Soluble curcumin prevents cadmium cytotoxicity in primary rat astrocytes by improving a lack of GFAP and glucose-6-phosphate-dehydrogenase
AbstractCadmium (Cd) is a heavy metal which is widespread in various environmental components. Moreover several occupational diseases have the complications that are related to Cd cytotoxicity. Low doses of Cd exposure could induce pathogenetic disturbances in several sensitive cells as result of its long biological half-life and accumulation in vital tissue types. Prolonged Cd exposure was determined as main factor in accumulation of this metal ion over time in the liver, kidneys and neural tissue cells. The neurotoxic effect of Cd was presented in several articles which reported both in vivo and in vitro study. One of the main causes of Cd neurotoxicity is the ability of this ion to increase the permeability of the blood brain barrier. Despite a focus of attention on Cd cytotoxicity over the last few decades, the effect of Cd in neural tissue cells has been presented in a limited number of articles. The neurotoxic effect of Cd is accompanied by biochemical changes as well as a lack of functional activity of the central nervous system. Taking into account that the cytotoxic effect of Cd is associated with oxidative stress, inflammation and selective cell death, antioxidants could be used to protect neural tissue cells against both chronic and acute Cd exposure. Antioxidants protect diverse cell types against metal induced cytotoxicity. Curcumin is a natural polyphenol which exhibits antioxidant and anti-inflammatory effect. Soluble forms of cucrcumin can penetrate the blood brain barrier and protect neural tissue cells against detrimental effects of cytotoxic compounds. Glial cells are the most numerous cell population in CNS. Astrocytes possess the ability to protect the neuronal cells against cytotoxicity and maintain CNS functions. The cytoskeleton of astrocytes is constructed with glial fibrillary acidic protein (GFAP). GFAP is involved in essential functions of astrocytes and reflects astrocyte reactivity. The molecular mechanisms of the neurotoxic effect of Cd on glial cytoskeleton remain unknown. Primary astrocyte cell culture was used as model to assess the gliotoxic effect of Cd as well as the potency of low doses of soluble curcumin to ameliorate the neurotoxic effect of Cd. The obtained results demonstrated depletion of GFAP and glucose-6-phosphate-dehydrogenase (G6PD) in astrocytes treated with 10 µM Cd. The exposure to 5 µM curcumin ameliorated the expression both of GFAP and G6PD in Cd suppressed astrocytes. Moreover, low doses of soluble curcumin significantly prevented the detrimental effects of Cd on cell viability and indices of oxidative stress. The obtained results are evidence that soluble forms of curcumin improve astrocyte viability, cytoskeleton depletion and glucose utilization pathway. Thus, soluble curcumin possesses a neuroprotective effect directed on astrocyte cytoskeleton and metabolic energy production.
Acan, N. L., & Tezcan, E. F. (1995). Inhibition kinetics of sheep brain glutathione reductase by cadmium ion. Biochemical and Molecular Medicine, 54, 33–37.
Al-Jassabi, S., Ahmed, K. A., & Ameen, M. (2012). Antioxidant effect of curcumin against microcystin-LR-induced renal oxidative damage in Balb/c mice. Tropical Journal of Pharmaceutical Research, 11, 531–536.
Baiomy, A. A., & Mansour, A. A. (2016). Genetic and histopathological responses to cadmium toxicity in rabbit's kidney and liver: Protection by ginger (Zingiber officinale). Biological Trace Element Research, 170(2), 320–329.
Bereswill, S., Muñoz, M., Fischer, A., Plickert, R., Haag, L., Otto, B., Kühl, A., Loddenkemper, C., Göbel, U., & Heimesaat, M. (2010). Anti-inflammatory effects of resveratrol, curcumin and simvastatin in acute small intestinal inflammation. PLoS One, 12(5), 3–15.
Bhullar, K. S., Jha, A., Youssef, D., & Rupasinghe, H. P. (2013). Curcumin and its carbocyclic analogs: Structure-activity in relation to antioxidant and selected biological properties. Molecules, 18(5), 5389–5404.
Bradford, M. M. (1976). Rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Analytical Biochemistry, 72, 248–254.
Cao, Y., Chen, A., & Radcliffe, J. (2009). Postnatal cadmium exposure, neurodevelopment, and blood pressure in children at 2, 5, and 7 years of age. Environmental Health Perspectives, 117(10), 1580–1586.
