Journal of Microbiology and Biotechnology

The Korean Society for Microbiology and Biotechnology (한국미생물·생명공학회)
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Korean Red Pine (Pinus densiflora) Bark Extract Attenuates Aβ-Induced Cognitive Impairment by Regulating Cholinergic Dysfunction and Neuroinflammation

  • Go, Min Ji (Division of Applied Life Science (BK21), Institute of Agriculture and Life Science, Gyeongsang National University) ;
  • Kim, Jong Min (Division of Applied Life Science (BK21), Institute of Agriculture and Life Science, Gyeongsang National University) ;
  • Kang, Jin Yong (Division of Applied Life Science (BK21), Institute of Agriculture and Life Science, Gyeongsang National University) ;
  • Park, Seon Kyeong (Division of Applied Life Science (BK21), Institute of Agriculture and Life Science, Gyeongsang National University) ;
  • Lee, Chang Jun (Division of Applied Life Science (BK21), Institute of Agriculture and Life Science, Gyeongsang National University) ;
  • Kim, Min Ji (Division of Applied Life Science (BK21), Institute of Agriculture and Life Science, Gyeongsang National University) ;
  • Lee, Hyo Rim (Division of Applied Life Science (BK21), Institute of Agriculture and Life Science, Gyeongsang National University) ;
  • Kim, Tae Yoon (Division of Applied Life Science (BK21), Institute of Agriculture and Life Science, Gyeongsang National University) ;
  • Joo, Seung Gyum (Division of Applied Life Science (BK21), Institute of Agriculture and Life Science, Gyeongsang National University) ;
  • Kim, Dae-Ok (Department of Food Science and Biotechnology, Kyung Hee University) ;
  • Heo, Ho Jin (Division of Applied Life Science (BK21), Institute of Agriculture and Life Science, Gyeongsang National University)
  • Received : 2022.07.07
  • Accepted : 2022.07.29
  • Published : 2022.09.28
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Abstract

In this study, we investigated the anti-amnesic effect of Korean red pine (Pinus densiflora) bark extract (KRPBE) against amyloid beta1-42 (Aβ1-42)-induced neurotoxicity. We found that treatment with KRPBE improved the behavioral function in Aβ-induced mice, and also boosted the antioxidant system in mice by decreasing malondialdehyde (MDA) content, increasing superoxide dismutase (SOD) activities, and reducing glutathione (GSH) levels. In addition, KRPBE improved the cholinergic system by suppressing reduced acetylcholine (ACh) content while also activating acetylcholinesterase (AChE), regulating the expression of choline acetyltransferase (ChAT), postsynaptic density protein-95 (PSD-95), and synaptophysin. KRPBE also showed an ameliorating effect on cerebral mitochondrial deficit by regulating reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and ATP levels. Moreover, KRPBE modulated the expression levels of neurotoxicity indicators Aβ and phosphorylated tau (p-tau) and inflammatory cytokines TNF-α, p-IκB-α, and IL-1β. Furthermore, we found that KRPBE improved the expression levels of neuronal apoptosis-related markers BAX and BCl-2 and increased the expression levels of BDNF and p-CREB. Therefore, this study suggests that KRPBE treatment has an anti-amnestic effect by modulating cholinergic system dysfunction and neuroinflammation in Aβ1-42-induced cognitive impairment in mice.

Keywords

Acknowledgement

This study (Certificate No. 202103560001) was conducted with funding from the Ministry of Agriculture, Food and Rural Affairs of Korea.

