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Minocycline Protects PC12 Cells Against Cadmium-Induced Neurotoxicity by Modulating Apoptosis

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Abstract

Cadmium (Cd) is a well-known heavy metal and a neurotoxic agent. Minocycline (Mino) is an anti-microbial agent with a lipophilic structure that crosses the blood–brain barrier and enters the cerebral tissue. In recent studies, Mino has been introduced as an antioxidant and anti-apoptotic chemical compound, and therefore, it was examined as a protective candidate against Cd-induced neurotoxicity. In this study, PC12 cells were exposed to Cd alone, or after being pre-treated with Mino. Initially, the cell viability and oxidative stress were analyzed using the MTT assay and fluorimetry, respectively. Then, Cd-induced apoptosis and Mino anti-apoptotic effect were evaluated in both intrinsic and extrinsic pathways using western blot analysis. Exposing PC12 cells to Cd for 24 h decreased cell viability and increased production of reactive oxygen species in comparison with the control group. Cd (35 μM) also elevated the level of caspase-8, Bax/Bcl-2, and caspase-3 proteins in the cells. Mino pre-treatment for 2 h (100 nM) increased the number of viable cells and decreased the production of reactive oxygen species, and the level of all apoptotic markers in comparison to Cd-treated cells. Considering all the evidence, it appears that Mino holds promising antioxidant and anti-apoptotic activity and can protect cells against Cd-induced oxidative stress and prevent apoptotic cell death.

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References

  1. Flora SJS, Agrawal S (2017) Arsenic, cadmium, and lead. In: Gupta R (ed) Reproductive and developmental toxicology. Elsevier, Hopkinsville, pp 537–566

    Chapter  Google Scholar 

  2. Kumar A, Pandey R, Siddiqi NJ, Sharma B (2019) Oxidative stress biomarkers of cadmium toxicity in mammalian systems and their distinct ameliorative strategy. J Appl Biotechnol 6:126–135. https://doi.org/10.15406/jabb.2019.06.00184

    Article  Google Scholar 

  3. Zhang H, Reynolds M (2019) Cadmium exposure in living organisms: a short review. Sci Total Env 678:761–767. https://doi.org/10.1016/j.scitotenv.2019.04.395

    Article  CAS  Google Scholar 

  4. Järup L, Åkesson A (2009) Current status of cadmium as an environmental health problem. Toxicol Appl Pharmacol 238:201–208

    Article  PubMed  Google Scholar 

  5. Nordberg GF (2004) Cadmium and health in the 21st Century – historical remarks and trends for the future. Biometals 17:485–489. https://doi.org/10.1023/B:BIOM.0000045726.75367.85

    Article  CAS  PubMed  Google Scholar 

  6. Fatima G, Raza AM, Hadi N et al (2019) Cadmium in human diseases: it’s more than just a mere metal. Indian J Clin Biochem 34:371–378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Rahimzadeh MR, Rahimzadeh MR, Kazemi S, Moghadamnia AA (2017) Cadmium toxicity and treatment: An update. Casp J Intern Med 8:135–145. https://doi.org/10.22088/cjim.8.3.135

    Article  Google Scholar 

  8. El-Kott AF, Alshehri AS, Khalifa HS et al (2020) Cadmium chloride induces memory deficits and hippocampal damage by activating the JNK/p66Shc/NADPH oxidase axis. Int J Toxicol 39:477–490. https://doi.org/10.1177/1091581820930651

    Article  CAS  PubMed  Google Scholar 

  9. Branca JJV, Morucci G, Pacini A (2018) Cadmium-induced neurotoxicity: Still much ado. Neural Regen Res 13:1879–1882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Malin AJ, Wright RO (2018) The developmental neurotoxicity of cadmium. Handbook of developmental neurotoxicology, 2nd edn. Elsevier, New York, pp 407–412

    Chapter  Google Scholar 

  11. Al Olayan EM, Aloufi AS, AlAmri OD, et al (2020) Protocatechuic acid mitigates cadmium-induced neurotoxicity in rats: role of oxidative stress, inflammation and apoptosis. Sci Total Env 723:.https://doi.org/10.1016/j.scitotenv.2020.137969

  12. Khan A, Ikram M, Muhammad T et al (2019) Caffeine modulates cadmium-induced oxidative stress, neuroinflammation, and cognitive impairments by regulating Nrf-2/HO-1 in vivo and in vitro. J Clin Med 8:680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Tabeshpour J, Mehri S, Shaebani Behbahani F, Hosseinzadeh H (2018) Protective effects of Vitis vinifera (grapes) and one of its biologically active constituents, resveratrol, against natural and chemical toxicities: a comprehensive review. Phytother Res 32:2164–2190. https://doi.org/10.1002/ptr.6168

