Fluoxetine-enhanced autophagy ameliorates early brain injury via inhibition of NLRP3 inflammasome activation following subarachnoid hemorrhage in rats

Li, Jianru; Xu, Hangzhe; Nie, Sheng; Peng, Yucong; Fan, Linfeng; Wang, Zhijiang; Wu, Cheng Hsien; Yan, Feng; Chen, Jing-yin; Gu, Chi; Wang, Chun; Chen, Jing-sen; Wang, Lin; Chen, Gao

doi:10.1186/s12974-017-0959-6

Cited by 70 publications

(60 citation statements)

References 55 publications

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“…Alcocer-Gómez posited that antidepressants containing fluoxetine show autophagy dependent-NLRP3-inflammasome inhibition in major depressive disorders ( 29 ). Fluoxetine can mitigate NLRP3 inflammasome activation through autophagy activation ( 30 ). In our study, Beclin-1 expression in A+C+P-FLX was increased (Figure 5B ).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Autophagy in Microglia Alters Depressive-Like Behavior via BDNF Pathway in Postpartum Depression

Tan

Jiang

et al. 2018

Front. Psychiatry

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Postpartum depression (PPD) is associated with mood disorders and elevated inflammation. Studies have evidenced the activation/inhibition of autophagy and excessive activation of microglia to have a close relationship with depression. C57 and microglia-specific autophagy-deficient mice (Cx3Cr1Cre/+ATG5loxp/loxp) were employed to establish the chronic unpredicted mild stress depression mice model from embryonic day 7 (E7) to embryonic day 16 (E16). Fluoxetine was administered for 3 weeks (commencing from 1 week after birth). Behavioral tests (open field, forced swimming, and sucrose preference tests) were implemented. Western blot and immunofluorescence staining were employed to assess the brain-derived neurotrophic factor (BDNF) expression level, autophagy-associated proteins, and inflammatory factors. Depressive behavior was reversed following fluoxetine treatment; this was evidenced via open field, sucrose preference, and forced swimming tests. Both BDNF and autophagy-associated proteins (ATG5, Beclin-1, and LC3II) were upregulated following fluoxetine treatment. Inflammatory factors including nuclear factor kappa B and inducible nitric oxide synthase were reduced while anti-inflammatory factor interleukin-10 (IL-10) was increased after fluoxetine treatment. Microglia-specific autophagy-deficient mice (Cx3Cr1Cre/+ATG5loxp/loxp) showed a curtailed autophagy level, higher inflammatory level, and reduced BDNF expression when compared with C57 mice. Autophagy inhibition in microglia contributes to inflammation, which further instigates PPD. Fluoxetine might mediate its antidepressant effect in PPD through the autophagic pathway while upregulating BDNF expression. In view of this, regulating BDNF in microglia is a potential novel therapy target for PPD.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Autophagy in Microglia Alters Depressive-Like Behavior via BDNF Pathway in Postpartum Depression

Tan

Jiang

et al. 2018

Front. Psychiatry

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“…The assessment of SAH grading score was performed at 24 h after SAH by an independent investigator blinded to the experimental group information as previously described [ 21 ]. Briefly, the basal cistern was divided into six segments that were scored from 0 to 3 according to the amounts of subarachnoid blood.…”

Section: Methodsmentioning

confidence: 99%

Aggf1 attenuates neuroinflammation and BBB disruption via PI3K/Akt/NF-κB pathway after subarachnoid hemorrhage in rats

