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N2L, a novel lipoic acid-niacin dimer protects HT22 cells against β-amyloid peptide-induced damage through attenuating apoptosis

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Abstract

β-amyloid protein (Aβ) is thought to be the primary cause of the pathogenesis of Alzheimer’s disease (AD). Niacin has been reported to have beneficial effects on AD. Previously, we synthesized a novel compound lipoicacid–niacin dimer (N2L) and revealed that it had potent blood-lipid regulation and antioxidative properties without aflushing effect. Given that lipid metabolism is also associated with AD, the present study aimed to investigate the neuroprotective effects of N2L on Aβ1–42-induced cytotoxicity in HT22 cells. We found that N2L significantly attenuated cell apoptosis, MDA level, ROS content, and the mitochondrial membrane potential corruption induced by Aβ1–42 in HT22 cells. In addition, the activities of SOD, GSH-px and CAT that were decreased by Aβ1–42 were also restored by N2L. Furthermore, N2L reduced proapoptotic signaling by increasing the expression of anti-apoptotic Bcl-2 and decreasing the protein expression of both pro-apoptotic Bax and cleaved Caspase-3. Together, these findings indicate that N2L holds great potential for neuroprotection against Aβ1–42-induced cytotoxicity via inhibition of oxidative stress and cell apoptosis, suggesting that N2L may be a promising agent for AD therapy.

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References

  • Abramov AY, Canevari L, Duchen MR (2004) Beta-amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase. J Neurosci 24:565–575

    CAS  PubMed  PubMed Central  Google Scholar 

  • Alkam T, Nitta A, Furukawa-Hibi Y, Niwa M, Mizoguchi H, Yamada K, Nabeshima T (2010) Oral supplementation with Leu-Ile, a hydrophobic dipeptide, prevents the impairment of memory induced by amyloid beta in mice via restraining the hyperphosphorylation of extracellular signal-regulated kinase. Behav Brain Res 210:184–190

    CAS  PubMed  Google Scholar 

  • Ashley RH, Harroun TA, Hauss T, Breen KC, Bradshaw JP (2006) Autoinsertion of soluble oligomers of Alzheimer's Abeta(1-42) peptide into cholesterol-containing membranes is accompanied by relocation of the sterol towards the bilayer surface. BMC Structural Biology 6:21

    PubMed  PubMed Central  Google Scholar 

  • Canevari L, Abramov AY, Duchen MR (2004) Toxicity of amyloid beta peptide: tales of calcium, mitochondria, and oxidative stress. Neurochem Res 29:637–650

    CAS  PubMed  Google Scholar 

  • Chang TY, Chang C (2017) ApoE and Lipid Homeostasis in Alzheimer's Disease: Introduction to the Thematic Review Series. J. Lipid Res 58:823

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chen X, Gao J, Jiang Y, Huang P, Xie Y, Pi R, Zhu S, Yao M (2014) Determination of newly synthesized lipoic acid-niacin dimer in rat plasma by UPLC/electrospray ionization tandem mass spectrometry: assay development, validation and application to a pharmacokinetic study. Biomed. Chromatogr: BMC 28:213–217

    CAS  PubMed  Google Scholar 

  • El Gaamouch F, Jing P, Xia J, Cai D (2016) Alzheimer's disease risk genes and lipid regulators. Am. J. Alzheimers Dis: JAD. 53:15–29

    Google Scholar 

  • Farr SA, Poon HF, Dogrukol-Ak D, Drake J, Banks WA, Eyerman E, Butterfield DA, Morley JE (2003) The antioxidants alpha-lipoic acid and N-acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8 mice. J Neurochem 84:1173–1183

    CAS  PubMed  Google Scholar 

  • Forman MS, Trojanowski JQ, Lee VM (2004) Neurodegenerative diseases: a decade of discoveries paves the way for therapeutic breakthroughs. Nat Med 10:1055–1063

    CAS  PubMed  Google Scholar 

  • Frisardi V, Solfrizzi V, Imbimbo PB, Capurso C, D'Introno A, Colacicco AM, Vendemiale G, Seripa D, Pilotto A, Capurso A (2010) Towards disease-modifying treatment of Alzheimer's disease: drugs targeting beta-amyloid. Curr Alzheimer Res 7:40–55

