p53 Mediates autophagy activation and mitochondria dysfunction in kainic acid-induced excitotoxicity in primary striatal neurons

Dong, Xiao-Xia; Wang, Y.R.; Qin, Shu Kui; Liang, Zhong‐Qin; Liu, Baohua; Qin, Zheng‐Hong; Wang, Y.

doi:10.1016/j.neuroscience.2012.01.018

Cited by 44 publications

(41 citation statements)

References 57 publications

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“…Our previous studies suggested that NF-κB pathway contributed to glutamate receptor-mediated excitotoxicity [26,27]. Our studies have also demonstrated that QA activates apoptosis and autophagy, evidenced by increases in the expression of pro-apoptotic proteins and autophagy regulatory proteins [19].…”

Section: Introductionsupporting

confidence: 57%

“…QA can prevail cellular redox homeostatis and ROS levels [17]. For these reasons, QA is widely used not only as a chemical inducer of the HD model but also as a selective NMDA receptor agonist to evaluate the excitotoxic mechanisms involved in the progression of neuronal degeneration and cell death in various CNS conditions [18][19][20][21][22][23][24].…”

Section: Introductionmentioning

confidence: 99%

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Microglia activation contributes to quinolinic acid-induced neuronal excitotoxicity through TNF-α

et al. 2017

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It has been reported that activation of NF-κB is involved in excitotoxicity; however, it is not fully understood how NF-κB contributes to excitotoxicity. The aim of this study is to investigate if NF-κB contributes to quinolinic acid (QA)-mediated excitotoxicity through activation of microglia. In the cultured primary cortical neurons and microglia BV-2 cells, the effects of QA on cell survival, NF-κB expression and cytokines production were investigated. The effects of BV-2-conditioned medium (BCM) on primary cortical neurons were examined. The effects of pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-κB, and minocycline (MC), an inhibitor of microglia activation, on QA-induced excitotoxicity were assessed. QA-induced NF-κB activation and TNF-α secretion, and the roles of TNF-α in excitotoxicity were studied. QA at the concentration below 1 mM had no apparent toxic effects on cultured primary neurons or BV-2 cells. However, addition of QA-primed BCM to primary neurons did aggravate QA-induced excitotoxicity. The exacerbation of QA-induced excitotoxicity by BCM was partially ameliorated by inhibiting NF-κB and microglia activation. QA induced activation of NF-κB and upregulation of TNF-α in BV-2 cells. Addition of recombinant TNF-α mimicked QA-induced excitotoxic effects on neurons, and neutralizing TNF-α with specific antibodies partially abolished exacerbation of QA-induced excitotoxicity by BCM. These studies suggested that QA activated microglia and upregulated TNF-α through NF-κB pathway in microglia. The microglia-mediated inflammatory pathway contributed, at least in part, to QA-induced excitotoxicity.

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Section: Introductionsupporting

confidence: 57%

Section: Introductionmentioning

confidence: 99%

Microglia activation contributes to quinolinic acid-induced neuronal excitotoxicity through TNF-α

et al. 2017

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“…Increased numbers of autophagosomes have been described in different in vitro situations of excitotoxicity such as long-term treatment and/or high doses of NMDA 30,31 or Ka, 19 or exposure to a specific glutamate uptake inhibitor. 32 The injection of toxic doses of Ka into the adult mice hippocampus 20,33 or striatum 34,35 also induces autophagy.…”

Section: Discussionmentioning

confidence: 99%

“…60,61 It has also been shown that 3-MA can suppress the mitochondrial ROS production associated with Ka-induced excitotoxicity in cultured striatal neurons. 19 Enhanced autophagy may therefore contribute to oxidative stress induced by KaHx. We showed also a protective effect of inhibiting lysosomal activity with E64/ PepA suggesting that autophagic degradation is involved as well in neuronal death.…”

Section: (E and F)mentioning

confidence: 99%

“…For the reasons explained above and in Results, we selected as excitotoxin, kainate (Ka), a potent glutamate receptor agonist that targets non-NMDA (N-methyl-D-aspartate) glutamate receptors. Furthermore, Ka induces both excitotoxicity 17,18 and autophagy in vitro 19 and in vivo. 18,20 Ka treatment was applied in a hypoxic environment since hypoxia can exacerbate the mitochondrial production of reactive oxygen species (ROS), especially H 2 O 2 and O 2 -, which can regulate autophagy, [21][22][23][24][25] or inversely autophagy can contribute to oxidative stress by its involvement in ROS accumulation.…”

Section: Introductionmentioning

confidence: 98%

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