References

  1. Jeremic D, Jimenez-Diaz L, Navarro-Lopez JD. 2021. Past, present and future of therapeutic strategies against amyloid-β peptides in Alzheimer's disease: a systematic review. Ageing Res. Rev. 72: 101496. https://doi.org/10.1016/j.arr.2021.101496
  2. Yu H, Wu J. 2021. Amyloid-β: A double agent in Alzheimer's disease?. Biomed. Pharmacother. 139: 111575. https://doi.org/10.1016/j.biopha.2021.111575
  3. Kuruva CS, Reddy PH. 2017. Amyloid beta modulators and neuroprotection in Alzheimer's disease: a critical appraisal. Drug Discov. Today 22: 223-233. https://doi.org/10.1016/j.drudis.2016.10.010
  4. Cheignon Cm, Tomas M, Bonnefont-Rousselot D, Faller P, Hureau C, Collin F. 2018. Oxidative stress and the amyloid beta peptide in Alzheimer's disease. Redox Biol. 14: 450-464. https://doi.org/10.1016/j.redox.2017.10.014
  5. Ma C, Hong F, Yang S. 2022. Amyloidosis in Alzheimer's disease: Pathogeny, etiology, and related therapeutic directions. Molecules 27: 1210. https://doi.org/10.3390/molecules27041210
  6. Sadigh-Eteghad S, Sabermarouf B, Majdi A, Talebi M, Farhoudi M, Mahmoudi J. 2015. Amyloid-beta: a crucial factor in Alzheimer's disease. Med. Princ. Pract. 24: 1-10.
  7. Azizi G, Navabi SS, Al-Shukaili A, Seyedzadeh MH, Yazdani R, Mirshafiey A. 2015. The role of inflammatory mediators in the pathogenesis of Alzheimer's disease. Sultan Qaboos Univ. Med. J. 15: 305. https://doi.org/10.18295/squmj.2015.15.03.002
  8. Meraz-Rios MA, Toral-Rios D, Franco-Bocanegra D, Villeda-Hernandez J, Campos-Pena V. 2013. Inflammatory process in Alzheimer's Disease. Front. Integr. Neurosci. 7: 59. https://doi.org/10.3389/fnint.2013.00059
  9. Zhang X-X, Tian Y, Wang Z-T, Ma Y-H, Tan L, Yu J-T. 2021. The epidemiology of Alzheimer's disease modifiable risk factors and prevention. J. Prev. Alzheimers Dis. 8: 313-321.
  10. Behl C, Moosmann B. 2002. Antioxidant neuroprotection in Alzheimer's disease as preventive and therapeutic approach. Free Radic. Biol. Med. 33: 182-191. https://doi.org/10.1016/S0891-5849(02)00883-3
  11. Kim KJ, Hwang E-S, Kim M-J, Park J-H, Kim D-O. 2020. Antihypertensive effects of polyphenolic extract from korean red pine (Pinus densiflora Sieb. et Zucc.) bark in spontaneously hypertensive rats. Antioxidants 9: 333. https://doi.org/10.3390/antiox9040333
  12. Ahn H, Jeong J, Moyo KM, Ryu Y, Min B, Yun SH, et al. 2017. Downregulation of hepatic de novo lipogenesis and adipogenesis in adipocytes by Pinus densiflora bark extract. J. Microbiol. Biotechnol. 27: 1925-1931. https://doi.org/10.4014/jmb.1707.07030
  13. Kim J-W, Im S, Jeong H-R, 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
  14. Hwang YJ, Yin J, Le TT, Youn SH, Ahn HS, Kwon SH, et al. 2016. Quantitative analysis of taxifolin,(+)-catechin and procyanidin B1 from the preparation of Pinus densiflora (PineXol®). Korean J. Pharmacogn. 47: 246-250.
  15. Lee YJ, Han OT, Choi H-S, Lee BY, Chung H-J, Lee O-H. 2013. Antioxidant and anti-adipogenic effects of PineXol. J. Food Sci. Technol. 45: 97-103.