    CAS  PubMed  Google Scholar 

  • Galimberti D, Scarpini E (2011) Inflammation and oxidative damage in Alzheimer's disease: friend or foe? Front Biosci (Schol Ed) 3:252–266

    Google Scholar 

  • Ganji SH, Qin S, Zhang L, Kamanna VS, Kashyap ML (2009) Niacin inhibits vascular oxidative stress, redox-sensitive genes, and monocyte adhesion to human aortic endothelial cells. Atherosclerosis. 202:68–75

    CAS  PubMed  Google Scholar 

  • Gunn AP, Wong BX, Johanssen T, Griffith JC, Masters CL, Bush AI, Barnham KJ, Duce JA, Cherny RA (2016) Amyloid-beta peptide Abeta3pE-42 induces lipid peroxidation, membrane Permeabilization, and calcium influx in neurons. J Biol Chem 291:6134–6145

    CAS  PubMed  Google Scholar 

  • Hager K, Marahrens A, Kenklies M, Riederer P, Munch G (2001) Alpha-lipoic acid as a new treatment option for Alzheimer [corrected] type dementia. Arch Gerontol Geriatr 32:275–282

    CAS  PubMed  Google Scholar 

  • Han SH, Park JC, Mook-Jung I (2016) Amyloid beta-interacting partners in Alzheimer's disease: from accomplices to possible therapeutic targets. Prog Neurobiol 137:17–38

    CAS  PubMed  Google Scholar 

  • Higgins G, Beart P, Shin Y, Chen M, Cheung N, Nagley P (2010) Oxidative stress: emerging mitochondrial and cellular themes and variations in neuronal injury. J Alzheimers Dis 20(Suppl 2):S453–S473

    PubMed  Google Scholar 

  • Kei A, Elisaf MS (2012) Nicotinic acid: clinical considerations. Expert Opin Drug Saf 11:551–564

    CAS  PubMed  Google Scholar 

  • Kim H, Kim G, Jang W, Kim SY, Chang N (2014) Association between intake of B vitamins and cognitive function in elderly Koreans with cognitive impairment. Nutr J 13:118

    PubMed  PubMed Central  Google Scholar 

  • Kong Y, Kong LP, Luo T, Li GW, Jiang W, Li S, Zhou Y, Wang HQ (2014) The protective effects of crocetin on abeta(1)(−)(4)(2)-induced toxicity in Ht22 cells. CNS Neurol. Disord. Drug Targets 13:1627–1632

    CAS  PubMed  Google Scholar 

  • Kwon WY, Suh GJ, Kim KS, Jung YS, Kim SH, Lee AR, You KM, Park MJ (2018) Niacin and selenium attenuate brain injury after cardiac arrest in rats by up-regulating DJ-1-Akt signaling. Crit Care Med 46:e788–e796

    CAS  PubMed  Google Scholar 

  • Lee HR, Park SY, Kim HY, Shin HK, Lee WS, Rhim BY, Hong KW, Kim CD (2012) Protection by cilostazol against amyloid-beta(1-40)-induced suppression of viability and neurite elongation through activation of CK2alpha in HT22 mouse hippocampal cells. J Neurosci Res 90:1566–1576

    CAS  PubMed  Google Scholar 

  • Lee JS, Kim JY, Kim HJ, Kim JC, Lee JS, Kim N, Park MJ (2016) Effects of combined radiofrequency field exposure on amyloid-beta-induced cytotoxicity in HT22 mouse hippocampal neurones. J Radiat Res 57:620–626

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lin Y, Desbois A, Jiang S, Hou ST (2004) Group B vitamins protect murine cerebellar granule cells from glutamate/NMDA toxicity. Neuroreport. 15:2241–2244

    CAS  PubMed  Google Scholar 

  • Liu Q, Zhang J (2014) Lipid metabolism in Alzheimer's disease. Neurosci Bull 30:331–345

    PubMed  PubMed Central  Google Scholar 

  • Lovell MA, Xie C, Xiong S, Markesbery WR (2003) Protection against amyloid beta peptide and iron/hydrogen peroxide toxicity by alpha lipoic acid. Am. J. Alzheimers Dis: JAD 5:229–239

