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Melatonin Rescue Oxidative Stress-Mediated Neuroinflammation/ Neurodegeneration and Memory Impairment in Scopolamine-Induced Amnesia Mice Model

  • Tahir Muhammad
  • Tahir Ali
  • Muhammad Ikram
  • Amjad Khan
  • Sayed Ibrar Alam
  • Myeong Ok KimEmail author
ORIGINAL ARTICLE

Abstract

Cognitive decline and memory impairment induced by oxidative brain damage are the critical pathological hallmarks of Alzheimer’s disease (AD). Based on the potential neuroprotective effects of melatonin, we here explored the possible underlying mechanisms of the protective effect of melatonin against scopolamine-induced oxidative stress-mediated c-Jun N-terminal kinase (JNK) activation, which ultimately results in synaptic dysfunction, neuroinflammation, and neurodegeneration. According to our findings, scopolamine administration resulted in LPO and ROS generation and decreased the protein levels of antioxidant proteins such as Nrf2 and HO-1; however, melatonin co-treatment mitigated the generation of oxidant factors while improving antioxidant protein levels. Similarly, melatonin ameliorated oxidative stress-mediated JNK activation, enhanced Akt/ERK/CREB signaling, promoted cell survival and proliferation, and promoted memory processes. Immunofluorescence and western blot analysis indicated that melatonin reduced activated gliosis via attenuation of Iba-1 and GFAP. We also found that scopolamine promoted neuronal loss by inducing Bax, Pro-Caspase-3, and Caspase-3 and reducing the levels of the antiapoptotic protein Bcl-2. In contrast, melatonin significantly decreased the levels of apoptotic markers and increased neuronal survival. We further found that scopolamine disrupted synaptic integrity and, conversely, that melatonin enhanced synaptic integrity as indicated by Syntaxin, PSD-95, and SNAP-23 expression levels. Furthermore, melatonin ameliorated scopolamine-induced impairments in spatial learning behavior and memory formation. On the whole, our findings revealed that melatonin attenuated scopolamine-induced synaptic dysfunction and memory impairments by ameliorating oxidative brain damage, stress kinase expression, neuroinflammation, and neurodegeneration.

Graphical Abstract

The proposed schematic diagram showing the neuroprotective effect of melatonin against scopolamine-induced oxidative stress-mediated synaptic dysfunction, memory impairment neuroinflammation and neurodegeneration.

Keywords

Amnesia Reactive oxygen species (ROS) Brain-derived neurotrophic factor (BDNF) Cyclic AMP response element-binding protein (CREB) Scopolamine Melatonin 

Notes

Acknowledgments

This research was supported by the Brain Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT (2016M3C7A1904391).

Compliance with Ethical Standards

Conflict of Interest

The authors declared no competing financial interests.

