Acta Scientific Neurology (ASNE) (ISSN: 2582-1121)

Research Article Volume 3 Issue 9

Evidence of a Neuroprotective Function for Niclosamide in Human SH-SY5Y Neuroblastoma and Rat PC12 Neural Cells

Kevin C Bermea1, Edgar A Casillas2, Liza D Morales3, Laura L Valdez1, Brenda Bin Su1, Andrew Tsin1 and Benxu Cheng1*

1Department of Molecular Science, School of Medicine, The University of Texas Rio Grande Valley, United States of America
2Department of Physical Therapy, School of Health Professions, The University of Texas Health Science Center at San Antonio, United States of America
3Department of Human Genetics and the South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, United States of America

*Corresponding Author: Benxu Cheng, Department of Molecular Science, School of Medicine, The University of Texas Rio Grande Valley, United States of America.

Received: June 24, 2020; Published: August 31, 2020

×

Abstract

  Neurodegenerative disease is a debilitating and incurable condition that affects millions. It results in the loss of function and eventual death of neural cells. It has been established that exposure of model neuronal-derived cell lines to the proteasome inhibitor MG132 emulates in vitro neurodegeneration as evidenced by a marked decrease in protein degradation concomitant with an increase in aggregate intracellular ubiquitinated proteins and endoplasmic reticulum (ER) stress (via upregulation of CHOP/GADD153). Consequently, apoptosis ensues corresponding to the upregulation of p53, activation of caspase-3, cleavage of poly (ADP-ribose) polymerase (PARP), and DNA condensation/fragmentation. In this study, we investigated the potential neuroprotective function of niclosamide and its associated signaling mechanisms in SH-SY5Y and PC12 neural cells exposed to MG132. All markers of MG132-induced neurodegeneration, including the accumulation of ubiquitinated proteins, were prevented by exposure to niclosamide. In addition, niclosamide was shown to induce autophagy independently and to enhance autophagy induced by MG132. These results show that niclosamide may serve as a potential neuroprotective agent through its ability to inhibit proteasome dysfunction-induced protein ubiquitination.

Keywords: Neurodegeneration; Proteasome Dysfunction; Protein Ubiquitination; ER Stress; Apoptosis; Autophagy; Niclosamide; Neuroprotection