    CAS  Google Scholar 

  • Luo L, Chen J, Su D, Chen M, Luo B, Pi R, Wang L, Shen W, Wang R (2017) L-F001, a multifunction ROCK inhibitor prevents 6-OHDA induced cell death through activating Akt/GSK-3beta and Nrf2/HO-1 signaling pathway in PC12 cells and attenuates MPTP-induced dopamine neuron toxicity in mice. Neurochem Res 42:615–624

    CAS  PubMed  Google Scholar 

  • Ly JD, Grubb DR, Lawen A (2003) The mitochondrial membrane potential (deltapsi(m)) in apoptosis; an update. Apoptosis 8:115–128

    CAS  PubMed  Google Scholar 

  • Meunier J, Ieni J, Maurice T (2006) The anti-amnesic and neuroprotective effects of donepezil against amyloid beta25-35 peptide-induced toxicity in mice involve an interaction with the sigma1 receptor. Br J Pharmacol 149:998–1012

    CAS  PubMed  PubMed Central  Google Scholar 

  • Morris MC, Evans DA, Bienias JL, Scherr PA, Tangney CC, Hebert LE, Bennett DA, Wilson RS, Aggarwal N (2004) Dietary niacin and the risk of incident Alzheimer's disease and of cognitive decline. J Neurol Neurosurg Psychiatry 75:1093–1099

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nordberg A (2004) PET imaging of amyloid in Alzheimer's disease. Lancet Neurol 3:519–527

    CAS  PubMed  Google Scholar 

  • Ono K, Hirohata M, Yamada M (2006) Alpha-lipoic acid exhibits anti-amyloidogenicity for beta-amyloid fibrils in vitro. Biochem Biophys Res Commun 341:1046–1052

    CAS  PubMed  Google Scholar 

  • Onyango IG, Khan SM (2006) Oxidative stress, mitochondrial dysfunction, and stress signaling in Alzheimer's disease. Curr Alzheimer Res 3:339–349

    CAS  PubMed  Google Scholar 

  • Padurariu M, Ciobica A, Hritcu L, Stoica B, Bild W, Stefanescu C (2010) Changes of some oxidative stress markers in the serum of patients with mild cognitive impairment and Alzheimer's disease. Neurosci Lett 469:6–10

    CAS  PubMed  Google Scholar 

  • Pi RB, Jiang YM, Cao XJ, Liu PQ, Huang Y, Yao MC, He XX (2011) Niacin derivatives, preparation methods and pharmaceutical compositions. Chinese Patent ZL201110430852.0

  • Qin B, Xun P, Jacobs DR Jr, Zhu N, Daviglus ML, Reis JP, Steffen LM, Van Horn L, Sidney S, He K (2017) Intake of niacin, folate, vitamin B-6, and vitamin B-12 through young adulthood and cognitive function in midlife: the Coronary Artery Risk Development in Young Adults (CARDIA) study. Am. J. Clin. Nutr 106:1032–1040

    CAS  PubMed  PubMed Central  Google Scholar 

  • Quinn JF, Bussiere JR, Hammond RS, Montine TJ, Henson E, Jones RE, Stackman RW Jr (2007) Chronic dietary alpha-lipoic acid reduces deficits in hippocampal memory of aged Tg2576 mice. Neurobiol. Aging 28:213–225

    CAS  PubMed  Google Scholar 

  • Rabie T, Muhlhofer W, Bruckner T, Schwab A, Bauer AT, Zimmermann M, Bonke D, Marti HH, Schenkel J (2010) Transient protective effect of B-vitamins in experimental epilepsy in the mouse brain. J. Mol. Neurosci: MN 41:74–79

    CAS  PubMed  Google Scholar 

  • Rojo AI, Pajares M, Rada P, Nunez A, Nevado-Holgado AJ, Killik R, Van Leuven F, Ribe E, Lovestone S, Yamamoto M, Cuadrado A (2017) NRF2 deficiency replicates transcriptomic changes in Alzheimer’s patients and worsens APP and TAU pathology. Redox biology. 13:444–451

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sancheti H, Akopian G, Yin F, Brinton RD, Walsh JP, Cadenas E (2013) Age-dependent modulation of synaptic plasticity and insulin mimetic effect of lipoic acid on a mouse model of Alzheimer’s disease. PloS one. 8:e69830

