Sodium para-aminosalicylic acid ameliorates lead-induced hippocampal neuronal apoptosis by suppressing the activation of the IP3R-Ca2+-ASK1-p38 signaling pathway

Li, Zhao-cong; Wang, Leilei; Zhao, Yue-song; Peng, Dongjun; Chen, Jing; Jiang, Si-yang; Zhao, Lin; Aschner, Michael; Li, Shaojun; Jiang, Yue-Ming

doi:10.1016/j.ecoenv.2022.113829

Cited by 8 publications

(5 citation statements)

References 49 publications

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“…Our previous studies showed that PAS-Na reduced Pb-induced ultrastructural damage in the hippocampus and afforded neuroprotection. The IP3R-Ca 2+ -ASK1-p38 signaling pathway has also been shown to mediate Pb-induced apoptosis in hippocampal neurons, and PAS-Na ameliorated this effect [ 58 ]. Besides, we found that PAS-Na may antagonize the neurotoxic effects of lead exposure through the expression of the SIRT1/HMGB1/NF-κB pathway and BDNF [ 59 ].…”

Section: Discussionmentioning

confidence: 99%

Protective Effects of Sodium Para-Aminosalicylic Acid on Lead and Cadmium Co-Exposure in SH-SY5Y Cells

et al. 2023

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Background: Combined exposure to lead and cadmium is common in occupational environments. However, the effects of co-exposure to Pb-Cd on neurotoxicity have not been fully clarified. Sodium para-aminosalicylic acid (PAS-Na) has previously been shown to protect neurons from Pb-induced toxicity. This study aimed to investigate the beneficial effect of PAS-Na against co-exposure to Pb-Cd-induced neurodegeneration in SH-SY5Y cells. Methods: The MTT assay was used to detect the effects of Pb and Cd alone, or in combination, on SH-SY5Y cell survival. The effects of Pb and Cd alone or in combination on oxidative stress were assessed by reactive oxygen species (ROS) level. Nrf2, the master switch for antioxidant responses, was detected by immunofluorescence. Protein expression levels of PI3K, Akt, p-Akt, Nrf2 and HO-1 were determined by Western blot analysis. Results: MTT assay results established that the survival rate of SH-SY5Y cells was not significantly affected by exposure to 1 μmol/L lead, 0.25 μmol/L cadmium, and 1-fold Pb-Cd mixture (1 μmol/L Pb + 0.25 μmol/L Cd), while 10-fold Pb-Cd combined exposure (10 μmol/L Pb + 2.5 μmol/L Cd) significantly reduced the survival rate of SH-SY5Y cells. Combined Pb-Cd exposure significantly increased intracellular ROS levels, and N-Acetyl-L-cysteine (NAC) treatment in the 10 μmol/L Pb + 2.5 μmol/L Cd group significantly decreased ROS expression levels, attenuating the levels of oxidative stress. Protein expression of PI3K and p-Akt significantly decreased in the 10 μmol/L Pb + 2.5 μmol/L Cd group, while the expression of PI3K and p-Akt protein increased after PAS-Na intervention. Immunofluorescence analysis showed that levels of Nrf2 in the nucleus increased in the 10 μmol/L Pb + 2.5 μmol/L Cd group, along with Nrf2 protein levels, suggesting that Nrf2 was translocated from the cytoplasm into the nucleus upon combined Pb-Cd exposure. In addition, HO-1 protein expression level, a downstream gene product of Nrf2, was increased. In response to NAC intervention, HO-1 protein expression levels significantly decreased. PAS-Na had the same intervention effect as NAC. Conclusion: Combined exposure to Pb-Cd induced oxidative stress and cytotoxicity in SH-SY5Y cells. PAS-Na displayed antagonistic effects on neurodegenerative changes induced by combined Pb-Cd exposure; hence, it may afford a novel treatment modality for exposure to these metals.

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Section: Discussionmentioning

confidence: 99%

Protective Effects of Sodium Para-Aminosalicylic Acid on Lead and Cadmium Co-Exposure in SH-SY5Y Cells

et al. 2023

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“…The rats were stained with Pb acetate (10 mg/kg) for 4 weeks, and treated with PAS-Na (80, 160, 240 mg/kg) for 2 weeks. It was found that the Pb in hippocampus of rats was significantly reduced by PAS-Na, suggesting that PAS-Na can promote the excretion of Pb in hippocampus of rats (Li et al, 2022). The results of our study showed that PAS-Na significantly increased murine urinary Pb levels, demonstrating a statistically significant difference compared with the control group.…”

Section: Discussionmentioning

confidence: 99%

“…Increased Pb burden in Pb-exposed workers has also been shown to increase Cu levels (Anetor et al, 2002). Pb exposure for 4 weeks significantly increased Pb content in rat hippocampus, and treatment with PAS-Na (80, 160, and 240 mg/kg) for 2 weeks significantly reduced hippocampal Pb levels (Li et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

