- Open Access
Beneficial effect of diosgenin as a stimulator of NGF on the brain with neuronal damage induced by Aβ-42 accumulation and neurotoxicant injection
Laboratory Animal Research volume 32, pages105–115(2016)
To investigate the beneficial effects of diosgenin (DC) on the multiple types of brain damage induced by Aβ-42 peptides and neurotoxicants, alterations in the specific aspects of brain functions were measured in trimethyltin (TMT)-injected transgenic 2576 (TG) mice that had been pretreated with DC for 21 days. Multiple types of damage were successfully induced by Aß-42 accumulation and TMT injection into the brains of TG mice. However, DC treatment significantly reduced the number of Aß-stained plaques and dead cells in the granule cells layer of the dentate gyrus. Significant suppression of acetylcholinesterase (AChE) activity and Bax/Bcl-2 expression was also observed in the DC treated TG mice (TG+DG group) when compared with those of the vehicle (VC) treated TG mice (TG+VC group). Additionally, the concentration of nerve growth factor (NGF) was dramatically enhanced in TG+DG group, although it was lower in the TG+VC group than the non-transgenic (nTG) group. Furthermore, the decreased phosphorylation of downstream members in the TrkA high affinity receptor signaling pathway in the TG+VC group was significantly recovered in the TG+DG group. A similar pattern was observed in p75NTR expression and JNK phosphorylation in the NGF low affinity receptor signaling pathway. Moreover, superoxide dismutase (SOD) activity was enhanced in the TG+DG group, while the level of malondialdehyde (MDA), a marker of lipid peroxidation, was lower in the TG+DG group than the TG+VC group. These results suggest that DC could exert a wide range of beneficial activities for multiple types of brain damage through stimulation of NGF biosynthesis.
Ziegler-Graham K, Brookmeyer R, Johnson E, Arrighi HM. Worldwide variation in the doubling time of Alzheimer’s disease incidence rates. Alzheimers Dement 2008; 4(5): 316–323.
Mattson MP. Pathways towards and away from Alzheimer’s disease. Nature 2004; 430(7000): 631–639.
Salloway S, Correia S. Alzheimer disease: time to improve its diagnosis and treatment. Cleve Clin J Med 2009; 76(1): 49–58.
Henley DB, May PC, Dean RA, Siemers ER. Development of semagacestat (LY450139), a functional gamma-secretase inhibitor, for the treatment of Alzheimer’s disease. Expert Opin Pharmacother 2009; 10(10): 1657–1664.
Dickson TC, Vickers JC. The morphological phenotype of beta- amyloid plaques and associated neuritic changes in Alzheimer’s disease. Neuroscience 2001; 105(1): 99–107.
Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R. Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 1991; 30(4): 572–580.
Tohda C, Kuboyama T, Komatsu K. Search for natural products related to regeneration of the neuronal network. Neurosignals 2005; 14(1-2): 34–443.
Salloway S, Sperling R, Gilman S, Fox NC, Blennow K, Raskind M, Sabbagh M, Honig LS, Doody R, van Dyck CH, Mulnard R, Barakos J, Gregg KM, Liu E, Lieberburg I, Schenk D, Black R, Grundman M; Bapineuzumab 201 Clinical Trial Investigators. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology 2009; 73(24): 2061–2070.
Tohda C, Urano T, Umezaki M, Nemere I, Kuboyama T. Diosgenin is an exogenous activator of 1,25D3-MARRS/Pdia3/ERp57 and improves Alzheimer’s disease pathologies in 5XFAD mice. Sci Rep 2012; 2: 535.
Baulieu EE, Robel P, Schumacher M. Neurosteroids: beginning of the story. Int Rev Neurobiol 2001; 46: 1–32.
Papadopoulos V, Lecanu L. Caprospinol: discovery of a steroid drug candidate to treat Alzheimer’s disease based on 22R- hydroxycholesterol structure and properties. J Neuroendocrinol 2012; 24(1): 93–101.
