Preliminary screening of Pioglitazone and Diosgenin novel combination for Alzheimer’s disease

Sheik Mohammed; Anuradha Nandhyala; Narasimha Rao Gaddam; Kalirajan Rajagopal; Nagarjuna Palathoti; Justin Antony

doi:10.7324/JAPS.2023.134926

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Abstract

The pathophysiology of Alzheimer’s disease (AD) is a complex phenomenon which mediating through Aβ plaque formation and neurofibrillary tangles. Since, last few decades preclinical and clinical research evidences strengthen the elucidation of underlying causes in disease progression. The ongoing studies are mainly focused to screen the potential clinical candidates which turndown the neurodegeneration or delaying in AD progression. Considering the complicated etiopathogenesis of AD, the therapies which target the multiple molecular pathways of AD is required to potentiate the treatment and which in turn regulates the AD related complications. Diosgenin (DG), a natural steroidal saponin which has proven for an antioxidant, neuroprotective effects, and Pioglitazone is a peroxisome proliferator-activated receptor-γ agonist that has been found to be effective in treating several neuropathies. DG and Pioglitazone combination may be a successful novel approach in treating AD and other neurodegenerative disorders; in the present study, we were targeted the neuro-inflammatory pathways with Pioglitazone and DG to evaluate the neuroprotective potential especially in AD like condition. Overall, the research findings revealed the possible therapeutic benefits with novel combination and it was notably down-regulated the cytokine storm and Aβ plaque formation.

Keyword: Alzheimer’s disease beta amyloid proteins PPAR-Ý neuroinflammation

Citation:

Mohammed S, Nandhyala A, Gaddam NR, Rajagopal K, Palathoti N, Antony J. Preliminary screening of Pioglitazone and Diosgenin novel combination for Alzheimer’s disease. J Appl Pharm Sci. 2023;13(Suppl 1):065–075. https://doi.org/10.7324/JAPS.2023.134926