Chang, C. Z., Wu, S. C., Lin, C. L., & Kwan, A. L. (2015). Curcumin, encapsulated in nano-sized PLGA, down-regulates nuclear factor κB (p65) and subarachnoid hemorrhage induced early brain injury in a rat model. Brain Research, 1608, 215–224.
Ciesielski, T. H., Schwartz, J., Bellinger, D. C., Hauser, R., Amarasiriwardena, C., Sparrow, D., & Wright, R. O. (2018). Iron-processing genotypes, nutrient intakes, and cadmium levels in the normative aging study: Evidence of sensitive subpopulations in cadmium risk assessment. Environment International, 119, 527–535.
Ciesielski, T., Bellinger, D. C., Schwartz, J., Hauser, R., & Wright, R. O. (2013). Associations between cadmium exposure and neurocognitive test scores in a cross-sectional study of US adults. Environmental Health Perspectives, 16(1), 7–19.
Ciesielski, T., Weuve, J., Bellinger, D. C., Schwartz, J., Lanphear, B., & Wright, R. O. (2012). Cadmium exposure and neurodevelopmental outcomes in U.S. children. Environmental Health Persectives, 120(5), 758–763.
Eng, L. F, Ghirnikar, R. S., & Lee, Y. L. (2000). Glial fibrillary acidic protein: GFAP-thirty-one years (1969–2000). Neurochemical Research, 25(9–10), 1439–1451.
Falnoga, I., Tusek-Znidaric, M., Horvat, M., & Stegnar, P. (2000). Mercury, selenium, and cadmium in human autopsy samples from Idrija residents and mercury mine workers. Environmental Research, 84(3), 211–218.
Fattori, V., Pinho-Ribeiro, F. A., Borghi, S. M., Alves-Filho, J. C., Cunha, T. M., Cunha, F. Q., Casagrande, R., & Verri, W. A. (2015). Curcumin inhibits superoxide anion-induced pain-like behavior and leukocyte recruitment by increasing Nrf2 expression and reducing NF-κB activation. Inflammation Research, 64(12), 993–1003.
Gullo, F., Ceriani, M., Aloia, A., Wanke, E., Constanti, A., Costa, B., & Lecchi, M. (2017). Plant polyphenols and exendin-4 prevent hyperactivity and TNF-a release in LPS-treated in vitro neuron/astrocyte/microglial networks. Frontiers in Neuroscience, 11, 1502–1513.
Guzyk, M. M., Tykhomyrov, A. A., & Nedzvetsky, V. S. (2016). Poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors reduce reactive gliosis and improve angiostatin levels in retina of diabetic rats. Neurochemical Research, 41(10), 2526–2537.
Hsu, F. T., Liu, Y. C., Liu, T. T., & Hwang, J. J. (2015). Curcumin sensitizes hepatocellular carcinoma cells to radiation via suppression of radiation-induced NF-κB activity. BioMed Research International, 215, 363–370.
Huang, Y., Chao, K. S., Liao, H., & Chen, Y. (2013). Targeting sonic hedgehog signaling by compounds and derivatives from natural products. Evidence-Based Complementary and Alternative Medicine, 74, 85–97.
Jeong, E. M., Moon, C. H., Kim, C. S., Lee, S. H., Baik, E. J., Moon, C. K., & Jung, Y. S. (2004). Cadmium stimulates the expression of ICAM-1 via NF-kappaB activation in cerebrovascular endothelial cells. Biochemical and Biophysical Research Communications, 320, 887–892.
Jung, Y. S., Jeong, E. M., Park, E. K., Kim, Y. M., Sohn, S., Lee, S. H., Baik, E. J., & Moon, C. H. (2008). Cadmium induces apoptotic cell death through p38 MAPK in brain microvessel endothelial cells. European Journal of Pharmacology, 578, 11–18.
Kamphuis, W., Kooijman, L., Orre, M., Stassen, O., Pekny, M., & Elly, M. H. (2015). GFAP and vimentin deficiency alters gene expression in astrocytes and microglia in wild-type mice and changes the transcriptional response of reactive glia in mouse model for Alzheimer’s disease. Glia, 63(6), 201–218.
Kutluay, S. B., Doroghazi, J., Roemer, M. E., & Triezenberg, S. J. (2008). Curcumin inhibits herpes simplex virus immediate-early gene expression by a mechanism independent of p300/CBP histone acetyltransferase activity. Virology, 373, 239–247.