Burkill IH. The organography and the evolution of Dioscoreaceae, the family of the Yams. J Linn Soc (Bot) 1960; 56(367): 319–412.
Yan LL, Zhang YJ, Gao WY, Man SL, Wang Y. In vitro and in vivo anticancer activity of steroid saponins of Paris polyphylla var. yunnanensis. Exp Oncol 2009; 31(1): 27–32.
Huang CH, Ku CY, Jan TR. Diosgenin attenuates allergen-induced intestinal inflammation and IgE production in a murine model of food allergy. Planta Med 2009; 75(12): 1300–1305.
Chiu CS, Chiu YJ, Wu LY, Lu TC, Huang TH, Hsieh MT, Lu CY, Peng WH. Diosgenin ameliorates cognition deficit and attenuates oxidative damage in senescent mice induced by D-galactose. Am J Chin Med 2011; 39(3): 551–563.
Kang TH, Moon E, Hong BN, Choi SZ, Son M, Park JH, Kim SY. Diosgenin from Dioscorea nipponica ameliorates diabetic neuropathy by inducing nerve growth factor. Biol Pharm Bull 2011; 34(9): 1493–1498.
Tohda C, Lee YA, Goto Y, Nemere I. Diosgenin-induced cognitive enhancement in normal mice is mediated by 1,25D3-MARRS. Sci Rep 2013; 3: 3395.
Prajapati KD, Sharma SS, Roy N. Upregulation of albumin expression in focal ischemic rat brain. Brain Res 2010; 1327: 118–124.
Kawarabayashi T, Younkin LH, Saido TC, Shoji M, Ashe KH, Younkin SG. Age-dependent changes in brain, CSF, and plasma amyloid (beta) protein in the Tg2576 transgenic mouse model of Alzheimer’s disease. J Neurosci 2001; 21(2): 372–381.
Massoulie J, Pezzementi L, Bon S, Krejci E, Vallette FM. Molecular and cellular biology of cholinesterases. Prog Neurobiol 1993; 41(1): 31–91.
Obara Y, Nakahata N. The signaling pathway of neurotrophic factor biosynthesis. Drug News Perspect 2002; 15(5): 290–298.
Takei N, Tsukui H, Hatanaka H. Intracellular storage and evoked release of acetylcholine from postnatal rat basal forebrain cholinergic neurons in culture with nerve growth factor. J Neurochem 1989; 53(5): 1405–1410.
Wyman T, Rohrer D, Kirigiti P, Nichols H, Pilcher K, Nilaver G, Machida C. Promoter-activated expression of nerve growth factor for treatment of neurodegenerative diseases. Gene Ther 1999; 6(10): 1648–1660.
Furukawa Y, Furukawa S, Satoyoshi E, Hayashi K. Catecholamines induce an increase in nerve growth factor content in the medium of mouse L-M cells. J Biol Chem 1986; 261(13): 6039–6047.
Furukawa Y, Furukawa S, Ikeda F, Satoyoshi E, Hayashi K. Aliphatic side chain of catecholamine potentiates the stimulatory effect of the catechol part on the synthesis of nerve growth factor. FEBS Lett 1986; 208(2): 258–262.
Obara Y, Nakahata N, Kita T, Takaya Y, Kobayashi H, Hosoi S, Kiuchi F, Ohta T, Oshima Y, Ohizumi Y. Stimulation of neurotrophic factor secretion from 1321N1 human astrocytoma cells by novel diterpenoids, scabronines. A and G Eur J Pharmacol 1999; 370(1): 79–84.
Marcotullio MC, Pagiotti R, Maltese F, Oball-Mond Mwankie GN, Hoshino T, Obara Y, Nakahata N. Cyathane diterpenes from Sarcodon cyrneus and evaluation of their activities of neuritegenesis and nerve growth factor production. Bioorg Med Chem 2007; 15(8): 2878–2882.