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Reference

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2. Rajmohan R, Reddy PH. Amyloid-beta and phosphorylated tau accumulations cause abnormalities at synapses of Alzheimer's disease neurons. J Alzheimers Dis. 2017;57(4):975-99. https://doi.org/10.3233/JAD-160612
3. Burns A, Iliffe S. Alzheimer's disease. BMJ. 2009;338:b158. https://doi.org/10.1136/bmj.b158
4. Ballard C, Mobley W, Hardy J, Williams G, Corbett A. Dementia in Down's syndrome. Lancet Neurol. 2016 May;15(6):622-36. https://doi.org/10.1016/S1474-4422(16)00063-6
5. Lammich S, Kojro E, Postina R, Gilbert S, Pfeiffer R, Jasionowski M, et al. Constitutive and regulated-secretase cleavage of Alzheimer's amyloid precursor protein by a disintegrin metalloprotease. [Internet]. Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3922-7. Available from: www.pnas.org https://doi.org/10.1073/pnas.96.7.3922
6. Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J. Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1456-60. https://doi.org/10.1073/pnas.97.4.1456
7. Sisodia SS, St George-Hyslop PH. Gamma-secretase, notch, abeta and Alzheimer's disease: where do the presenilins fit in? Nat Rev Neurosci. 2002 Apr;3(4):281-90. https://doi.org/10.1038/nrn785
8. Atwood CS, Bowen RL. A unified hypothesis of early- and late-onset Alzheimer's disease pathogenesis. J Alzheimers Dis [Internet]. 2015 Jul;47(1):33-47. https://doi.org/10.3233/JAD-143210
9. Citron M, Vigo-Pelfrey C, Teplow DB, Miller C, Schenk D, Johnston J, et al. Excessive production of amyloid beta-protein by peripheral cells of symptomatic and presymptomatic patients carrying the Swedish familial Alzheimer disease mutation. Proc Natl Acad Sci [Internet]. 1994 Dec;91(25):11993-7. https://doi.org/10.1073/pnas.91.25.11993
10. Justin A, Mandal S, Prabitha P, Dhivya S, Yuvaraj S, Kabadi P, et al. Rational design, synthesis, and in vitro neuroprotective evaluation of novel glitazones for PGC-1α activation via PPAR-γ: a new therapeutic strategy for neurodegenerative disorders. Neurotox Res. 2020;37(3):508-24. https://doi.org/10.1007/s12640-019-00132-9
11. Sethi G, Shanmugam MK, Warrier S, Merarchi M, Arfuso F, Kumar AP, et al. Pro-apoptotic and anti-cancer properties of Diosgenin: a comprehensive and critical review. Nutrients. 2018;10:645. 12. Chiang SS, Chang SP, Pan TM. Osteoprotective effect of monascus-fermented Dioscorea in ovariectomized rat model of postmenopausal osteoporosis. J Agric Food Chem. 2011;59(17):9150-7. https://doi.org/10.1021/jf201640j
13. Jesus M, Martins APJ, Gallardo E, Silvestre S. Diosgenin: recent highlights on pharmacology and analytical methodology. J Anal Methods Chem. 2016;2016:4156293. https://doi.org/10.1155/2016/4156293
14. Lv YC, Yang J, Yao F, Xie W, Tang YY, Ouyang XP, et al. Diosgenin inhibits atherosclerosis via suppressing the MiR-19b-induced downregulation of ATP-binding cassette transporter A1. Atherosclerosis. 2015 May;240(1):80-9. https://doi.org/10.1016/j.atherosclerosis.2015.02.044
15. Hua S, Li Y, Su L, Liu X. Diosgenin ameliorates gestational diabetes through inhibition of sterol regulatory element-binding protein-1. Biomed Pharmacother. 2016;84:1460-5. https://doi.org/10.1016/j.biopha.2016.10.049
16. Kim JE, Go J, Koh EK, Song SH, Sung JE, Lee HA, et al. Diosgenin effectively suppresses skin inflammation induced by phthalic anhydride in IL-4/Luc/CNS-1 transgenic mice. Biosci Biotechnol Biochem. 2016;80(5):891-901. https://doi.org/10.1080/09168451.2015.1135040
17. Blunden G, Rhodes CT. Stability of Diosgenin. J Pharm Sci [Internet]. 1968 Apr;57(4):602-4. https://doi.org/10.1002/jps.2600570411
18. Okawara M, Hashimoto F, Todo H, Sugibayashi K, Tokudome Y. Effect of liquid crystals with cyclodextrin on the bioavailability of a poorly water-soluble compound, Diosgenin, after its oral administration to rats. Int J Pharm. 2014;472(1-2):257-61. https://doi.org/10.1016/j.ijpharm.2014.06.032
19. Fu WY, Wang X, Ip NY. Targeting neuroinflammation as a therapeutic strategy for Alzheimer's disease: mechanisms, drug candidates, and new opportunities. ACS Chem Neurosci. 2019;10:872-9. https://doi.org/10.1021/acschemneuro.8b00402
20. Wang S, Wang F, Yang H, Li R, Guo H, Hu L. Diosgenin glucoside provides neuroprotection by regulating microglial M1 polarization. Int Immunopharmacol. 2017;50:22-9. https://doi.org/10.1016/j.intimp.2017.06.008
21. Tohda C, Lee YA, Goto Y, Nemere I. Diosgenin-induced cognitive enhancement in normal mice is mediated by 1,25D 3-MARRS. Sci Rep. 2013;3:3395. https://doi.org/10.1038/srep03395
22. Tohda C, Yang X, Matsui M, Inada Y, Kadomoto E, Nakada S, et al. Diosgenin-rich yam extract enhances cognitive function: a placebo-controlled, randomized, double-blind, crossover study of healthy adults. Nutrients. 2017;9(10):1160. https://doi.org/10.3390/nu9101160
23. Som S, Antony J, Dhanabal SP, Ponnusankar S. Neuroprotective role of Diosgenin, a NGF stimulator, against A (142) induced neurotoxicity in animal model of Alzheimer's disease. Metab Brain Dis [Internet]. 2022 Jan;37(2):359-72. https://doi.org/10.1007/s11011-021-00880-8