    Article  CAS  PubMed  Google Scholar 

  14. Omidkhoda SF, Razavi BM, Hosseinzadeh H (2019) Protective effects of Ginkgo biloba L. against natural toxins, chemical toxicities, and radiation: a comprehensive review. Phytother Res 33:2821–2840. https://doi.org/10.1002/ptr.6469

    Article  CAS  PubMed  Google Scholar 

  15. Tavakkoli A, Ahmadi A, Razavi BM, Hosseinzadeh H (2017) Black Seed (Nigella Sativa) and its constituent Thymoquinone as an antidote or a protective agent against natural or chemical toxicities. Iran J Pharm Res IJPR 16:2–23

    PubMed  Google Scholar 

  16. Alavi MS, Fanoudi S, Ghasemzadeh Rahbardar M, et al (2020) An updated review of protective effects of rosemary and its active constituents against natural and chemical toxicities. Phyther Res ptr.6894. https://doi.org/10.1002/ptr.6894

  17. Metz LM, Li DKB, Traboulsee AL et al (2017) Trial of minocycline in a clinically isolated syndrome of Multiple Sclerosis. N Engl J Med 376:2122–2133. https://doi.org/10.1056/nejmoa1608889

    Article  CAS  PubMed  Google Scholar 

  18. Gunn GB, Mendoza TR, Garden AS et al (2020) Minocycline for symptom reduction during radiation therapy for head and neck cancer: a randomized clinical trial. Support Care Cancer 28:261–269. https://doi.org/10.1007/s00520-019-04791-4

    Article  PubMed  Google Scholar 

  19. Bonelli RM, Hödl AK, Hofmann P, Kapfhammer H-P (2004) Neuroprotection in Huntington’s disease: a 2-year study on minocycline. Int Clin Psychopharmacol 19:337–342

    Article  PubMed  Google Scholar 

  20. Verma DK, Singh DK, Gupta S et al (2018) Minocycline diminishes the rotenone induced neurotoxicity and glial activation via suppression of apoptosis, nitrite levels and oxidative stress. Neurotoxicology 65:9–21. https://doi.org/10.1016/j.neuro.2018.01.006

    Article  CAS  PubMed  Google Scholar 

  21. Popovic N, Schubart A, Goetz BD et al (2002) Inhibition of autoimmune encephalomyelitis by a tetracycline. Ann Neurol 51:215–223. https://doi.org/10.1002/ana.10092

    Article  CAS  PubMed  Google Scholar 

  22. Choi Y, Kim H-S, Shin KY et al (2007) Minocycline attenuates neuronal cell death and improves cognitive impairment in Alzheimer’s Disease models. Neuropsychopharmacology 32:2393–2404. https://doi.org/10.1038/sj.npp.1301377

    Article  CAS  PubMed  Google Scholar 

  23. Du Y, Ma Z, Lin S et al (2001) Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson’s disease. Proc Natl Acad Sci U S A 98:14669–14674. https://doi.org/10.1073/pnas.251341998

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. O’Dell JR, Blakely KW, Mallek JA et al (2001) Treatment of early seropositive rheumatoid arthritis: a two-year, double-blind comparison of minocycline and hydroxychloroquine. Arthritis Rheum 44:2235–2241

    Article  PubMed  Google Scholar 

  25. Lian HD, Ren B, Gao XW (2011) Effects of minocycline on expression of bcl-2, bax in early retinal neuropathy of diabetes in rats. Int J Ophthalmol 4:162–164. https://doi.org/10.3980/j.issn.2222-3959.2011.02.10

    Article  PubMed  PubMed Central  Google Scholar 

  26. Zhou YQ, Liu DQ, Chen SP et al (2018) Minocycline as a promising therapeutic strategy for chronic pain. Pharmacol Res 134:305–310

    Article  CAS  PubMed  Google Scholar 

  27. Bastos LFS, Prazeres JDM, Godin AM et al (2013) Sex-independent suppression of experimental inflammatory pain by minocycline in two mouse strains. Neurosci Lett 553:110–114. https://doi.org/10.1016/j.neulet.2013.08.026

    Article  CAS  PubMed  Google Scholar 

  28. Cho I-H, Chung YM, Park C-K et al (2006) Systemic administration of minocycline inhibits formalin-induced inflammatory pain in rat. Brain Res 1072:208–214. https://doi.org/10.1016/j.brainres.2005.12.039

    Article  CAS  PubMed  Google Scholar 

  29. Zhang G, Yu L, Chen Z-Y et al (2016) Activation of corticotropin-releasing factor neurons and microglia in paraventricular nucleus precipitates visceral hypersensitivity induced by colorectal distension in rats. Brain Behav Immun 55:93–104. https://doi.org/10.1016/j.bbi.2015.12.022