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sancheti H, Kanamori K, Patil I, Diaz Brinton R, Ross BD, Cadenas E (2014) Reversal of metabolic deficits by lipoic acid in a triple transgenic mouse model of Alzheimer’s disease: a 13C NMR study. J Cereb Blood Flow Metab 34:288–296

    Google Scholar 

  • Schenk D (2004) Hopes remain for an Alzheimer’s vaccine. Nature. 431:398

    CAS  PubMed  Google Scholar 

  • Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science. 298:789–791

    CAS  PubMed  Google Scholar 

  • Selkoe DJ (2008) Soluble Oligomers of the Amyloid β-Protein: Impair Synaptic Plasticity and Behavior. Behav. Brain Res. 192:106–113

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shehadah A, Chen J, Cui X, Roberts C, Lu M, Chopp M (2010) Combination treatment of experimental stroke with Niaspan and Simvastatin, reduces axonal damage and improves functional outcome. J. Neurol. Sci. 294:107–111

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shen W, Wang L, Pi R, Li Z, Rikang W (2015) L-F001, a multifunctional ROCK inhibitor prevents paraquat-induced cell death through attenuating ER stress and mitochondrial dysfunction in PC12 cells. Biochem. Biophys. Res. Commun. 464:794–799

    CAS  PubMed  Google Scholar 

  • Smith AD, Refsum H (2016) Homocysteine, B Vitamins, and Cognitive Impairment. Annu. Rev. Nutr. 36:211–239

    CAS  PubMed  Google Scholar 

  • Sorrentino SA, Besler C, Rohrer L, Meyer M, Heinrich K, Bahlmann FH, Mueller M, Horvath T, Doerries C, Heinemann M, Flemmer S, Markowski A, Manes C, Bahr MJ, Haller H, von Eckardstein A, Drexler H, Landmesser U (2010) Endothelial-vasoprotective effects of high-density lipoprotein are impaired in patients with type 2 diabetes mellitus but are improved after extended-release niacin therapy. Circulation. 121:110–122

    CAS  PubMed  Google Scholar 

  • Surjana D, Halliday GM, Damian DL (2010) Role of nicotinamide in DNA damage, mutagenesis, and DNA repair. J Nucleic Acids 2010:157591

  • Tai ST, Fu YH, Yang YC, Wang JJ (2015) Niacin ameliorates kidney warm ischemia and reperfusion injury-induced ventricular dysfunction and oxidative stress and disturbance in mitochondrial metabolism in rats. Transplant. Proc. 47:1079–1082

    CAS  PubMed  Google Scholar 

  • Thomas T, Nadackal TG, Thomas K (2001) Aspirin and non-steroidal anti-inflammatory drugs inhibit amyloid-beta aggregation. Neuroreport. 12:3263–3267

    CAS  PubMed  Google Scholar 

  • Tillement L, Lecanu L, Papadopoulos V (2011) Further evidence on mitochondrial targeting of β-amyloid and specificity of β-amyloid-induced mitotoxicity in neurons. Neurodegener Dis. 8:331–344

    CAS  PubMed  Google Scholar 

  • Trubetskaya VV, Stepanichev MY, Onufriev MV, Lazareva NA, Markevich VA, Gulyaeva NV (2003) Administration of aggregated beta-amyloid peptide (25–35) induces changes in long-term potentiation in the hippocampus in vivo. Neurosci. Behav. Physiol. 33:95–98

    CAS  PubMed  Google Scholar 

  • Turunc Bayrakdar E, Uyanikgil Y, Kanit L, Koylu E, Yalcin A (2014) Nicotinamide treatment reduces the levels of oxidative stress, apoptosis, and PARP-1 activity in Abeta(1–42)-induced rat model of Alzheimer’s disease. Free Radic. Res. 48:146–158

    CAS  PubMed  Google Scholar 

  • Virag L, Szabo C (2002) The therapeutic potential of poly (ADP-ribose) polymerase inhibitors. Pharmacol. Rev. 54:375–429