×

References

  1. Marras C., et al. “Prevalence of Parkinson's disease across North America”. NPJ Parkinson's Disease 4 (2018): 21-21.
  2. Martínez-Banaclocha MA. “N-acetyl-cysteine in the treatment of Parkinson’s disease. What are we waiting for?” Medical Hypotheses1 (2012): 8-12.
  3. Nedelsky NB., et al. “Autophagy and the ubiquitin-proteasome system: collaborators in neuroprotection”. Biochimica et Biophysica Acta12 (2008): 691-699.
  4. Lennox, G., et al. “Anti-ubiquitin immunocytochemistry is more sensitive than conventional techniques in the detection of diffuse Lewy body disease”. Journal of Neurology, Neurosurgery, and Psychiatry1 (1989): 67-71.
  5. Chung KKK., et al. “Parkin ubiquitinates the [alpha]-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease”. Nature Medicine10 (2001): 1144-1150.
  6. Ardley HC and PA Robinson. “The Role of Ubiquitin-Protein Ligases in Neurodegenerative Disease”. Neurodegenerative Diseases 1 (2004): 71-87.
  7. Tofaris GK., et al. “Ubiquitination of alpha-synuclein in Lewy bodies is a pathological event not associated with impairment of proteasome function”. Journal of Biological Chemistry 45 (2003): 44405-44411.
  8. Friguet B., et al. “Protein Degradation by the Proteasome and Its Implications in Aging”. Annals of the New York Academy of Sciences1 (2000): 143-154.
  9. Mah LY and KM Ryan. “Autophagy and Cancer”. Cold Spring Harbor Perspectives in Biology1 (2012): a008821.
  10. Wani WY., et al. “O-GlcNAc regulation of autophagy and α-synuclein homeostasis; implications for Parkinson’s disease”. Molecular Brain 10 (2017): 32.
  11. Xilouri M., et al. “Autophagy and Alpha-Synuclein: Relevance to Parkinson's Disease and Related Synucleopathies”. Movement Disorders2 (2016): 178-192.
  12. Bang Y., et al. “Preconditioning stimulus of proteasome inhibitor enhances aggresome formation and autophagy in differentiated SH-SY5Y cells”. Neuroscience Letters 566 (2014): 263-268.
  13. Regitz C., et al. “Resveratrol reduces amyloid-beta (Aβ1–42)-induced paralysis through targeting proteostasis in an Alzheimer model of Caenorhabditis elegans”. European Journal of Nutrition 2 (2016): 741-747.
  14. Xu P., et al. “Triptolide Inhibited Cytotoxicity of Differentiated PC12 Cells Induced by Amyloid-Beta (25–35) via the Autophagy Pathway”. PLoS ONE11 (2015): e0142719.
  15. Ross CA and SJ Tabrizi. “Huntington's disease: from molecular pathogenesis to clinical treatment”. The Lancet Neurology1 (2011): 83-98.
  16. Cook C and L Petrucelli. “A critical evaluation of the ubiquitin–proteasome system in Parkinson's disease”. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease7 (2009): 664-675.
  17. Gadhave K., et al. “The ubiquitin proteasomal system: a potential target for the management of Alzheimer's disease”. Journal of Cellular and Molecular Medicine7 (2016): 1392-1407.
  18. Yoshida H. “ER stress and diseases”. FEBS Journal3 (2007): 630-658.
  19. Szegezdi E., et al. “Mediators of endoplasmic reticulum stress‐induced apoptosis”. EMBO Reports9 (2006): 880-885.
  20. Ron D and P Walter. “Signal integration in the endoplasmic reticulum unfolded protein response”. Nature Reviews Molecular Cell Biology 7 (2007): 519-529.
  21. Ustundag Y., et al. “Proteasome inhibition-induces endoplasmic reticulum dysfunction and cell death of human cholangiocarcinoma cells”. World Journal of Gastroenterology : WJG6 (2007): 851-857.
  22. Cheng B., et al. “Insulin-like Growth Factor-I Mediates Neuroprotection in Proteasome Inhibition-Induced Cytotoxicity in SH-SY5Y Cells”. Molecular and Cellular Neurosciences3 (2011): 181-190.
  23. Cheng B., et al. “Retinoic acid protects against proteasome inhibition associated cell death in SH-SY5Y cells via the AKT pathway”. Neurochemistry International1 (2013): 31-42.
  24. Gies E., et al. “Niclosamide Prevents the Formation of Large Ubiquitin-Containing Aggregates Caused by Proteasome Inhibition”. PLoS ONE12 (2010): e14410.
  25. Bhattacharyya J., et al. “Niclosamide-conjugated polypeptide nanoparticles inhibit Wnt signaling and colon cancer growth”. Nanoscale (2017).
  26. Arend RC., et al. “Niclosamide and its analogs are potent inhibitors of Wnt/β-catenin, mTOR and STAT3 signaling in ovarian cancer”. Oncotarget52 (2016): 86803-86815.
  27. You S., et al. “Disruption of STAT3 by niclosamide reverses radioresistance of human lung cancer”. Molecular Cancer Therapeutics3 (2014): 606-616.
  28. Ren X., et al. “Identification of Niclosamide as a New Small-Molecule Inhibitor of the STAT3 Signaling Pathway”. ACS Medicinal Chemistry Letters9 (2010): 454-459.