    Article  CAS  PubMed  Google Scholar 

  30. Kumar V, Singh BK, Chauhan AK et al (2016) Minocycline rescues from zinc-induced nigrostriatal dopaminergic neurodegeneration: biochemical and molecular iInterventions. Mol Neurobiol 53:2761–2777. https://doi.org/10.1007/s12035-015-9137-y

    Article  CAS  PubMed  Google Scholar 

  31. Zhang L, Xiao H, Yu X, Deng Y (2020) Minocycline attenuates neurological impairment and regulates iron metabolism in a rat model of traumatic brain injury. Arch Biochem Biophys 682:108302. https://doi.org/10.1016/j.abb.2020.108302

    Article  CAS  PubMed  Google Scholar 

  32. Guo J, Chen Q, Tang J et al (2015) Minocycline-induced attenuation of iron overload and brain injury after experimental germinal matrix hemorrhage. Brain Res 1594:115–124. https://doi.org/10.1016/j.brainres.2014.10.046

    Article  CAS  PubMed  Google Scholar 

  33. Zhao F, Wang J, Lu H et al (2020) Neuroprotection by walnut-derived peptides through autophagy promotion via Akt/mTOR signaling pathway against oxidative stress in PC12 cells. J Agric Food Chem 68:3638–3648. https://doi.org/10.1021/acs.jafc.9b08252

    Article  CAS  PubMed  Google Scholar 

  34. Peng S, Hou Y, Yao J, Fang J (2019) Neuroprotection of mangiferin against oxidative damage via arousing Nrf2 signaling pathway in PC12 cells. BioFactors 45:381–392. https://doi.org/10.1002/biof.1488

    Article  CAS  PubMed  Google Scholar 

  35. Mehri S, Abnous K, Mousavi SH et al (2012) Neuroprotective effect of crocin on acrylamide-induced cytotoxicity in PC12 cells. Cell Mol Neurobiol 32:227–235. https://doi.org/10.1007/s10571-011-9752-8

    Article  CAS  PubMed  Google Scholar 

  36. Ganguly K, Levänen B, Palmberg L et al (2018) Cadmium in tobacco smokers: a neglected link to lung disease? Eur Respir Rev 27:1–8. https://doi.org/10.1183/16000617.0122-2017

    Article  Google Scholar 

  37. Cankaya S, Cankaya B, Kilic U et al (2019) The therapeutic role of minocycline in Parkinson’s disease. Drugs Context 8:1–14. https://doi.org/10.7573/dic.212553

    Article  Google Scholar 

  38. Banik S, Akter M, Corpus Bondad SE et al (2019) Carvacrol inhibits cadmium toxicity through combating against caspase dependent/independent apoptosis in PC12 cells. Food Chem Toxicol 134:110835. https://doi.org/10.1016/j.fct.2019.110835

    Article  CAS  PubMed  Google Scholar 

  39. Binte Hossain KF, Rahman MM, Sikder MT et al (2018) Inhibitory effects of selenium on cadmium-induced cytotoxicity in PC12 cells via regulating oxidative stress and apoptosis. Food Chem Toxicol 114:180–189. https://doi.org/10.1016/j.fct.2018.02.034

    Article  CAS  PubMed  Google Scholar 

  40. Ben P, Zhang Z, Xuan C et al (2015) Protective effect of l-Theanine on cadmium-induced apoptosis in PC12 cells by inhibiting the mitochondria-mediated pathway. Neurochem Res 40:1661–1670. https://doi.org/10.1007/s11064-015-1648-4

    Article  CAS  PubMed  Google Scholar 

  41. López E, Arce C, Oset-Gasque MJ et al (2006) Cadmium induces reactive oxygen species generation and lipid peroxidation in cortical neurons in culture. Free Radic Biol Med 40:940–951. https://doi.org/10.1016/j.freeradbiomed.2005.10.062

    Article  CAS  PubMed  Google Scholar 

  42. Chen L, Xu B, Liu L et al (2011) Cadmium induction of reactive oxygen species activates the mTOR pathway, leading to neuronal cell death. Free Rad Biol Medi 50:624–632. https://doi.org/10.1016/j.freeradbiomed.2010.12.032

    Article  CAS  Google Scholar 

  43. Jiang B-P, Le L, Xu L-J, Xiao P-G (2014) Minocycline inhibits ICAD degradation and the NF-κB activation induced by 6-OHDA in PC12 cells. Brain Res 1586:1–11. https://doi.org/10.1016/j.brainres.2014.08.001

    Article  CAS  PubMed  Google Scholar 

  44. Algeciras-Schimnich A, Barnhart BC, Peter ME (2013) Apoptosis dependent and independent functions of caspases. In: Madame Curie Bioscience Database [Internet]. Landes Bioscience, Austin, pp 98–119

  45. Fulda S, Debatin K-M (2006) Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene 25:4798–4811. https://doi.org/10.1038/sj.onc.1209608