Zhu

Enkhjargal

Huang

et al. 2018

J Neuroinflammation

127

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BackgroundNeuroinflammation and blood-brain barrier (BBB) disruption are two critical mechanisms of subarachnoid hemorrhage (SAH)-induced brain injury, which are closely related to patient prognosis. Recently, angiogenic factor with G-patch and FHA domain 1 (Aggf1) was shown to inhibit inflammatory effect and preserve vascular integrity in non-nervous system diseases. This study aimed to determine whether Aggf1 could attenuate neuroinflammation and preserve BBB integrity after experimental SAH, as well as the underlying mechanisms of its protective roles.MethodsTwo hundred forty-nine male Sprague-Dawley rats were subjected to the endovascular perforation model of SAH. Recombinant human Aggf1 (rh-Aggf1) was administered intravenously via tail vein injection at 1 h after SAH induction. To investigate the underlying neuroprotection mechanism, Aggf1 small interfering RNA (Aggf1 siRNA) and PI3K-specific inhibitor LY294002 were administered through intracerebroventricular (i.c.v.) before SAH induction. SAH grade, neurological score, brain water content, BBB permeability, Western blot, and immunohistochemistry were performed.ResultsExpression of endogenous Aggf1 was markedly increased after SAH. Aggf1 was primarily expressed in endothelial cells and astrocytes, as well as microglia after SAH. Administration of rh-Aggf1 significantly reduced brain water content and BBB permeability, decreased the numbers of infiltrating neutrophils, and activated microglia in the ipsilateral cerebral cortex following SAH. Furthermore, rh-Aggf1 treatment improved both short- and long-term neurological functions after SAH. Meanwhile, exogenous rh-Aggf1 significantly increased the expression of PI3K, p-Akt, VE-cadherin, Occludin, and Claudin-5, as well as decreased the expression of p-NF-κB p65, albumin, myeloperoxidase (MPO), TNF-α, and IL-1β. Conversely, knockdown of endogenous Aggf1 aggravated BBB breakdown, inflammatory response and neurological impairments at 24 h after SAH. Additionally, the protective roles of rh-Aggf1 were abolished by LY294002.ConclusionsTaken together, exogenous Aggf1 treatment attenuated neuroinflammation and BBB disruption, improved neurological deficits after SAH in rats, at least in part through the PI3K/Akt/NF-κB pathway.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1211-8) contains supplementary material, which is available to authorized users.

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“…Astrocyte activation and inflammation are closely associated with autophagic disorders (Hong, Liu, Zhang, Wu, & Hou, ; Li et al, ). Autophagy is a cellular process of degradation that eliminates aberrant cellular components and maintains cellular homeostasis (He & Klionsky, ).…”

Section: Resultsmentioning

confidence: 99%

“…Astrocyte activation and inflammation are closely associated with autophagic disorders (Hong, Liu, Zhang, Wu, & Hou, 2018;Li et al, 2017).…”

Section: Astrocyte Activation Is Associated With Decreased Autophagmentioning

confidence: 99%

Activation of G protein‐coupled receptor 30 protects neurons by regulating autophagy in astrocytes

Wang

Yue

et al. 2019

Glia

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Ischemic stroke leads to neuronal damage induced by excitotoxicity, inflammation, and oxidative stress. Astrocytes play diverse roles in stroke and ischemia‐induced inflammation, and autophagy is critical for maintaining astrocytic functions. Our previous studies showed that the activation of G protein‐coupled receptor 30 (GPR30), an estrogen membrane receptor, protected neurons from excitotoxicity. However, the role of astrocytic GPR30 in maintaining autophagy and neuroprotection remained unclear. In this study, we found that the neuroprotection induced by G1 (GPR30 agonist) in wild‐type mice after a middle cerebral artery occlusion was completely blocked in GPR30 conventional knockout (KO) mice but partially attenuated in astrocytic or neuronal GPR30 KO mice. In cultured primary astrocytes, glutamate exposure induced astrocyte proliferation and decreased astrocyte autophagy by activating mammalian target of rapamycin (mTOR) and c‐Jun N‐terminal kinase (JNK) and inhibiting p38 mitogen‐activated protein kinase (MAPK) pathway. G1 treatment restored autophagy to its basal level by regulating the p38 pathway but not the mTOR and JNK signaling pathways. Our findings revealed a key role of GPR30 in neuroprotection via the regulation of astrocyte autophagy and support astrocytic GPR30 as a potential drug target against ischemic brain damage.

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Fluoxetine-enhanced autophagy ameliorates early brain injury via inhibition of NLRP3 inflammasome activation following subarachnoid hemorrhage in rats

Cited by 70 publications

References 55 publications

Inhibition of Autophagy in Microglia Alters Depressive-Like Behavior via BDNF Pathway in Postpartum Depression

Inhibition of Autophagy in Microglia Alters Depressive-Like Behavior via BDNF Pathway in Postpartum Depression

Aggf1 attenuates neuroinflammation and BBB disruption via PI3K/Akt/NF-κB pathway after subarachnoid hemorrhage in rats

Activation of G protein‐coupled receptor 30 protects neurons by regulating autophagy in astrocytes

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