  16. Kwak CS, Moon SC, Lee MS. 2006. Antioxidant, antimutagenic, and antitumor effects of pine needles (Pinus densiflora). Nutr. Cancer 56: 162-171. https://doi.org/10.1207/s15327914nc5602_7
  17. Yoo S-K, Kim J-M, Lee U, Kang J-Y, Park S-K, Han H-J, et al. 2021. Immature persimmon suppresses Amyloid Beta (Aβ) mediated cognitive dysfunction via tau pathology in ICR mice. Curr. Issues Mol. Biol. 43: 405-422. https://doi.org/10.3390/cimb43010033
  18. Kraeuter A-K, Guest PC, Sarnyai Z. 2019. Pre-clinical models, pp. 105-111. Springer, Berlin, Heidelberg.
  19. Senechal Y, Kelly PH, Dev KK. 2008. Amyloid precursor protein knockout mice show age-dependent deficits in passive avoidance learning. Behav. Brain Res. 186: 126-132. https://doi.org/10.1016/j.bbr.2007.08.003
  20. DeNoble VJ. 1987. Vinpocetine enhances retrieval of a step-through passive avoidance response in rats. Pharmacol. Biochem. Behav. 26: 183-186. https://doi.org/10.1016/0091-3057(87)90552-1
  21. Choi SJ, Jeong C-H, Choi S-G, Chun J-Y, Kim YJ, Lee J, et al. 2009. Zeatin prevents amyloid β-induced neurotoxicity and scopolamine-induced cognitive deficits. J. Med. Food 12: 271-277. https://doi.org/10.1089/jmf.2007.0678
  22. Morris R. 1984. Developments of a water-maze procedure for studying spatial learning in the rat. J. Neurosci. Methods 11: 47-60. https://doi.org/10.1016/0165-0270(84)90007-4
  23. Bradford MM. 1976. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72: 248-254. https://doi.org/10.1006/abio.1976.9999
  24. Hissin PJ, Hilf R. 1976. A fluorometric method for determination of oxidized and reduced glutathione in tissues. Anal. Biochem. 74: 214-226. https://doi.org/10.1016/0003-2697(76)90326-2
  25. Uchiyama M, Mihara M. 1978. Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal. Biochem. 86: 271-278. https://doi.org/10.1016/0003-2697(78)90342-1
  26. MC V. 1958. Presented at the Annales pharmaceutiques francaises.
  27. Ellman GL, Courtney KD, Andres Jr V, Featherstone RM. 1961. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem. Pharmacol. 7: 88-95. https://doi.org/10.1016/0006-2952(61)90145-9
  28. Kim JM, Kang JY, Park SK, Moon JH, Kim MJ, Lee HL, et al. 2021. Powdered Green Tea (Matcha) attenuates the cognitive dysfunction via the regulation of systemic inflammation in chronic PM2.5-exposed BALB/c mice. Antioxidants 10: 1932. https://doi.org/10.3390/antiox10121932
  29. Wang Y-Q, Chang S-Y, Wu Q, Gou Y-J, Jia L, Cui Y-M, et al. 2016. The protective role of mitochondrial ferritin on erastin-induced ferroptosis. Front. Aging Neurosci. 8: 308.