  29. Tao H., et al. “Niclosamide ethanolamine-induced mild mitochondrial uncoupling improves diabetic symptoms in mice”. Nature Medicine11 (2014): 1263-1269.
  30. Han P., et al. “Niclosamide ethanolamine improves diabetes and diabetic kidney disease in mice”. American Journal of Translational Research 4 (2018): 1071-1084.
  31. Cerles O., et al. “Niclosamide Inhibits Oxaliplatin Neurotoxicity while Improving Colorectal Cancer Therapeutic Response”. Molecular Cancer Therapeutics2 (2017): 300.
  32. Zhang LX., et al. “Niclosamide attenuates inflammatory cytokines via the autophagy pathway leading to improved outcomes in renal ischemia/reperfusion injury”. Molecular Medicine Reports 2 (2017): 1810-1816.
  33. Cheng B., et al. “Niclosamide induces protein ubiquitination and inhibits multiple pro-survival signaling pathways in the human glioblastoma U-87 MG cell line”. PloS one7 (2017): e0184324-e0184324.
  34. Park HS., et al. “Proteasome inhibitor MG132-induced apoptosis via ER stress-mediated apoptotic pathway and its potentiation by protein tyrosine kinase p56lck in human Jurkat T cells”. Biochemical Pharmacology9 (2011): 1110-1125.
  35. Nguyen H and BD Uhal. “The unfolded protein response controls ER stress-induced apoptosis of lung epithelial cells through angiotensin generation”. American Journal of Physiology - Lung Cellular and Molecular Physiology5 (2016): L846.
  36. Liu XA., et al. “Expression of the hyperphosphorylated tau attenuates ER stress-induced apoptosis with upregulation of unfolded protein response”. Apoptosis 10 (2012): 1039-1049.
  37. Pandey UB., et al. “HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS”. Nature 7146 (2017): 860-864.
  38. Cheng B., et al. “N-Acetylcysteine in Combination with IGF-1 Enhances Neuroprotection against Proteasome Dysfunction-Induced Neurotoxicity in SH-SY5Y Cells”. Parkinson's Disease (2016): 6564212.
  39. Ding WX., et al. “Linking of Autophagy to Ubiquitin-Proteasome System Is Important for the Regulation of Endoplasmic Reticulum Stress and Cell Viability”. The American Journal of Pathology2 (2007): 513-524.
  40. Marciniak SJ., et al. “CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum”. Genes and Development24 (2004): 3066-3077.
  41. Kaufmann SH., et al. “Specific Proteolytic Cleavage of Poly (ADP-ribose) Polymerase: An Early Marker of Chemotherapy-induced Apoptosis”. Cancer Research7 (1993): 3976-3985.
  42. Harhouri K., et al. “MG132‐induced progerin clearance is mediated by autophagy activation and splicing regulation”. EMBO Molecular Medicine9 (2017): 1294-1313.
  43. Marino G., et al. “Autophagy for tissue homeostasis and neuroprotection”. Current Opinion in Cell Biology 2 (2011): 198-206.
  44. Sánchez-Pérez AM., et al. “Parkinson's Disease and Autophagy”. Parkinson's Disease (2012): 429524.
  45. Ouyang, L., et al. “Programmed cell death pathways in cancer: a review of apoptosis, autophagy and programmed necrosis”. Cell Prolif6 (2012): 487-498.
  46. Tan CC., et al. “Autophagy in aging and neurodegenerative diseases: implications for pathogenesis and therapy”. Neurobiology Aging5 (2014): 941-957.
  47. Mariño G and C López-Otín. “Autophagy: molecular mechanisms, physiological functions and relevance in human pathology”. Cellular and Molecular Life Sciences CMLS 12 (2004): 1439-1454.
  48. Zhang Y., et al. “The role of ubiquitin proteasomal system and autophagy-lysosome pathway in Alzheimer’s disease”. Reviews in the Neurosciences (2017).
  49. Yuan J., et al. “Diversity in the Mechanisms of Neuronal Cell Death”. Neuron 2 (2003): 401-413.
×

Citation

Citation: Benxu Cheng., et al. “Evidence of a Neuroprotective Function for Niclosamide in Human SH-SY5Y Neuroblastoma and Rat PC12 Neural Cells". Acta Scientific Neurology 3.9 (2020): 85-94.




Metrics

Acceptance rate32%
Acceptance to publication20-30 days

Indexed In




News and Events


  • Certification for Review
    Acta Scientific certifies the Editors/reviewers for their review done towards the assigned articles of the respective journals.
  • Submission Timeline for Upcoming Issue
    The last date for submission of articles for regular Issues is December 25, 2024.
  • Publication Certificate
    Authors will be issued a "Publication Certificate" as a mark of appreciation for publishing their work.
  • Best Article of the Issue
    The Editors will elect one Best Article after each issue release. The authors of this article will be provided with a certificate of "Best Article of the Issue"

Contact US