    Article  CAS  PubMed  Google Scholar 

  46. Wajant H (2002) The Fas signaling pathway: more than a paradigm. Science 296:1635–1636. https://doi.org/10.1126/science.1071553

    Article  CAS  PubMed  Google Scholar 

  47. Ospondpant D, Phuagkhaopong S, Suknuntha K et al (2019) Cadmium induces apoptotic program imbalance and cell cycle inhibitor expression in cultured human astrocytes. Env Toxicol Pharmacol 65:53–59. https://doi.org/10.1016/j.etap.2018.12.001

    Article  CAS  Google Scholar 

  48. Yuan Y, Zhang Y, Zhao S et al (2018) Cadmium-induced apoptosis in neuronal cells is mediated by Fas/FasL-mediated mitochondrial apoptotic signaling pathway w. Sci Rep 8:1–11. https://doi.org/10.1038/s41598-018-27106-9

    Article  CAS  Google Scholar 

  49. Lee CY, Su CH, Tsai PK et al (2018) Cadmium nitrate-induced neuronal apoptosis is protected by N-acetyl-L-cysteine via reducing reactive oxygen species generation and mitochondria dysfunction. Biomed Pharmacother 108:448–456. https://doi.org/10.1016/j.biopha.2018.09.054

    Article  CAS  PubMed  Google Scholar 

  50. Alian NS, Khodarahmi P, Naseh V (2018) The effect of cadmium on apoptotic genes mRNA expression of Bax and Bcl-2 in small intestine of rats. Iran J Pathol 13:408–414

    Google Scholar 

  51. Chouit Z, Djellal D, Haddad S et al (2021) Potentiation of the apoptotic signaling pathway in both the striatum and hippocampus and neurobehavioral impairment in rats exposed chronically to a low−dose of cadmium. Environ Sci Pollut Res 28:3307–3317. https://doi.org/10.1007/s11356-020-10755-7

    Article  CAS  Google Scholar 

  52. Wen S, Wang L, Zhang W, et al (2021) Induction of mitochondrial apoptosis pathway mediated through caspase-8 and c-Jun N-terminal kinase by cadmium-activated Fas in rat cortical neurons. Metallomics 13:.https://doi.org/10.1093/mtomcs/mfab042

  53. Wang X, Zhu S, Drozda M et al (2003) Minocycline inhibits caspase-independent and -dependent mitochondrial cell death pathways in models of Huntington’s disease. Proc Natl Acad Sci U S A 100:10483–10487. https://doi.org/10.1073/pnas.1832501100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kelly KJ, Sutton TA, Weathered N et al (2004) Minocycline inhibits apoptosis and inflammation in a rat model of ischemic renal injury. Am J Physiol Ren Physiol Ren Physiol 287:760–766. https://doi.org/10.1152/ajprenal.00050.2004

    Article  CAS  Google Scholar 

  55. Heo K, Cho YJ, Cho KJ et al (2006) Minocycline inhibits caspase-dependent and -independent cell death pathways and is neuroprotective against hippocampal damage after treatment with kainic acid in mice. Neurosci Lett 398:195–200. https://doi.org/10.1016/j.neulet.2006.01.027

    Article  CAS  PubMed  Google Scholar 

  56. Wang B, Lin W, Zhu H (2021) Minocycline improves the recovery of nerve function and alleviates blood-brain barrier damage by inhibiting endoplasmic reticulum in traumatic brain injury mice model. Eur J Inflamm 19:205873922110108. https://doi.org/10.1177/20587392211010898

    Article  CAS  Google Scholar 

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Acknowledgements

The authors are thankful to the Vice-Chancellor of Research, Mashhad University of Medical Sciences, for financial support. The results presented in this paper are part of a Pharm.D thesis.

Funding

This study was financially supported by a grant from the Vice-Chancellor of Research, Mashhad University of Medical Sciences (Grant number: 981440).

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Authors and Affiliations

  1. School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

    Mersedeh Shayan

  2. Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

    Soghra Mehri & Hossein Hosseinzadeh

  3. Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

    Soghra Mehri, Bibi Marjan Razavi & Hossein Hosseinzadeh

  4. Targeted Drug Delivery Research Center, Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

    Bibi Marjan Razavi

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  1. Mersedeh Shayan
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MSH did the research, analyzed the data, and wrote the paper. SM supervised, designed the experiments, verified the analytical methods, and checked the whole procedure and paper. BMR designed the experiments. HH supervised, conceived the original idea, and checked the whole procedure and paper.

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Correspondence to Soghra Mehri or Hossein Hosseinzadeh.

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Shayan, M., Mehri, S., Razavi, B.M. et al. Minocycline Protects PC12 Cells Against Cadmium-Induced Neurotoxicity by Modulating Apoptosis. Biol Trace Elem Res 201, 1946–1954 (2023). https://doi.org/10.1007/s12011-022-03305-4

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