  30. Burke AS, MacMillan-Crow LA, Hinson JA. 2010. Reactive nitrogen species in acetaminophen-induced mitochondrial damage and toxicity in mouse hepatocytes. Chem. Res. Toxicol. 23: 1286-1292. https://doi.org/10.1021/tx1001755
  31. Buckner RL, Snyder AZ, Shannon BJ, LaRossa G, Sachs R, Fotenos AF, et al. 2005. Molecular, structural, and functional characterization of Alzheimer's disease: evidence for a relationship between default activity, amyloid, and memory. J. Neurosci. 25: 7709-7717. https://doi.org/10.1523/JNEUROSCI.2177-05.2005
  32. Choi JR, Kim JH, Lee S, Cho EJ, Kim HY. 2020. Protective effects of protocatechuic acid against cognitive impairment in an amyloid beta-induced Alzheimer's disease mouse model. Food Chem. Toxicol. 144: 111571. https://doi.org/10.1016/j.fct.2020.111571
  33. Nguyen TT, Nguyen TTD, Nguyen TKO, Vo TK. 2021. Advances in developing therapeutic strategies for Alzheimer's disease. Biomed. Pharmacother. 139: 111623. https://doi.org/10.1016/j.biopha.2021.111623
  34. dos Santos Petry F, Hoppe JB, Klein CP, Dos Santos BG, Hozer RM, Bifi F, et al. 2021. Genistein attenuates amyloid-beta-induced cognitive impairment in rats by modulation of hippocampal synaptotoxicity and hyperphosphorylation of Tau. J. Nutr. Biochem. 87: 108525. https://doi.org/10.1016/j.jnutbio.2020.108525
  35. Du F, Zhao H, Yao M, Yang Y, Jiao J, Li C. 2022. Deer antler extracts reduce amyloid-beta toxicity in a Caenorhabditis elegans model of Alzheimer's disease. J. Ethnopharmacol. 285: 114850. https://doi.org/10.1016/j.jep.2021.114850
  36. Xu P, Wang K, Lu C, Dong L, Gao L, Yan M, et al. 2017. Protective effects of linalool against amyloid beta-induced cognitive deficits and damages in mice. Life Sci. 174: 21-27. https://doi.org/10.1016/j.lfs.2017.02.010
  37. Reddy PH, Beal MF. 2008. Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer's disease. Trends Mol. Med. 14: 45-53. https://doi.org/10.1016/j.molmed.2007.12.002
  38. dos Santos VV, Santos DB, Lach G, Rodrigues ALS, Farina M, De Lima TC, et al. 2013. Neuropeptide Y (NPY) prevents depressive-like behavior, spatial memory deficits and oxidative stress following amyloid-β (Aβ1-40) administration in mice. Behav. Brain Res. 244: 107-115. https://doi.org/10.1016/j.bbr.2013.01.039
  39. Kim JM, Lee U, Kang JY, Park SK, Shin EJ, Kim H-J, et al. 2020. Anti-amnesic effect of walnut via the regulation of BBB function and neuro-inflammation in Aβ1-42-induced mice. Antioxidants 9: 976. https://doi.org/10.3390/antiox9100976
  40. Postu PA, Sadiki FZ, El Idrissi M, Cioanca O, Trifan A, Hancianu M, et al. 2019. Pinus halepensis essential oil attenuates the toxic Alzheimer's amyloid beta (1-42)-induced memory impairment and oxidative stress in the rat hippocampus. Biomed. Pharmacother. 112: 108673. https://doi.org/10.1016/j.biopha.2019.108673
  41. Sharma L, Sharma A, Goyal R, Alam J. 2020. Pinus Roxburghii Sarg. Ameliorates Alzheimer's disease-type neurodegeneration and cognitive deficits caused by intracerebroventricular-streptozotocin in rats: an in vitro and in vivo Study. Indian J. Pharm. Sci. 82: 861-870.
  42. Ishrat T, Parveen K, Hoda MN, Khan MB, Yousuf S, Ansari MA, et al. 2009. Effects of Pycnogenol and vitamin E on cognitive deficits and oxidative damage induced by intracerebroventricular streptozotocin in rats. Behav. Pharmacol. 20: 567-575. https://doi.org/10.1097/FBP.0b013e32832c7125