24. Qin Y, Wu X, Huang W, Gong G, Li D, He Y, et al. Acute toxicity and sub-chronic toxicity of steroidal saponins from Dioscorea zingiberensis C. H. Wright in rodents. J Ethnopharmacol [Internet]. 2009 Dec;126(3):543-50. https://doi.org/10.1016/j.jep.2009.08.047
25. Peila R, Rodriguez BL, Launer LJ. Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: the Honolulu-Asia aging study. Diabetes. 2002;51(4):1256-62. https://doi.org/10.2337/diabetes.51.4.1256
26. Craft S, Watson GS. Insulin and neurodegenerative disease: shared and specific mechanisms. Lancet Neurol. 2004;3:169-78. https://doi.org/10.1016/S1474-4422(04)00681-7
27. Landreth G. Therapeutic use of agonists of the nuclear receptor PPARgamma in Alzheimer's disease. Curr Alzheimer Res. 2007;4(2):159-64. https://doi.org/10.2174/156720507780362092
28. Pa P, Justin A, Ananda Kumar TD, Chinaswamy M, Kumar BRP. Glitazones activate PGC-1α signaling via PPAR-γ: a promising strategy for antiparkinsonism therapeutics. ACS Chem Neurosci. 2021;12:2261-72. https://doi.org/10.1021/acschemneuro.1c00085
29. Egan WJ, Kenneth M. Merz, Baldwin JJ. Prediction of drug absorption using multivariate statistics. J Med Chem [Internet]. 2000 Sep;43(21):3867-77. https://doi.org/10.1021/jm000292e
30. Sabe VT, Ntombela T, Jhamba LA, Maguire GEM, Govender T, Naicker T, et al. Current trends in computer aided drug design and a highlight of drugs discovered via computational techniques: a review. Eur J Med Chem [Internet]. 2021 Nov;224:113705. https://doi.org/10.1016/j.ejmech.2021.113705
31. Stanzione F, Giangreco I, Cole JC. Use of molecular docking computational tools in drug discovery. In: Progress in medicinal chemistry [Internet]. Elsevier; 2021. pp 273-343. https://doi.org/10.1016/bs.pmch.2021.01.004
32. Bowers KJ, Sacerdoti FD, Salmon JK, Shan Y, Shaw DE, Chow E, et al. Molecular dynamics-scalable algorithms for molecular dynamics simulations on commodity clusters. In: Proceedings of the 2006 ACM/IEEE Conference on Supercomputing-SC 06 [Internet]. ACM Press; 2006. https://doi.org/10.1145/1188455.1188544
33. Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML. Comparison of simple potential functions for simulating liquid water. J Chem Phys [Internet]. 1983 Jul;79(2):926-35. https://doi.org/10.1063/1.445869
34. Jupudi S, Rajagopal K, Murugesan S, Kumar BK, Raman K, Byran G, et al. Identification of papain-like protease inhibitors of SARS CoV-2 through HTVS, molecular docking, MMGBSA and molecular dynamics approach. South Afr J Botany [Internet]. 2022 Dec;151:82-91. doi: https://doi.org/10.1016%2Fj.sajb.2021.11.033 https://doi.org/10.1016/j.sajb.2021.11.033
35. Pike CJ, Burdick D, Walencewicz AJ, Glabe CG, Cotman CW. Neurodegeneration induced by beta-amyloid peptides in vitro: the role of peptide assembly state. J Neurosci [Internet]. 1993 Apr;13(4):1676- 87. https://doi.org/10.1523/JNEUROSCI.13-04-01676.1993
36. Wang X, Zhang M, Liu H. LncRNA17A regulates autophagy and apoptosis of SH-SY5Y cell line as an in vitro/imodel for Alzheimer's disease. Biosci Biotechnol Biochem [Internet]. 2019 Apr;83(4):609- 21. https://doi.org/10.1080/09168451.2018.1562874
37. Mairuae N, Connor JR, Lee SY, Cheepsunthorn P, Tongjaroenbuangam W. The effects of okra (Abelmoschus esculentus Linn.) on the cellular events associated with Alzheimer's disease in a stably expressed HFE neuroblastoma SH-SY5Y cell line. Neurosci Lett [Internet]. 2015 Aug;603:6-11. https://doi.org/10.1016/j.neulet.2015.07.011
38. Lecanu L, Yao W, Teper GL, Yao ZX, Greeson J, Papadopoulos V. Identification of naturally occurring spirostenols preventing β-amyloid-induced neurotoxicity. Steroids. 2004;69(1):1-16. https://doi.org/10.1016/j.steroids.2003.09.007
39. Jiang Q, Heneka M, Landreth GE. The role of peroxisome proliferator-activated receptor-γ (PPARγ) in Alzheimer's disease: therapeutic implications. CNS Drugs. 2008;22:1-14. https://doi.org/10.2165/00023210-200822010-00001
40. Shearman MS, Hawtin SR, Tailor VJ. The intracellular component of cellular 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction is specifically inhibited by β-amyloid peptides. J Neurochem. 1995;65(1):218-27. https://doi.org/10.1046/j.1471-4159.1995.65010218.x
41. Sastre M, Klockgether T, Heneka MT. Contribution of inflammatory processes to Alzheimer's disease: molecular mechanisms. Int J Dev Neurosci. 2006;24:167-76. https://doi.org/10.1016/j.ijdevneu.2005.11.014
42. von Bernhardi R, Tichauer JE, Eugenín J. Aging-dependent changes of microglial cells and their relevance for neurodegenerative disorders. J Neurochem. 2010;112:1099-114. https://doi.org/10.1111/j.1471-4159.2009.06537.x
43. Wang DB, Dayton RD, Zweig RM, Klein RL. Transcriptome analysis of a tau overexpression model in rats implicates an early pro-inflammatory response. Exp Neurol. 2010;224(1):197-206. https://doi.org/10.1016/j.expneurol.2010.03.011

