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Red Pine Bark Extract Alleviates Akt/GSK-3β Signaling Disruption in the Hippocampus of Streptozotocin-Induced Diabetic Sprague-Dawley Rats

  • Kwan Joong Kim (Graduate School of Biotechnology, Kyung Hee University) ;
  • Zukhra Akhmedova (Graduate School of Biotechnology, Kyung Hee University) ;
  • Ho Jin Heo (Division of Applied Life Science (BK21), Institute of Agriculture and Life Science, Gyeongsang National University) ;
  • Dae-Ok Kim (Graduate School of Biotechnology, Kyung Hee University)
  • Received : 2024.03.19
  • Accepted : 2024.04.19
  • Published : 2024.06.28

Abstract

This study investigates whether red pine (Pinus densiflora Sieb. et Zucc.) bark extract (PBE) can alleviate diabetes and abnormal apoptosis signaling pathways in the hippocampus of streptozotocin (STZ)-induced diabetic Sprague-Dawley (SD) rats. Two dosages of PBE (15 and 30 mg/kg of body weight/day) were administered orally to STZ-induced diabetic SD rats for 20 days. Blood glucose level and body weight were measured once per week. After 20 days of oral administration of PBE, the rat hippocampus was collected, and the production of Akt, p-Akt, GSK-3β, p-GSK-3β, tau, p-tau, Bax, and Bcl-2 proteins were determined by western blot analysis. A decrease in blood glucose level and recovery of body weight were observed in PBE-treated diabetic rats. In the Akt/GSK-3β/tau signaling pathway, PBE inhibited diabetes-induced Akt inactivation, GSK-3β inactivation, and tau hyperphosphorylation. The protein production ratio of Bax/Bcl-2 was restored to the control group level. These results suggest that PBE, rich in phenolic compounds, can be used as a functional food ingredient to ameliorate neuronal apoptosis in diabetes mellitus.

Keywords

Acknowledgement

This work was supported by the Ministry of Education of the Republic of Korea and the National Research Foundation of Korea (NRF-2020R1F1A1060767).