  43. Zhao S, Zhang L, Yang C, Li Z, Rong S. 2019. Procyanidins and Alzheimer's disease. Mol. Neurobiol. 56: 5556-5567. https://doi.org/10.1007/s12035-019-1469-6
  44. Ahmed ME, Khan MM, Javed H, Vaibhav K, Khan A, Tabassum R, et al. 2013. Amelioration of cognitive impairment and neurodegeneration by catechin hydrate in rat model of streptozotocin-induced experimental dementia of Alzheimer's type. Neurochem. Int. 62: 492-501. https://doi.org/10.1016/j.neuint.2013.02.006
  45. Chen S-Y, Gao Y, Sun J-Y, Meng X-L, Yang D, Fan L-H, et al. 2020. Traditional Chinese medicine: role in reducing β-amyloid, apoptosis, autophagy, neuroinflammation, oxidative stress, and mitochondrial dysfunction of Alzheimer's disease. Front. Pharmacol. 11: 497. https://doi.org/10.3389/fphar.2020.00497
  46. Spuch C, Ortolano S, Navarro C. 2012. New insights in the amyloid-Beta interaction with mitochondria. J. Aging Res. 2012: 324968. https://doi.org/10.1155/2012/324968
  47. Butterfield DA, Lauderback CM. 2002. Lipid peroxidation and protein oxidation in Alzheimer's disease brain: potential causes and consequences involving amyloid β-peptide-associated free radical oxidative stress. Free Radic. Biol. Med. 32: 1050-1060. https://doi.org/10.1016/S0891-5849(02)00794-3
  48. Budzynska B, Boguszewska-Czubara A, Kruk-Slomka M, Skalicka-Wozniak K, Michalak A, Musik I, et al. 2015. Effects of imperatorin on scopolamine-induced cognitive impairment and oxidative stress in mice. Psychopharmacology 232: 931-942. https://doi.org/10.1007/s00213-014-3728-6
  49. Kim J, Choung S-Y. 2017. Pinus densiflora bark extract prevents selenite-induced cataract formation in the lens of Sprague Dawley rat pups. Mol. Vis. 23: 638.
  50. Sunil C, Xu B. 2019. An insight into the health-promoting effects of taxifolin (dihydroquercetin). Phytochemistry 166: 112066. https://doi.org/10.1016/j.phytochem.2019.112066
  51. Makni M, Chtourou Y, Barkallah M, Fetoui H. 2012. Protective effect of vanillin against carbon tetrachloride (CCl4)-induced oxidative brain injury in rats. Toxicol. Ind. Health 28: 655-662. https://doi.org/10.1177/0748233711420472
  52. Auld DS, Kornecook TJ, Bastianetto S, Quirion R. 2002. Alzheimer's disease and the basal forebrain cholinergic system: relations to β-amyloid peptides, cognition, and treatment strategies. Prog. Neurobiol. 68: 209-245. https://doi.org/10.1016/S0301-0082(02)00079-5
  53. Oda Y. 1999. Choline acetyltransferase: the structure, distribution and pathologic changes in the central nervous system. Pathol. Int. 49: 921-937. https://doi.org/10.1046/j.1440-1827.1999.00977.x
  54. Majdi A, Sadigh-Eteghad S, Aghsan SR, Farajdokht F, Vatandoust SM, Namvaran A, et al. 2020. Amyloid-β, tau, and the cholinergic system in Alzheimer's disease: Seeking direction in a tangle of clues. Rev. Neurosci. 31: 391-413. https://doi.org/10.1515/revneuro-2019-0089
  55. Wei L, Lv S, Huang Q, Wei J, Zhang S, Huang R, et al. 2015. Pratensein attenuates Aβ-induced cognitive deficits in rats: enhancement of synaptic plasticity and cholinergic function. Fitoterapia 101: 208-217. https://doi.org/10.1016/j.fitote.2015.01.017
  56. Dinamarca MC, Sagal JP, Quintanilla RA, Godoy JA, Arrazola MS, Inestrosa NC. 2010. Amyloid-β-Acetylcholinesterase complexes potentiate neurodegenerative changes induced by the Aβ peptide. Implications for the pathogenesis of Alzheimer's disease. Mol. Neurodegener. 5: 4. https://doi.org/10.1186/1750-1326-5-4