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Nandhyala A [PubMed] [Google Scholar ]

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1. Tam JHK, Pasternak SH. Alzheimer's disease. In: The cerebral cortex in neurodegenerative and neuropsychiatric disorders: experimental approaches to clinical issues. Elsevier Inc.; 2017. pp 83-118. https://doi.org/10.1016/B978-0-12-801942-9.00004-5

2. Rajmohan R, Reddy PH. Amyloid-beta and phosphorylated tau accumulations cause abnormalities at synapses of Alzheimer's disease neurons. J Alzheimers Dis. 2017;57(4):975-99. https://doi.org/10.3233/JAD-160612

3. Burns A, Iliffe S. Alzheimer's disease. BMJ. 2009;338:b158. https://doi.org/10.1136/bmj.b158

4. Ballard C, Mobley W, Hardy J, Williams G, Corbett A. Dementia in Down's syndrome. Lancet Neurol. 2016 May;15(6):622-36. https://doi.org/10.1016/S1474-4422(16)00063-6

5. Lammich S, Kojro E, Postina R, Gilbert S, Pfeiffer R, Jasionowski M, et al. Constitutive and regulated-secretase cleavage of Alzheimer's amyloid precursor protein by a disintegrin metalloprotease. [Internet]. Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3922-7. Available from: www.pnas.org https://doi.org/10.1073/pnas.96.7.3922

6. Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J. Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1456-60. https://doi.org/10.1073/pnas.97.4.1456

7. Sisodia SS, St George-Hyslop PH. Gamma-secretase, notch, abeta and Alzheimer's disease: where do the presenilins fit in? Nat Rev Neurosci. 2002 Apr;3(4):281-90. https://doi.org/10.1038/nrn785

8. Atwood CS, Bowen RL. A unified hypothesis of early- and late-onset Alzheimer's disease pathogenesis. J Alzheimers Dis [Internet]. 2015 Jul;47(1):33-47. https://doi.org/10.3233/JAD-143210

9. Citron M, Vigo-Pelfrey C, Teplow DB, Miller C, Schenk D, Johnston J, et al. Excessive production of amyloid beta-protein by peripheral cells of symptomatic and presymptomatic patients carrying the Swedish familial Alzheimer disease mutation. Proc Natl Acad Sci [Internet]. 1994 Dec;91(25):11993-7. https://doi.org/10.1073/pnas.91.25.11993

10. Justin A, Mandal S, Prabitha P, Dhivya S, Yuvaraj S, Kabadi P, et al. Rational design, synthesis, and in vitro neuroprotective evaluation of novel glitazones for PGC-1α activation via PPAR-γ: a new therapeutic strategy for neurodegenerative disorders. Neurotox Res. 2020;37(3):508-24. https://doi.org/10.1007/s12640-019-00132-9

11. Sethi G, Shanmugam MK, Warrier S, Merarchi M, Arfuso F, Kumar AP, et al. Pro-apoptotic and anti-cancer properties of Diosgenin: a comprehensive and critical review. Nutrients. 2018;10:645. 12. Chiang SS, Chang SP, Pan TM. Osteoprotective effect of monascus-fermented Dioscorea in ovariectomized rat model of postmenopausal osteoporosis. J Agric Food Chem. 2011;59(17):9150-7. https://doi.org/10.1021/jf201640j

13. Jesus M, Martins APJ, Gallardo E, Silvestre S. Diosgenin: recent highlights on pharmacology and analytical methodology. J Anal Methods Chem. 2016;2016:4156293. https://doi.org/10.1155/2016/4156293

