Probucol inhibits LPS-induced microglia activation and ameliorates brain ischemic injury in normal and hyperlipidemic mice

Jung, Youn-Sang; Park, Jung Hwa; Kim, Hyunha; Kim, So Young; Hwang, Ji Young; Hong, Ki Whan; Bae, Sun Sik; Choi, Byung Tae; Lee, Sae-Won; Shin, Hwa Kyoung

doi:10.1038/aps.2016.51

Cited by 48 publications

(32 citation statements)

References 47 publications

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“…In response to LPS, n-3 LC-PUFA-supplemented mice display an anti-inflammatory SPM profile whereas n-3 LC-PUFA-deficient mice exhibit a pro-inflammatory SPM profile [69]. These results corroborate previous ones in vivo [171][172][173][174][175][176] and in vitro in macrophages [177,178] and microglia [179][180][181].…”

Section: Nutrition As a Factor Of Variation Of Spm Levelssupporting

confidence: 86%

Polyunsaturated Fatty Acid Metabolism in the Brain and Brain Cells

Joffre¹

2019

Feed Your Mind - How Does Nutrition Modulate Brain Function Throughout Life?

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Dietary polyunsaturated fatty acids (PUFAs) have gained more importance these last decades since they regulate the level of long-chain PUFAs (LC-PUFAs) in all cells and especially in brain cells. Because LC-PUFAs, especially those of the n-3 family, display both anti-inflammatory and pro-resolution properties, they play an essential role in neuroinflammation. Neuroinflammation is a hallmark of neurological disorders and requires to be tightly controlled or at least limited otherwise it can have functional consequences and negatively impact the quality of life and well-being of patients. LC-PUFAs exert these beneficial properties in part through the synthesis of specialized pro-resolving mediators (SPMs) that are involved in the resolution of inflammation and to the return of homeostasis. SPMs are promising relevant candidates to resolve brain inflammation and to contribute to neuroprotective functions and lead to novel therapeutics for brain inflammatory diseases. Here we present an overview of the origin and accumulation of PUFAs in the brain and brain cells and their conversion into SPMs that are involved in neuroinflammation and how nutrition induces variations in LC-PUFA and SPM levels in the brain and in brain cells.

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Section: Nutrition As a Factor Of Variation Of Spm Levelssupporting

confidence: 86%

Polyunsaturated Fatty Acid Metabolism in the Brain and Brain Cells

Joffre¹

2019

Feed Your Mind - How Does Nutrition Modulate Brain Function Throughout Life?

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“…Conversely, simvastatin inhibited phagocytosis in microglia in a cholesterolindependent manner [148] . Probucol, another lipid-lowering agent, inhibited microglial release of NO, PGE 2 , IL-1β and IL-6 by down-regulating the NF-κB, MAPK and AP-1 signaling pathways in LPS-stimulated primary mouse and BV2 microglia; the in vivo pre-administration of probucol reduced microglial production of pro-inflammatory mediators (iNOS, COX-2, IL-1, IL-6) and improved outcomes after MCAO [149] . Treatment with indomethacin, one of the non-steroidal antiinflammatory drugs, remarkably reduced the number of Iba-1 cells and microglia activation but increased neuroblast proliferation 7 d after stroke [150] .…”

Section: Potential Therapy Targeting Microglial Responsesmentioning

confidence: 98%

Regulation of microglial activation in stroke

et al. 2017

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When ischemic stroke occurs, oxygen and energy depletion triggers a cascade of events, including inflammatory responses, glutamate excitotoxicity, oxidative stress, and apoptosis that result in a profound brain injury. The inflammatory response contributes to secondary neuronal damage, which exerts a substantial impact on both acute ischemic injury and the chronic recovery of the brain function. Microglia are the resident immune cells in the brain that constantly monitor brain microenvironment under normal conditions. Once ischemia occurs, microglia are activated to produce both detrimental and neuroprotective mediators, and the balance of the two counteracting mediators determines the fate of injured neurons. The activation of microglia is defined as either classic (M1) or alternative (M2): M1 microglia secrete pro-inflammatory cytokines (TNFα, IL-23, IL-1β, IL-12, etc) and exacerbate neuronal injury, whereas the M2 phenotype promotes anti-inflammatory responses that are reparative. It has important translational value to regulate M1/M2 microglial activation to minimize the detrimental effects and/or maximize the protective role. Here, we discuss various regulators of microglia/macrophage activation and the interaction between microglia and neurons in the context of ischemic stroke.

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“…Neuroinflammatory injury is considered to be one of the main reasons that microglia cells aggravate the pathological process of depression (Zhang et al 2018). In particular, pro-inflammatory cytokines (such as IL-1β, TNF-α) not only affect the neural function but also induce secondary activation of microglia (Jung et al 2016;Zhang et al 2016). ASA Ⅵ also inhibited the LPS-induced increase in expression of IL-1β, TNF-α, iNOS, and IL-6 both in the hippocampus and prefrontal cortex.…”

Section: Discussionmentioning

confidence: 99%

The antidepressant effects of asperosaponin VI are mediated by the suppression of microglial activation and reduction of TLR4/NF-ĸB induced IDO expression

Zhang

et al. 2020

Preprint

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Aim: Indoleamine 2, 3-dioxygenase (IDO) is responsible for the progression of the kynurenine pathway, which has been implicated in the pathophysiology of inflammation-induced depression. It has been reported that asperosaponin Ⅵ (ASA Ⅵ) could play a neuroprotective role through anti-inflammatory and antioxidant. In this study, we examined the antidepressant effect of ASA Ⅵ in LPS-treated mice and further explored its molecular mechanism by insight into the microglial kynurenine pathway. Methods: To produce the model, lipopolysaccharide (LPS) (0.83 mg/kg) was administered intraperitoneally to mice. The mice received ASA Ⅵ (10 mg/kg, 20mg/kg, 40mg/kg and 80mg/kg, i.p.) thirty minutes prior to LPS injection. Depressive-like behaviors were evaluated based on the duration of immobility in the forced swim test. Microglial activation and inflammatory cytokines were detected by immunohistochemistry, real-time PCR and ELISA. The TLR4/NF-ĸB signaling pathway and the expression of IDO, GluA2, and CamKIIβ were measured by western blotting. Results: ASA Ⅵ demonstrated significant antidepressant activity in the presence of LPS on immobility and latency times in the forced swim test. The LPS-induced activation of microglia and inflammatory response were inhabited by ASA Ⅵ in a dose-dependent manner. TLR4/NF-κB signaling pathway also was suppressed by ASA Ⅵ in the hippocampus and prefrontal cortex of LPS-treated mice. Furthermore, ASA Ⅵ inhibited the increase in IDO protein expression and normalized the aberrant glutamate transmission in the hippocampus and prefrontal cortex as a result of LPS administration. Conclusion: Our results propose a promising antidepressant effect for ASA Ⅵ possibly through the downregulation of IDO expression and normalization of the aberrant glutamate transmission. This remedying effect of ASA Ⅵ could be attributed to suppress microglia-mediated neuroinflammatory response via inhibiting the TLR4/NF-κB signaling pathway.

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Probucol inhibits LPS-induced microglia activation and ameliorates brain ischemic injury in normal and hyperlipidemic mice

Cited by 48 publications

References 47 publications

Polyunsaturated Fatty Acid Metabolism in the Brain and Brain Cells

Polyunsaturated Fatty Acid Metabolism in the Brain and Brain Cells

Regulation of microglial activation in stroke

The antidepressant effects of asperosaponin VI are mediated by the suppression of microglial activation and reduction of TLR4/NF-ĸB induced IDO expression

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