References

  1. Biessels GJ, Deary IJ, Ryan CM. 2008. Cognition and diabetes: a lifespan perspective. Lancet Neurol. 7: 184-190. https://doi.org/10.1016/S1474-4422(08)70021-8
  2. McCall AL. 1992. The impact of diabetes on the CNS. Diabetes. 41: 557-570. https://doi.org/10.2337/diab.41.5.557
  3. Kitagishi Y, Nakanishi A, Ogura Y, Matsuda S. 2014. Dietary regulation of PI3K/AKT/GSK-3β pathway in Alzheimer's disease. Alzheimer's Res. Ther. 6: 35.
  4. Sharifi AM, Mousavi SH, Farhadi M, Larijani B. 2007. Study of high glucose-induced apoptosis in PC12 cells: role of bax protein. J. Pharmacol. Sci. 104: 258-262. https://doi.org/10.1254/jphs.FP0070258
  5. Qi Y, Dou DQ, Jiang H, Zhang BB, Qin WY, Kang K, et al. 2017. Arctigenin attenuates learning and memory deficits through PI3k/Akt/GSK-3β pathway reducing tau hyperphosphorylation in Aβ-induced AD mice. Planta Med. 83: 51-56. https://doi.org/10.1055/s-0042-107471
  6. Xiong R, Wang XL, Wu JM, Tang Y, Qiu WQ, Shen X, et al. 2020. Polyphenols isolated from lychee seed inhibit Alzheimer's disease-associated Tau through improving insulin resistance via the IRS-1/PI3K/Akt/GSK-3β pathway. J. Ethnopharmacol. 251: 112548.
  7. Zhang YP, Liu SY, Sun QY, Ren J, Liu HX, Li H. 2018. Proanthocyanidin B2 attenuates high-glucose-induced neurotoxicity of dorsal root ganglion neurons through the PI3K/Akt signaling pathway. Neural Regen. Res. 13: 1628-1636. https://doi.org/10.4103/1673-5374.237174
  8. Yao RQ, Qi DS, Yu HL, Liu J, Yang LH, Wu XX. 2012. Quercetin attenuates cell apoptosis in focal cerebral ischemia rat brain via activation of BDNF-TrkB-PI3K/Akt signaling pathway. Neurochem. Res. 37: 2777-2786. https://doi.org/10.1007/s11064-012-0871-5
  9. Kim JW, Im S, Jeong HR, Jung YS, Lee I, Kim KJ, et al. 2018. Neuroprotective effects of Korean red pine (Pinus densiflora) bark extract and its phenolics. J. Microbiol. Biotechnol. 28: 679-687. https://doi.org/10.4014/jmb.1801.01053
  10. Kim KJ, Hwang ES, Kim MJ, Park JH, Kim DO. 2020. Antihypertensive effects of polyphenolic extract from Korean red pine (Pinus densiflora Sieb. et Zucc.) bark in spontaneously hypertensive rats. Antioxidants 9: 333.
  11. Hassan EBM, Mun SP. 2002. Liquefaction of pine bark using phenol and lower alcohols with methanesulfonic acid catalyst. J. Ind. Eng. Chem. 8: 359-364.
  12. Kim KJ, Hwang ES, Kim MJ, Rha CS, Song MC, Maeng S, et al. 2022. Effects of phenolic-rich Pinus densiflora extract on learning, memory, and hippocampal long-term potentiation in scopolamine-induced amnesic rats. Antioxidants 11: 2497.
  13. Bennett RA, Pegg AE. 1981. Alkylation of DNA in rat tissues following administration of streptozotocin. Cancer Res. 41: 2786-2790.
  14. Kietzmann T, Petry A, Shvetsova A, Gerhold JM, Gorlach A. 2017. The epigenetic landscape related to reactive oxygen species formation in the cardiovascular system. Br. J. Pharmacol. 174: 1533-1554. https://doi.org/10.1111/bph.13792
  15. Matsunami T, Sato Y, Hasegawa Y, Ariga S, Kashimura H, Sato T, et al. 2011. Enhancement of reactive oxygen species and induction of apoptosis in streptozotocin-induced diabetic rats under hyperbaric oxygen exposure. Int. J. Clin. Exp. Pathol. 4: 255-266.
  16. Robertson RP. 2004. Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet beta cells in diabetes. J. Biol. Chem. 279: 42351-42354. https://doi.org/10.1074/jbc.R400019200
  17. Vinayagamoorthi R, Bobby Z, Sridhar MG. 2008. Antioxidants preserve redox balance and inhibit c-Jun-N-terminal kinase pathway while improving insulin signaling in fat-fed rats: evidence for the role of oxidative stress on IRS-1 serine phosphorylation and insulin resistance. J. Endocrinol. 197: 287-296. https://doi.org/10.1677/JOE-08-0061
  18. Moosavi M, Zarifkar AH, Farbood Y, Dianat M, Sarkaki A, Ghasemi R. 2014. Agmatine protects against intracerebroventricular streptozotocin-induced water maze memory deficit, hippocampal apoptosis and Akt/GSK3β signaling disruption. Eur. J. Pharmacol. 736: 107-114. https://doi.org/10.1016/j.ejphar.2014.03.041
  19. Good PF, Werner P, Hsu A, Olanow CW, Perl DP. 1996. Evidence of neuronal oxidative damage in Alzheimer's disease. Am. J. Pathol. 149: 21-28.
  20. Grunblatt E, Salkovic-Petrisic M, Osmanovic J, Riederer P, Hoyer S. 2007. Brain insulin system dysfunction in streptozotocin intracerebroventricularly treated rats generates hyperphosphorylated tau protein. J. Neurochem. 101: 757-770. https://doi.org/10.1111/j.1471-4159.2006.04368.x
  21. Silva-Reis R, Faustino-Rocha AI, Silva J, Valada A, Azevedo T, Anjos L, et al. 2023. Studying and analyzing humane endpoints in the fructose-fed and streptozotocin-injected rat model of diabetes. Animals 13: 1397.
  22. Seung TW, Park SK, Kang JY, Kim JM, Park SH, Kwon BS, et al. 2018. Ethyl acetate fraction from Hibiscus sabdariffa L. attenuates diabetes-associated cognitive impairment in mice. Food Res. Int. 105: 589-598. https://doi.org/10.1016/j.foodres.2017.11.063
  23. Kim YM, Wang MH, Rhee HI. 2004. A novel α-glucosidase inhibitor from pine bark. Carbohydr. Res. 339: 715-717. https://doi.org/10.1016/j.carres.2003.11.005
  24. Min HJ, Kim EJ, Shinn SW, Bae YS. 2019. Antidiabetic activities of Korean red pine (Pinus densiflora) inner bark extracts. J. Korean Wood Sci. Technol. 47: 498-508. https://doi.org/10.5658/WOOD.2019.47.4.498
  25. Wang Y, Wu C, Han B, Xu F, Mao M, Guo X, et al. 2016. Dexmedetomidine attenuates repeated propofol exposure-induced hippocampal apoptosis, PI3K/Akt/Gsk-3β signaling disruption, and juvenile cognitive deficits in neonatal rats. Mol. Med. Rep. 14: 769-775. https://doi.org/10.3892/mmr.2016.5321
  26. Kodl CT, Seaquist ER. 2008. Cognitive dysfunction and diabetes mellitus. Endocr. Rev. 29: 494-511. https://doi.org/10.1210/er.2007-0034
  27. Kopke E, Tung YC, Shaikh S, Alonso AC, Iqbal K, Grundke-Iqbal I. 1993. Microtubule-associated protein tau. Abnormal phosphorylation of a non-paired helical filament pool in Alzheimer disease. J. Biol. Chem. 268: 24374-24384. https://doi.org/10.1016/S0021-9258(20)80536-5
  28. Kim SH, Hwang SY, Park OS, Kim MK, Chung YJ. 2005. Effect of Pinus densiflora extract on blood glucose level, OGTT and biochemical parameters in streptozotocin induced diabetic rats. J. Korean Soc. Food Sci. Nutr. 34: 973-979. https://doi.org/10.3746/jkfn.2005.34.7.973