  57. Ahmed T, Enam S, Gilani A. 2010. Curcuminoids enhance memory in an amyloid-infused rat model of Alzheimer's disease. Neuroscience 169: 1296-1306. https://doi.org/10.1016/j.neuroscience.2010.05.078
  58. Scheff SW, Ansari MA, Roberts KN. 2013. Neuroprotective effect of Pycnogenol® following traumatic brain injury. Exp. Neurol. 239: 183-191. https://doi.org/10.1016/j.expneurol.2012.09.019
  59. Adedara IA, Fasina OB, Ayeni MF, Ajayi OM, Farombi EO. 2019. Protocatechuic acid ameliorates neurobehavioral deficits via suppression of oxidative damage, inflammation, caspase-3 and acetylcholinesterase activities in diabetic rats. Food Chem. Toxicol. 125: 170-181. https://doi.org/10.1016/j.fct.2018.12.040
  60. Wang Y, Wang Q, Bao X, Ding Y, Shentu J, Cui W, et al. 2018. Taxifolin prevents β-amyloid-induced impairments of synaptic formation and deficits of memory via the inhibition of cytosolic phospholipase A2/prostaglandin E2 content. Metab Brain Dis. 33: 1069-1079. https://doi.org/10.1007/s11011-018-0207-5
  61. Pagani L, Eckert A. 2011. Amyloid-Beta interaction with mitochondria. Int. J. Alzheimer's Dis. 2011: 925050. https://doi.org/10.4061/2011/925050
  62. Wang D-M, Li S-Q, Wu W-L, Zhu X-Y, Wang Y, Yuan H-Y. 2014. Effects of long-term treatment with quercetin on cognition and mitochondrial function in a mouse model of Alzheimer's disease. Neurochem. Res. 39: 1533-1543. https://doi.org/10.1007/s11064-014-1343-x
  63. Tao L, Liu X, Da W, Tao Z, Zhu Y. 2020. Pycnogenol achieves neuroprotective effects in rats with spinal cord injury by stabilizing the mitochondrial membrane potential. Neurol. Res. 42: 597-604. https://doi.org/10.1080/01616412.2020.1773610
  64. Han L, Yang Q, Li J, Cheng F, Zhang Y, Li Y, et al. 2019. Protocatechuic acid-ameliorated endothelial oxidative stress through regulating acetylation level via CD36/AMPK pathway. J. Agric. Food Chem. 67: 7060-7072. https://doi.org/10.1021/acs.jafc.9b02647
  65. Ghosh P, Singh R, Ganeshpurkar A, Pokle AV, bhushan Singh R, Singh SK, et al. 2021. Cellular and molecular influencers of neuroinflammation in Alzheimer's disease: Recent concepts & roles. Neurochem. Int. 151: 105212. https://doi.org/10.1016/j.neuint.2021.105212
  66. Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, et al. 2015. Neuroinflammation in Alzheimer's disease. Lancet Neurol. 14: 388-405. https://doi.org/10.1016/S1474-4422(15)70016-5
  67. Li Y, Fan H, Ni M, Zhang W, Fang F, Sun J, et al. 2022. Etanercept reduces neuron injury and neuroinflammation via inactivating c-Jun N-terminal kinase and nuclear factor-κB pathways in Alzheimer's disease: An in vitro and in vivo investigation. Neuroscience 484: 140-150. https://doi.org/10.1016/j.neuroscience.2021.11.001
  68. Kim JM, Park SK, Kang JY, Park SB, Yoo SK, Han HJ, et al. 2019. Green tea seed oil suppressed Aβ1-42-induced behavioral and cognitive deficit via the Aβ-related Akt pathway. Int. J. Mol. Sci. 20: 1865. https://doi.org/10.3390/ijms20081865
  69. Ma X, Fang F, Song M, Ma S. 2015. The effect of isoliquiritigenin on learning and memory impairments induced by high-fat diet via inhibiting TNF-α/JNK/IRS signaling. Biochem. Biophy. Res. Commun. 464: 1090-1095. https://doi.org/10.1016/j.bbrc.2015.07.081
