreased secondary inflammation and tissue apoptosis, increased the number of neurons retained, and promoted the recovery of motor function after SCI. The upregulation of Lcn2 and the activation of the JAK2-STAT3 pathway after SCI were suppressed by PBM. In vitro experiments also proved that PBM can inhibit the activation of M1 microglia and A1 astrocytes, and the effect is related to the level of Lcn2 and the activation of the JAK2-STAT3 pathway.ConclusionThe crosstalk of Lcn2/JAK2-STAT3 is involved in the activation of neurotoxic microglia and astrocytes after SCI, and this process can be alleviated by PBM.

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Section: Discussionmentioning

confidence: 74%

Photobiomodulation Inhibits the Activation of Neurotoxic Microglia and Astrocytes Through Inhibiting the Crosstalk of Lcn2/JAK2-STAT3 after Spinal Cord Injury in Rats

Wang

Zuo

et al. 2021

Preprint

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“…Activated astrocytes and microglia are found around dense amyloid plaques in the brains of AD patients [ 84 , 85 ]. GFAP and Iba-1 are markers of reactive astrocytes and microglia [ 86 , 87 ], respectively, which were downregulated in the hippocampus and cortex of 5xFAD+OABL mice compared with 5xFAD+vehicle mice, as shown by immunofluorescence and western blotting and ( Fig. 6 , Fig.…”

Section: Discussionmentioning

confidence: 99%

Cognitive enhancement and neuroprotective effects of OABL, a sesquiterpene lactone in 5xFAD Alzheimer's disease mice model

et al. 2022

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Alzheimer's disease (AD) is a neurodegenerative disease in which oxidative stress and neuroinflammation were demonstrated to be associated with neuronal loss and cognitive deficits. However, there are still no specific treatments that can prevent the progression of AD. In this study, a screening of anti-inflammatory hits from 4207 natural compounds of two different molecular libraries indicated 1,6- O,O -diacetylbritannilactone (OABL), a 1,10- seco -eudesmane sesquiterpene lactone isolated from the herb Inula britannica L., exhibited strong anti-inflammatory activity in vitro as well as favorable BBB penetration property. OABL reduced LPS-induced neuroinflammation in BV-2 microglial cells as assessed by effects on the levels of inflammatory mediators including NO, PGE 2 , TNF-α, iNOS, and COX-2, as well as the translocation of NF-κB. Besides, OABL also exhibited pronounced neuroprotective effects against oxytosis and ferroptosis in the rat pheochromocytoma PC12 cell line. For in vivo research, OABL (20 mg/kg B.W., i.p. ) for 21 d attenuated the impairments in cognitive function observed in 6-month-old 5xFAD mice, as assessed with the Morris water maze test. OABL restored neuronal damage and postsynaptic density protein 95 (PSD95) expression in the hippocampus. OABL also significantly reduced the accumulation of amyloid plaques, the Aβ expression, the phosphorylation of Tau protein, and the expression of BACE1 in AD mice brain. In addition, OABL attenuated the overactivation of microglia and astrocytes by suppressing the expressions of inflammatory cytokines, and increased glutathione (GSH) and reduced malondialdehyde (MDA) and super oxide dismutase (SOD) levels in the 5xFAD mice brain. In conclusion, these results highlight the beneficial effects of the natural product OABL as a novel treatment with potential application for drug discovery in AD due to its pharmacological profile.

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“…The sections were then immersed in a solution containing avidin–biotin peroxidase complex (Vector Laboratories) for 1 hour, and 3,3′‐diaminobenzidine was utilized as the chromogen. Digital images were acquired under an upright microscope (BX51; Olympus, Tokyo, Japan) using an attached digital microscope camera (DP72; Olympus) and an IBM PC …”

Section: Methodsmentioning

confidence: 99%

“…We recently suggested that the GPx‐1 gene has a protective potential against psychostimulant‐induced oxidative stress, and found that GPx‐1 plays a protective role in response to cocaine‐induced drug dependence . In addition, we proposed that the GPx‐1 gene could provide protection against cocaine‐induced neurotoxicity via interactive astrocytic modulation with Janus kinase (JAK)/the signal transducers and activators of transcription 3 (STAT3) …”

Section: Introductionmentioning

confidence: 99%

“…16 In addition, we proposed that the GPx-1 gene could provide protection against cocaine-induced neurotoxicity via interactive astrocytic modulation with Janus kinase (JAK)/the signal transducers and activators of transcription 3 (STAT3). 14 To determine the mechanism underlying these potential effects, in this study, we investigated whether σ-1 receptor might be a pharmacological target for GPx-1-mediated psychoprotection against cocaine-induced CPP. Toward this end, we employed GPx-1 knockout (GPx-1 KO) and GPx-1-overexpressing transgenic mice (GPx-1 TG) to gain a better understanding on the significance of GPx-1 gene in cocaine-induced CPP.…”

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confidence: 99%

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Glutathione peroxidase‐1 gene rescues cocaine‐induced conditioned place preference in mice by inhibiting σ‐1 receptor expression

Pham

Chung

Nhu

et al. 2019

Clin Exp Pharma Physio

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The aim of this study was to investigate whether the glutathione peroxidase‐1 gene (GPx‐1) affects cocaine‐induced conditioned place preference (CPP) using a mouse model. Cocaine‐induced CPP was accompanied by an increase in the level of σ‐1 receptor in the nucleus accumbens (NAc). This phenomenon was more pronounced in the GPx‐1 gene knockout (GPx‐1 KO) than in wild type (WT) mice. In contrast, the CPP and expression of σ‐1 receptor were much less pronounced in GPx‐1‐overexpressing transgenic (GPx‐1 TG) mice than non‐transgenic (non‐TG) mice. Treatment of the mice with , a σ‐1 receptor antagonist, significantly attenuated both cocaine‐induced CPP and c‐Fos‐immunoreactivity (c‐Fos‐IR) in WT and GPx‐1 KO mice, although the effects were more evident in the latter group. Despite the protective effects of on cocaine‐induced CPP and c‐Fos in non‐TG mice, there were no additional protective effects in cocaine‐treated GPx‐1 TG mice, indicating that the σ‐1 receptor is a critical target for GPx‐1‐mediated psychoprotective activity. Overall, our results suggest that GPx‐1 attenuates cocaine‐induced CPP via inhibition of σ‐1 receptor expression.

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Astrocytic mobilization of glutathione peroxidase-1 contributes to the protective potential against cocaine kindling behaviors in mice via activation of JAK2/STAT3 signaling

Cited by 20 publications

References 91 publications

Photobiomodulation Inhibits the Activation of Neurotoxic Microglia and Astrocytes Through Inhibiting the Crosstalk of Lcn2/JAK2-STAT3 after Spinal Cord Injury in Rats

Photobiomodulation Inhibits the Activation of Neurotoxic Microglia and Astrocytes Through Inhibiting the Crosstalk of Lcn2/JAK2-STAT3 after Spinal Cord Injury in Rats

Cognitive enhancement and neuroprotective effects of OABL, a sesquiterpene lactone in 5xFAD Alzheimer's disease mice model

Glutathione peroxidase‐1 gene rescues cocaine‐induced conditioned place preference in mice by inhibiting σ‐1 receptor expression

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