    CAS  PubMed  Google Scholar 

  • Wang GF, Li WL, Zou XL, Zou YP, Pi RB, Yao M (2013) Protective effects of lipoic acid-niacin diad on ARPE-19 cells induced by acrolein. Rec Adv Ophthalmol (Chinese) 33:106–109

    Google Scholar 

  • Wang R, Sun Y, Huang H, Wang L, Chen J, Shen W (2015) Rutin, A Natural Flavonoid Protects PC12 Cells Against Sodium Nitroprusside-Induced Neurotoxicity Through Activating PI3K/Akt/mTOR and ERK1/2 Pathway. Neurochem. Res. 40:1945–1953

    CAS  PubMed  Google Scholar 

  • Wohlrab J, Kreft D (2014) Niacinamide - mechanisms of action and its topical use in dermatology. Skin Pharmacol. Physiol. 27:311–315

    CAS  PubMed  Google Scholar 

  • Xie Y, Hou W, Song X, Yu Y, Huang J, Sun X, Kang R, Tang D (2016) Ferroptosis: process and function. Cell Death Differ. 23:369–379

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yalcin A, Soddu E, Turunc Bayrakdar E, Uyanikgil Y, Kanit L, Armagan G, Rassu G, Gavini E, Giunchedi P (2016) Neuroprotective Effects of Engineered Polymeric Nasal Microspheres Containing Hydroxypropyl-beta-cyclodextrin on beta-Amyloid (1–42)-Induced Toxicity. J. Pharm. Sci. 105:2372–2380

    CAS  PubMed  Google Scholar 

  • Yamada K, Nabeshima T (2000) Animal models of Alzheimer’s disease and evaluation of anti-dementia drugs. Pharmacol. Ther. 88:93

    CAS  PubMed  Google Scholar 

  • Zhang YH, Wang DW, Xu SF, Zhang S, Fan YG, Yang YY, Guo SQ, Wang S, Guo T, Wang ZY, Guo C (2018) alpha-Lipoic acid improves abnormal behavior by mitigation of oxidative stress, inflammation, ferroptosis, and tauopathy in P301S Tau transgenic mice. Redox Biol. 14:535–548

    CAS  PubMed  Google Scholar 

  • Zheng WH, Bastianetto S, Mennicken F, Ma W, Kar S (2002) Amyloid β peptide induces tau phosphorylation and loss of cholinergic neurons in rat primary septal cultures. Neuroscience. 115:201–211

    CAS  PubMed  Google Scholar 

  • Zhu TB, Zhang Z, Luo P, Wang SS, Peng Y, Chu SF, Chen NH (2018) Lipid metabolism in Alzheimer’s disease. Brain Res. Bull.

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (No.81560662, No.81803536); Guangdong Provincial Key Laboratory of Construction Foundation (No.2017B030314030); Science and Technology Planning Project of Guangdong Province (No.2016A020226036, No 2016A020226011); Shenzhen Basic Research Projects (No.JCYJ20170818100811018) and Health and Family Planning Commission of Jiangxi Province (No.20185520).

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  1. Rikang Wang and Lang Zhang contributed equally to this study.

Authors and Affiliations

  1. National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330006, China

    Rikang Wang

  2. Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Shenzhen University Health Science Center, Shenzhen, 518060, China

    Rikang Wang

  3. Jiangxi Provincial Children’s Hospital, Nanchang, 330006, People’s Republic of China

    Lang Zhang

  4. Department of Pharmacy, Sun Yat-sen Memorial Hospital, SunYat-sen University, Guangzhou, 510120, China

    Rifang Liao

  5. Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510120, China

    Qian Li & Xiaobo Yang

  6. Department of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510080, China

    Rongbiao Pi

  7. International Joint Laboratory (SYSU-PolyU HK) of Novel Anti-Dementia Drugs of Guangdong, Guangzhou, 510006, China

    Rongbiao Pi

  8. National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Sun Yat-Sen University, Guangzhou, 510080, China

    Rongbiao Pi

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  1. Rikang Wang
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Wang, R., Zhang, L., Liao, R. et al. N2L, a novel lipoic acid-niacin dimer protects HT22 cells against β-amyloid peptide-induced damage through attenuating apoptosis. Metab Brain Dis 34, 1761–1770 (2019). https://doi.org/10.1007/s11011-019-00482-5

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