  70. Qu R, Chen X, Hu J, Fu Y, Peng J, Li Y, et al. 2019. Ghrelin protects against contact dermatitis and psoriasiform skin inflammation by antagonizing TNF-α/NF-κB signaling pathways. Sci. Rep. 9: 1348. https://doi.org/10.1038/s41598-018-38174-2
  71. Khan MM, Kempuraj D, Thangavel R, Zaheer A. 2013. Protection of MPTP-induced neuroinflammation and neurodegeneration by Pycnogenol. Neurochem. Int. 62: 379-388. https://doi.org/10.1016/j.neuint.2013.01.029
  72. Park JH, Kim JD, Lee T-K, Han X, Sim H, Kim B, et al. 2021. Neuroprotective and anti-inflammatory effects of Pinus densiflora bark extract in Gerbil Hippocampus following transient Forebrain Ischemia. Molecules 26: 4592. https://doi.org/10.3390/molecules26154592
  73. Chetsawang B, Putthaprasart C, Phansuwan-Pujito P, Govitrapong P. 2006. Melatonin protects against hydrogen peroxide-induced cell death signaling in SH-SY5Y cultured cells: involvement of nuclear factor kappa B, Bax and Bcl-2. J. Pineal Res. 41: 116-123. https://doi.org/10.1111/j.1600-079X.2006.00335.x
  74. Nguyen KC, Willmore WG, Tayabali AF. 2013. Cadmium telluride quantum dots cause oxidative stress leading to extrinsic and intrinsic apoptosis in hepatocellular carcinoma HepG2 cells. Toxicology 306: 114-123. https://doi.org/10.1016/j.tox.2013.02.010
  75. Okkay U, Ferah Okkay I, Cicek B, Aydin IC, Ozkaraca M. 2022. Hepatoprotective and neuroprotective effect of taxifolin on hepatic encephalopathy in rats. Metab. Brain Dis. 37: 1541-1556. https://doi.org/10.1007/s11011-022-00952-3
  76. Li Z, Liu Y, Wang F, Gao Z, Elhefny MA, Habotta OA, et al. 2021. Neuroprotective effects of protocatechuic acid on sodium arsenate induced toxicity in mice: Role of oxidative stress, inflammation, and apoptosis. Chem. Biol. Interact. 337: 109392. https://doi.org/10.1016/j.cbi.2021.109392
  77. Mohammadi A, Amooeian VG, Rashidi E. 2018. Dysfunction in brain-derived neurotrophic factor signaling pathway and susceptibility to schizophrenia, Parkinson's and Alzheimer's diseases. Curr. Gene Ther. 18: 45-63. https://doi.org/10.2174/1566523218666180302163029
  78. Rosa E, Fahnestock M. 2015. CREB expression mediates amyloid β-induced basal BDNF downregulation. Neurobiol. Aging 36: 2406-2413. https://doi.org/10.1016/j.neurobiolaging.2015.04.014
  79. Garzon DJ, Fahnestock M. 2007. Oligomeric amyloid decreases basal levels of brain-derived neurotrophic factor (BDNF) mRNA via specific downregulation of BDNF transcripts IV and V in differentiated human neuroblastoma cells. J. Neurosci. 27: 2628-2635. https://doi.org/10.1523/JNEUROSCI.5053-06.2007
  80. Kim MJ, Park S-Y, Kim Y, Jeon S, Cha MS, Kim YJ, et al. 2022. Beneficial Effects of a combination of Curcuma longa L. and Citrus junos against beta-amyloid peptide-induced neurodegeneration in mice. J. Med. Food 25: 12-23. https://doi.org/10.1089/jmf.2021.K.0138
  81. Lee J-S, Kim H-G, Lee H-W, Han J-M, Lee S-K, Kim D-W, et al. 2015. Hippocampal memory enhancing activity of pine needle extract against scopolamine-induced amnesia in a mouse model. Sci. Rep. 5: 19651.
  82. Kale S, Sarode LP, Kharat A, Ambulkar S, Prakash A, Sakharkar AJ, et al. 2021. Protocatechuic acid prevents early hour ischemic reperfusion brain damage by restoring imbalance of neuronal cell death and survival proteins. J. Stroke Cerebrovasc. Dis. 30: 105507. https://doi.org/10.1016/j.jstrokecerebrovasdis.2020.105507