“…Pb can also activate the ERK1/2-p90RSK/NF-κB pathway and increase the level of the inflammatory cytokines, IL-1β, in rat hippocampus. PAS-Na can restore or ameliorate Pb-induced learning and memory deficits, secondary to reduction in hippocampal Pb levels and induction of anti-inflammatory effects (Lu et al, 2022; Li et al, 2022; Zhao et al, 2022). Therefore, herein, we investigated the effects of PAS-Na on the excretion of Pb, Cu, and Mn from brain, blood, and urine of mice exposed to Pb for a short-term, to provide a scientific basis for the clinical application of PAS-Na in the treatment of Pb poisoning.…”

Section: Introductionmentioning

confidence: 99%

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Effects of sodium para-aminosalicylic acid on chelation treatment in Pb-exposed mice

Liang

Fang

et al. 2023

Toxicol Ind Health

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Lead (Pb) is a corrosion-resistant, heavy, non-ferrous metal. Several metal chelators have been used for the treatment of Pb poisoning. However, the efficacy of sodium para-aminosalicylic acid (PAS-Na) in enhancing Pb excretion has yet to be fully characterized. Healthy male mice (90) were divided into six groups, the normal control group was intraperitoneally (i.p.) injected with saline and the remaining group of mice i.p. 120 mg/kg Pb acetate. Four hour later, mice were subcutaneously (back) injected (s.c.) with (80, 160, 240 mg/kg) PAS-Na or 240 mg/kg edetate calcium disodium (CaNa2EDTA) or an equivalent amount of saline, once per day for 6 days. After 24-h urine sample collections, the animals were anesthetized with 5% chloral hydrate and sacrificed in batches on the 2nd, 4th, or 6th day. Levels of Pb [including manganese (Mn) and copper (Cu)] in the urine, whole blood, and brain tissues were analyzed by graphite furnace atomic absorption spectrometry. The results showed that Pb exposure increased its levels in urine and blood, and PAS-Na treatment may afford antagonistic effect on Pb poisoning, suggesting that PAS-Na is a potentially effective treatment to promote excretion of Pb.

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“…C57BL/6 mice (18 days pregnant) were anesthetized with 1.2% Avertin, and fetal mice were extracted via laparotomy. Subsequently, hippocampal neuronal cells were obtained from fetal mice brains, as previously described [40]. During the culturing period, the purity of hippocampal neuronal cells was characterized by immuno uorescence.…”

Section: Primary Hippocampal Neuron Culturementioning

confidence: 99%

The Role of TNF-R1-RIPK1/RIPK3 Signaling Pathway in Lead-Induced Necroptosis in the Hippocampus of Mice

Li,

Yang

et al. 2024

Preprint

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Lead (Pb), a dense, soft, blue-gray metal, is widely used in metallurgy, cables, storage batteries, pigments, and other industrial applications. Pb has been shown to cause hippocampal neurodegeneration. Necroptosis, a newly described cell death modality, is closely associated with neurodegenerative diseases. Whether Pb can cause programmed neuronal cell death and its mechanisms has yet to be characterized. Here, we explored the role of the TNF-R1-RIPK1/RIPK3 signaling pathway in necroptosis induced by Pb. Our results showed that Pb exposure elevated lead levels in murine whole blood and hippocampal tissue in a dose-response relationship. Protein expression levels of PARP, c-PARP, RIPK1, p-RIPK1, RIPK3, MLKL, and p-MLKL in the hippocampal tissues were elevated, while the protein expression of caspase-8 was decreased. Furthermore, Pb exposure reduced the survival rates in HT-22 cells and primary mouse hippocampal neurons, while increasing the protein expressions of RIPK1 and p-MLKL. Collectively, these novel findings suggest that the TNF-R1/RIPK1/RIPK3 signaling pathway mediates Pb-induced necroptosis in hippocampal neurons in mice.

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Sodium para-aminosalicylic acid ameliorates lead-induced hippocampal neuronal apoptosis by suppressing the activation of the IP3R-Ca2+-ASK1-p38 signaling pathway

Cited by 8 publications

References 49 publications

Protective Effects of Sodium Para-Aminosalicylic Acid on Lead and Cadmium Co-Exposure in SH-SY5Y Cells

Protective Effects of Sodium Para-Aminosalicylic Acid on Lead and Cadmium Co-Exposure in SH-SY5Y Cells

Effects of sodium para-aminosalicylic acid on chelation treatment in Pb-exposed mice

The Role of TNF-R1-RIPK1/RIPK3 Signaling Pathway in Lead-Induced Necroptosis in the Hippocampus of Mice

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