14. Lv YC, Yang J, Yao F, Xie W, Tang YY, Ouyang XP, et al. Diosgenin inhibits atherosclerosis via suppressing the MiR-19b-induced downregulation of ATP-binding cassette transporter A1. Atherosclerosis. 2015 May;240(1):80-9. https://doi.org/10.1016/j.atherosclerosis.2015.02.044

15. Hua S, Li Y, Su L, Liu X. Diosgenin ameliorates gestational diabetes through inhibition of sterol regulatory element-binding protein-1. Biomed Pharmacother. 2016;84:1460-5. https://doi.org/10.1016/j.biopha.2016.10.049

16. Kim JE, Go J, Koh EK, Song SH, Sung JE, Lee HA, et al. Diosgenin effectively suppresses skin inflammation induced by phthalic anhydride in IL-4/Luc/CNS-1 transgenic mice. Biosci Biotechnol Biochem. 2016;80(5):891-901. https://doi.org/10.1080/09168451.2015.1135040

17. Blunden G, Rhodes CT. Stability of Diosgenin. J Pharm Sci [Internet]. 1968 Apr;57(4):602-4. https://doi.org/10.1002/jps.2600570411

18. Okawara M, Hashimoto F, Todo H, Sugibayashi K, Tokudome Y. Effect of liquid crystals with cyclodextrin on the bioavailability of a poorly water-soluble compound, Diosgenin, after its oral administration to rats. Int J Pharm. 2014;472(1-2):257-61. https://doi.org/10.1016/j.ijpharm.2014.06.032

19. Fu WY, Wang X, Ip NY. Targeting neuroinflammation as a therapeutic strategy for Alzheimer's disease: mechanisms, drug candidates, and new opportunities. ACS Chem Neurosci. 2019;10:872-9. https://doi.org/10.1021/acschemneuro.8b00402

20. Wang S, Wang F, Yang H, Li R, Guo H, Hu L. Diosgenin glucoside provides neuroprotection by regulating microglial M1 polarization. Int Immunopharmacol. 2017;50:22-9. https://doi.org/10.1016/j.intimp.2017.06.008

21. Tohda C, Lee YA, Goto Y, Nemere I. Diosgenin-induced cognitive enhancement in normal mice is mediated by 1,25D 3-MARRS. Sci Rep. 2013;3:3395. https://doi.org/10.1038/srep03395

22. Tohda C, Yang X, Matsui M, Inada Y, Kadomoto E, Nakada S, et al. Diosgenin-rich yam extract enhances cognitive function: a placebo-controlled, randomized, double-blind, crossover study of healthy adults. Nutrients. 2017;9(10):1160. https://doi.org/10.3390/nu9101160

23. Som S, Antony J, Dhanabal SP, Ponnusankar S. Neuroprotective role of Diosgenin, a NGF stimulator, against A (142) induced neurotoxicity in animal model of Alzheimer's disease. Metab Brain Dis [Internet]. 2022 Jan;37(2):359-72. https://doi.org/10.1007/s11011-021-00880-8

24. Qin Y, Wu X, Huang W, Gong G, Li D, He Y, et al. Acute toxicity and sub-chronic toxicity of steroidal saponins from Dioscorea zingiberensis C. H. Wright in rodents. J Ethnopharmacol [Internet]. 2009 Dec;126(3):543-50. https://doi.org/10.1016/j.jep.2009.08.047

25. Peila R, Rodriguez BL, Launer LJ. Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: the Honolulu-Asia aging study. Diabetes. 2002;51(4):1256-62. https://doi.org/10.2337/diabetes.51.4.1256

26. Craft S, Watson GS. Insulin and neurodegenerative disease: shared and specific mechanisms. Lancet Neurol. 2004;3:169-78. https://doi.org/10.1016/S1474-4422(04)00681-7

27. Landreth G. Therapeutic use of agonists of the nuclear receptor PPARgamma in Alzheimer's disease. Curr Alzheimer Res. 2007;4(2):159-64. https://doi.org/10.2174/156720507780362092

28. Pa P, Justin A, Ananda Kumar TD, Chinaswamy M, Kumar BRP. Glitazones activate PGC-1α signaling via PPAR-γ: a promising strategy for antiparkinsonism therapeutics. ACS Chem Neurosci. 2021;12:2261-72. https://doi.org/10.1021/acschemneuro.1c00085

29. Egan WJ, Kenneth M. Merz, Baldwin JJ. Prediction of drug absorption using multivariate statistics. J Med Chem [Internet]. 2000 Sep;43(21):3867-77. https://doi.org/10.1021/jm000292e