Lee, J. Y., Tokumoto, M., Hattori, Y., Fujiwara, Y., Shimada, A., & Satoh, M. (2016). Different regulation of p53 expression by cadmium exposure in kidney, liver, intestine, vasculature, and brain astrocytes. Toxicology Research, 32(1), 73–80.
Liu, C., Cui, G., Zhu, M., Kang, X., & Guo, H. (2014). Neuroinflammation in Alzheimer's disease: Chemokines produced by astrocytes and chemokine receptors. International Journal of Clinical and Experimental Pathology, 7(12), 8342–8355.
Liu, L., Sun, L., Wu, Q., Guo, W., Li, L., Chen, Y., Li, Y., Gong, C., Qian, Z., & Wei, Y. (2013). Curcumin loaded polymeric micelles inhibit breast tumor growth and spontaneous pulmonary metastasis. International Journal of Pharmaceutics, 443(1–2), 175–182.
Maele-Fabry, G., Lombaert, N., & Lison, D. (2016). Dietary exposure to cadmium and risk of breast cancer in postmenopausal women: A systematic review and meta-analysis. Environment International, 86, 1–13.
Marini, E., Di Giulio, M., Magi, G., Di Lodovico, S., Cimarelli, M. E., Brenciani, A., Nostro, A., Cellini, L., & Facinelli, B. (2018). Curcumin, an antibiotic resistance breaker against a multiresistant clinical isolate of Mycobacterium abscessus. Phytotherapy Research, 32(3), 488–495.
Mori, H., Sasaki, G., Nishikawa, M., & Hara, M. (2015). Effects of subcytotoxic cadmium on morphology of glial fibrillaryacidic protein network in astrocytes derived from murine neuralstem/progenitor cells. Environmental Toxicology and Pharmacology, 40, 639–644.
Nair, A. R., Degheselle, O., Smeets, K., Van Kerkhove, E., & Cuypers, A. (2013). Cadmium-induced pathologies: Where is the oxidative balance lost (or not). International Journal of Molecular Sciences, 14, 6116–6143.
Nedzvetsky, V. S., Tuzcu, M., Yasar, A., Tikhomirov, A. A., & Baydas, G. (2006). Effects of vitamin E against aluminum neurotoxicity in rats. Biochemistry (Moscow), 71(3), 239–244.
Nedzvetsky, V., Agca, C. A., & Kyrychenko, S. (2017). Neuroprotective effect of curcumin on LPS-activated astrocytes is related to the prevention of GFAP and NF-κB upregulation. Neurophysiology, 49(4), 305–307.
Neuhaus, W., Gaiser, F., Mahringer, A., Franz, J., Riethmüller, C., & Förster, C. (2014). The pivota lrole of astrocytes in an in vitro stroke model of the blood-brain barrier. Frontiers in Cellular Neuroscience, 8, 352–365.
Nilesh, M. Kalariya, A., Nancy, K., Wills, B., Kota, V., Ramana, C., Satish, K., Srivastava, C., Frederik, J. G., & Van Kuijk, M. (2009). Cadmium-induced apoptotic death of human retinal pigment epithelial cells is mediated by MAPK pathway. Experimental Eye Research, 89, 494–502.
Ninkov, M., Popov, A., Aleksandrov, A., Demenesku, J., Mirkov, I., Mileusnic, D., Petrovic, A., Grigorov, I., Zolotarevski, L., Tolinacki, M., Kataranovski, D., Brceski, I., & Kataranovski, M. (2015). Toxicity of oral cadmium intake: Impact on gut immunity. Toxicology Letters, 237, 89–99.
Owens, R., Grabert, K., Davies, C. L., Alfieri, A., Antel, J. P., Healy, L. M., & McColl, B. W. (2017). Divergent neuroinflammatory regulation of microglial TREM expression and involvement of NF-κB. Frontiers in Cellular Neuroscience, 11, 56–68.
Phuagkhaopong, S., Ospondpant, D., Kasemsuk, T., Sibmooh, N., Soodvilai, S., Power, C., & Vivithanaporn, P. (2017). Cadmium-induced IL-6 and IL-8 expression and release from astrocytes are mediated by MAPK and NF-κB pathways. Neurotoxicology, 60, 82–91.
