Differential effects of heavy metals on CCL2 release from human astrocytes

[Speaker] Norapat Rungreangplangkool:1
[Co-author] Suttinee Phuagkhaopong:2, Thitima Kasemsuk:3, Ruedeemars Yubolphan:2, Pornpun Vivithanaporn:2
1:Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, 2:Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, Thailand, 3:Faculty of Pharmaceutical Science, Burapha University, Chonburi, Thailand

Background: Nowadays heavy metal toxicity remains one of world public health concern. In addition to systemic toxicity, heavy metals are toxic to the central nervous system (CNS). Manganese induced Parkinson's like symptoms. Cadmium is associated with Alzheimer's disease and learning disability. Excessive copper is linked with Alzheimer's disease, Parkinson's disease and Wilson's disease. Intrathecal injection of magnesium also leads to neurodegeneration. Astrocytes are major glial cells in the CNS. In addition to their neuronal supportive roles, astrocytes also play an important role in neuroinflammation by releasing various cytokines and chemokines. Manganese and cadmium induced interleukin-6 and interleukin-8 release from astrocytes. C-C motif ligand 2 (CCL2), also known as monocyte chemoattractant protein 1 (MCP1), is a major chemokine released by astrocytes. CCL2 plays a role in the pathogenesis of Alzheimer's disease, HIV-associated dementia, multiple sclerosis, and ischemic brain injury. This study aims to compare the effects of several heavy metals including cadmium, copper, magnesium, manganese and nickel on CCL2 release from astrocytes.
Method: U-87 MG cells were exposed to heavy metals at 10 µM for 24 hours and CCL2 levels in supernatant were measured by ELISAs.
Results: CCL2 levels of cells treated with cadmium chloride and manganese chloride were 550% and 140% compared to mock-treated cells. Copper sulfate, magnesium chloride and nickel chloride at 10 µM have no effect on CCL2 expression. Cadmium chloride at 1 µM also induced CCL2 release by 3 folds. Because cadmium chloride at does higher than 10 µM was toxic to human astrocytes, the maximum test dose for cadmium is 10 µM. Manganese chloride at 100 µM also increased CCL2 release similar to 10 µM.
Conclusion: Cadmium has the highest stimulative effect on CCL2 release. The increased CCL2 levels could explain the association of cadmium and dementia. The reduction of CCL2 levels could be beneficial to reduce CNS toxicity by cadmium and manganese.

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