30. Sabe VT, Ntombela T, Jhamba LA, Maguire GEM, Govender T, Naicker T, et al. Current trends in computer aided drug design and a highlight of drugs discovered via computational techniques: a review. Eur J Med Chem [Internet]. 2021 Nov;224:113705. https://doi.org/10.1016/j.ejmech.2021.113705

31. Stanzione F, Giangreco I, Cole JC. Use of molecular docking computational tools in drug discovery. In: Progress in medicinal chemistry [Internet]. Elsevier; 2021. pp 273-343. https://doi.org/10.1016/bs.pmch.2021.01.004

32. Bowers KJ, Sacerdoti FD, Salmon JK, Shan Y, Shaw DE, Chow E, et al. Molecular dynamics-scalable algorithms for molecular dynamics simulations on commodity clusters. In: Proceedings of the 2006 ACM/IEEE Conference on Supercomputing-SC 06 [Internet]. ACM Press; 2006. https://doi.org/10.1145/1188455.1188544

33. Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML. Comparison of simple potential functions for simulating liquid water. J Chem Phys [Internet]. 1983 Jul;79(2):926-35. https://doi.org/10.1063/1.445869

34. Jupudi S, Rajagopal K, Murugesan S, Kumar BK, Raman K, Byran G, et al. Identification of papain-like protease inhibitors of SARS CoV-2 through HTVS, molecular docking, MMGBSA and molecular dynamics approach. South Afr J Botany [Internet]. 2022 Dec;151:82-91. doi: https://doi.org/10.1016%2Fj.sajb.2021.11.033 https://doi.org/10.1016/j.sajb.2021.11.033

35. Pike CJ, Burdick D, Walencewicz AJ, Glabe CG, Cotman CW. Neurodegeneration induced by beta-amyloid peptides in vitro: the role of peptide assembly state. J Neurosci [Internet]. 1993 Apr;13(4):1676- 87. https://doi.org/10.1523/JNEUROSCI.13-04-01676.1993

36. Wang X, Zhang M, Liu H. LncRNA17A regulates autophagy and apoptosis of SH-SY5Y cell line as an in vitro/imodel for Alzheimer's disease. Biosci Biotechnol Biochem [Internet]. 2019 Apr;83(4):609- 21. https://doi.org/10.1080/09168451.2018.1562874

37. Mairuae N, Connor JR, Lee SY, Cheepsunthorn P, Tongjaroenbuangam W. The effects of okra (Abelmoschus esculentus Linn.) on the cellular events associated with Alzheimer's disease in a stably expressed HFE neuroblastoma SH-SY5Y cell line. Neurosci Lett [Internet]. 2015 Aug;603:6-11. https://doi.org/10.1016/j.neulet.2015.07.011

38. Lecanu L, Yao W, Teper GL, Yao ZX, Greeson J, Papadopoulos V. Identification of naturally occurring spirostenols preventing β-amyloid-induced neurotoxicity. Steroids. 2004;69(1):1-16. https://doi.org/10.1016/j.steroids.2003.09.007

39. Jiang Q, Heneka M, Landreth GE. The role of peroxisome proliferator-activated receptor-γ (PPARγ) in Alzheimer's disease: therapeutic implications. CNS Drugs. 2008;22:1-14. https://doi.org/10.2165/00023210-200822010-00001

40. Shearman MS, Hawtin SR, Tailor VJ. The intracellular component of cellular 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction is specifically inhibited by β-amyloid peptides. J Neurochem. 1995;65(1):218-27. https://doi.org/10.1046/j.1471-4159.1995.65010218.x

41. Sastre M, Klockgether T, Heneka MT. Contribution of inflammatory processes to Alzheimer's disease: molecular mechanisms. Int J Dev Neurosci. 2006;24:167-76. https://doi.org/10.1016/j.ijdevneu.2005.11.014

42. von Bernhardi R, Tichauer JE, Eugenín J. Aging-dependent changes of microglial cells and their relevance for neurodegenerative disorders. J Neurochem. 2010;112:1099-114. https://doi.org/10.1111/j.1471-4159.2009.06537.x

43. Wang DB, Dayton RD, Zweig RM, Klein RL. Transcriptome analysis of a tau overexpression model in rats implicates an early pro-inflammatory response. Exp Neurol. 2010;224(1):197-206. https://doi.org/10.1016/j.expneurol.2010.03.011