Poliandri, A. H., Cabilla, J. P., Velardez, M. O., Bodo, C. C., & Duvilanski, B. H. (2003). Cadmium induces apoptosis in anterior pituitary cells that can be reversed by treatment with antioxidants. Toxicology and Applied Pharmacology, 190, 17–24.
Rajitha, B., Belalcazar, A., Nagaraju, G. P., Shaib, W. L., Snyder, J. P., Shoji, M., Pattnaik, S., Alam, A., & El-Rayes, B. F. (2016). Inhibition of NF-κB translocation by curcumin analogs induces G0/G1 arrest and downregulates thymidylate synthase in colorectal cancer. Cancer Letters, 373(2), 227–233.
Shekh, K., Tang, S., Niyogi, S., & Hecker, M. (2017). Expression stability and selection of optimal reference genes for gene expression normalization in early life stage rainbow trout exposed to cadmium and copper. Aquatic Toxicology, 190, 217–227.
Shukla, G. S., Hussain, T., Srivastava, R. S., & Chandra, S. V. (1989). Glutathione peroxidase and catalase in liver, kidney, testis and brain regions of rats following cadmium exposure and subsequent withdrawal. Industrial Health, 27, 59–69.
Strasser, E. M., Wessner, B., Manhart, N., & Roth, E. (2005). The relationship between the anti-inflammatory effects of curcumin and cellular glutathione content in myelomonocytic cells. Biochemistry Pharmacology, 70, 552–559.
Tandon, S. K., Singh, S., Prasad, S., Khandekar, K., Dwivedi, V. K., Chatterjee, M., & Mathur, N. (2003). Reversal of cadmium induced oxidative stress by chelating agent, antioxidant or their combination in rat. Toxicology Letters, 145, 211–217.
Taylor, M., Moore, S., Mourtas, S., Niarakis, A., Re, F., Zona, C., La Ferla, B., Nicotra, F., Masserini, M., Antimisiaris, S. G., Gregori, M., & Allsop, D. (2011). Effect of curcumin-associated and lipid ligand-functionalized nanoliposomes on aggregation of the Alzheimer's Aβ peptide. Nanomedicine, 7(5), 541–550.
Tu, X. K., Yang, W. Z., Chen, J. P., Chen, Y., Ouyang, L. Q., Xu, Y. C., & Shi, S. S. (2014). Curcumin inhibits TLR2/4-NF-κB signaling pathway and attenuates brain damage in permanent focal cerebral ischemia in rats. Inflammation, 37(5), 1544–1551.
Ullah, F., Liang, A., Rangel, A., Gyengesi, E., Niedermayer, G., & Münch, G. (2017). High bioavailability curcumin: an anti-inflammatory and neurosupportive bioactive nutrient for neurodegenerative diseases characterized by chronic neuroinflammation. Archives of Toxicology, 91(4), 1623–1634.
Wang, L., Shen, Y., Song, R., Sun, Y., Xu, J., & Xu, Q. (2009). An anticancer effect of curcumin mediated by down-regulating phosphatase of regenerating liver-3 expression on highly metastatic melanoma cells. Molecular Pharmacology, 76, 1238–2178.
Yang, C. S., Tzou, B. C., Liu, Y. P., Tsai, M. J., Shyue, S. K., & Tzeng, S. F. (2008). Inhibition of cadmium-induced oxidative injury in rat primary astrocytes by the addition of antioxidants and the reduction of intracellular calcium. Journal of Cellular Biochemistry, 103, 825–834.
Yogosawa, S., Yamada, Y., Yasuda, S., Sun, Q., Takizawa, K., & Sakai, T. (2012). Dehydrozingerone, a structural analogue of curcumin, induces cell-cycle arrest at the G2/M phase and accumulates intracellular ROS in HT-29 human colon cancer cells. Journal Natural Products, 75(12), 2088–2093.
Yu, B., Changsheng, Y., Wenjun, Z., Ben, L., Hai, Q., Jing, M., Guangwei, X., Shuhua, W., Fang, L., Aschner, M., & Rongzhu, L. (2015). Differential protection of pre-versus post-treatment with curcumin, trolox, and N-acetylcysteine against acrylonitrile-induced cytotoxicity in primary rat astrocytes. Neurotoxicology, 51, 58–66.
Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons «Attribution» 4.0 License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.