Ma BJ, Shen JW, Yu HY, Ruan Y, Wu TT, Zhao X. Hericenones and erinacines: stimulators of nerve growth factor (NGF) biosynthesis in Hericium erinaceus. Mycol 2010; 1(2): 92–98.
Kumar S, Walter J. Phosphorylation of amyloid beta (Aβ) peptides - a trigger for formation of toxic aggregates in Alzheimer’s disease. Aging (Albany NY) 2011; 3(8): 803–812.
Huang Y, Mucke L. Alzheimer mechanisms and therapeutic strategies. Cell 2012; 148(6): 1204–1222.
Leuner K, Schutt T, Kurz C, Eckert SH, Schiller C, Occhipinti A, Mai S, Jendrach M, Eckert GP, Kruse SE, Palmiter RD, Brandt U, Drose S, Wittig I, Willem M, Haass C, Reichert AS, Muller WE. Mitochondrion-derived reactive oxygen species lead to enhanced amyloid beta formation. Antioxid Redox Signal 2012; 16(12): 1421–1433.
Leuner K, Muller WE, Reichert AS. From mitochondrial dysfunction to amyloid beta formation: novel insights into the pathogenesis of Alzheimer’s disease. Mol Neurobiol 2012; 46(1): 186–193.
Park D, Joo SS, Kim TK, Lee SH, Kang H, Lee HJ, Lim I, Matsuo A, Tooyama I, Kim YB, Kim SU. Human neural stem cells overexpressing choline acetyltransferase restore cognitive function of kainic acid-induced learning and memory deficit animals. Cell Transplant 2012; 21(1): 365–371.
Nunes-Tavares N, Santos LE, Stutz B, Brito-Moreira J, Klein WL, Ferreira ST, de Mello FG. Inhibition of choline acetyltransferase as a mechanism for cholinergic dysfunction induced by amyloid- ß peptide oligomers. J Biol Chem 2012; 287(23): 19377–19385.
Nabeshima T, Noda Y, Kamei H. Anti-dementia drugs for Alzheimer disease in present and future. Nihon Yakurigaku Zasshi 2002; 120(1): 24–29.
Kar S, Slowikowski SP, Westaway D, Mount HT. Interactions between beta-amyloid and central cholinergic neurons: implications for Alzheimer’s disease. J Psychiatry Neurosci 2004; 29(6): 427–441.
Ingkaninan K, Temkitthawon P, Chuenchom K, Yuyaem T, Thongnoi W. Screening for acetylcholinesterase inhibitory activity in plants used in Thai traditional rejuvenating and neurotonic remedies. J Ethnopharmacol 2003; 89(2-3): 261–1267.
Chattipakorn S, Pongpanparadorn A, Pratchayasakul W, Pongchaidacha A, Ingkaninan K, Chattipakorn N. Tabernaemontana divaricata extract inhibits neuronal acetylcholinesterase activity in rats. J Ethnopharmacol 2007; 110(1): 61–68.
Nakdook W, Khongsombat O, Taepavarapruk P, Taepavarapruk N, Ingkaninan K. The effects of Tabernaemontana divaricata root extract on amyloid beta-peptide 25–35 peptides induced cognitive deficits in mice. J Ethnopharmacol 2010; 130(1): 122–126.
Nitta A, Ogihara Y, Onishi J, Hasegawa T, Furukawa S, Nabeshima T. Oral administration of propentofylline, a stimulator of nerve growth factor (NGF) synthesis, recovers cholinergic neuronal dysfunction induced by the infusion of anti-NGF antibody into the rat septum. Behav Brain Res 1997; 83(1-2): 201–204.
About this article
Cite this article
Koh, E., Yun, W., Kim, J. et al. Beneficial effect of diosgenin as a stimulator of NGF on the brain with neuronal damage induced by Aβ-42 accumulation and neurotoxicant injection. Lab Anim Res 32, 105–115 (2016). https://doi.org/10.5625/lar.2016.32.2.105
- neurodegenerative disorder
- nerve growth factor