References

  1. Ali T, Kim MO (2015) Melatonin ameliorates amyloid beta-induced memory deficits, tau hyperphosphorylation and neurodegeneration via PI3/Akt/GSk3beta pathway in the mouse hippocampus. J Pineal Res 59:47–59.  https://doi.org/10.1111/jpi.12238 CrossRefPubMedGoogle Scholar
  2. Ali T, Yoon GH, Shah SA, Lee HY, Kim MO (2015) Osmotin attenuates amyloid beta-induced memory impairment, tau phosphorylation and neurodegeneration in the mouse hippocampus. Sci Rep 5:11708.  https://doi.org/10.1038/srep11708 CrossRefPubMedPubMedCentralGoogle Scholar
  3. Amin FU, Shah SA, Kim MO (2016) Glycine inhibits ethanol-induced oxidative stress, neuroinflammation and apoptotic neurodegeneration in postnatal rat brain. Neurochem Int 96:1–12.  https://doi.org/10.1016/j.neuint.2016.04.001 CrossRefPubMedGoogle Scholar
  4. Amin FU, Shah SA, Kim MO (2017) Vanillic acid attenuates Abeta1-42-induced oxidative stress and cognitive impairment in mice. Sci Rep 7:40753.  https://doi.org/10.1038/srep40753 CrossRefPubMedPubMedCentralGoogle Scholar
  5. Badshah H, Ali T, Shafiq-ur R, Faiz-ul A, Ullah F, Kim TH, Kim MO (2016) Protective effect of Lupeol against lipopolysaccharide-induced Neuroinflammation via the p38/c-Jun N-terminal kinase pathway in the adult mouse brain. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 11:48–60.  https://doi.org/10.1007/s11481-015-9623-z CrossRefGoogle Scholar
  6. Balaban H, Naziroglu M, Demirci K, Ovey IS (2017) The protective role of selenium on scopolamine-induced memory impairment, oxidative stress, and apoptosis in aged rats: the involvement of TRPM2 and TRPV1 channels. Mol Neurobiol 54:2852–2868.  https://doi.org/10.1007/s12035-016-9835-0 CrossRefPubMedGoogle Scholar
  7. Blasko I, Grubeck-Loebenstein B (2003) Role of the immune system in the pathogenesis, prevention and treatment of Alzheimer's disease. Drugs Aging 20:101–113CrossRefGoogle Scholar
  8. Block ML, Zecca L, Hong JS (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8:57–69.  https://doi.org/10.1038/nrn2038 CrossRefPubMedGoogle Scholar
  9. Broadbent NJ, Squire LR, Clark RE (2004) Spatial memory, recognition memory, and the hippocampus. Proc Natl Acad Sci U S A 101:14515–14520.  https://doi.org/10.1073/pnas.0406344101 CrossRefPubMedPubMedCentralGoogle Scholar
  10. Budzynska B, Boguszewska-Czubara A, Kruk-Slomka M, Skalicka-Wozniak K, Michalak A, Musik I, Biala G (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 CrossRefPubMedGoogle Scholar
  11. Calabrese V, Cornelius C, Cuzzocrea S, Iavicoli I, Rizzarelli E, Calabrese EJ (2011) Hormesis, cellular stress response and vitagenes as critical determinants in aging and longevity. Mol Asp Med 32:279–304.  https://doi.org/10.1016/j.mam.2011.10.007 CrossRefGoogle Scholar
  12. Chaanine AH, Jeong D, Liang L, Chemaly ER, Fish K, Gordon RE, Hajjar RJ (2012) JNK modulates FOXO3a for the expression of the mitochondrial death and mitophagy marker BNIP3 in pathological hypertrophy and in heart failure. Cell Death Dis 3:265.  https://doi.org/10.1038/cddis.2012.5 CrossRefPubMedPubMedCentralGoogle Scholar
  13. Combs CK (2009) Inflammation and microglia actions in Alzheimer's disease. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 4:380–388.  https://doi.org/10.1007/s11481-009-9165-3 CrossRefGoogle Scholar
  14. Du CN et al (2015) Deer bone extract prevents against scopolamine-induced memory impairment in mice. J Med Food 18:157–165.  https://doi.org/10.1089/jmf.2014.3187 CrossRefPubMedPubMedCentralGoogle Scholar
  15. Duarte AI, Santos P, Oliveira CR, Santos MS, Rego AC (2008) Insulin neuroprotection against oxidative stress is mediated by Akt and GSK-3beta signaling pathways and changes in protein expression. Biochim Biophys Acta 1783:994–1002.  https://doi.org/10.1016/j.bbamcr.2008.02.016 CrossRefPubMedGoogle Scholar
  16. Embury CM, Dyavarshetty B, Lu Y, Wiederin JL, Ciborowski P, Gendelman HE, Kiyota T (2017) Cathepsin B improves ss-amyloidosis and learning and memory in models of Alzheimer's disease. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 12:340–352.  https://doi.org/10.1007/s11481-016-9721-6 CrossRefGoogle Scholar
  17. Farlow M, Veloso F, Moline M, Yardley J, Brand-Schieber E, Bibbiani F, Zou H, Hsu T, Satlin A (2011) Safety and tolerability of donepezil 23 mg in moderate to severe Alzheimer's disease. BMC Neurol 11:57.  https://doi.org/10.1186/1471-2377-11-57 CrossRefPubMedPubMedCentralGoogle Scholar
  18. Ferguson SA, Rajaratnam SM, Dawson D (2010) Melatonin agonists and insomnia. Expert Rev Neurother 10:305–318.  https://doi.org/10.1586/ern.10.1 CrossRefPubMedGoogle Scholar
  19. Fernandez MA, Saenz MT, Garcia MD (1998) Anti-inflammatory activity in rats and mice of phenolic acids isolated from Scrophularia frutescens. J Pharm Pharmacol 50:1183–1186CrossRefGoogle Scholar
  20. Goel R, Bhat SA, Hanif K, Nath C, Shukla R (2018) Angiotensin II receptor blockers attenuate lipopolysaccharide-induced memory impairment by modulation of NF-kappaB-mediated BDNF/CREB expression and apoptosis in spontaneously hypertensive rats. Mol Neurobiol 55:1725–1739.  https://doi.org/10.1007/s12035-017-0450-5 CrossRefPubMedGoogle Scholar
  21. Goverdhan P, Sravanthi A, Mamatha T (2012) Neuroprotective effects of meloxicam and selegiline in scopolamine-induced cognitive impairment and oxidative stress. Int J Alzheimers Dis 2012:974013–974018.  https://doi.org/10.1155/2012/974013 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Haider S, Tabassum S, Perveen T (2016) Scopolamine-induced greater alterations in neurochemical profile and increased oxidative stress demonstrated a better model of dementia: a comparative study. Brain Res Bull 127:234–247.  https://doi.org/10.1016/j.brainresbull.2016.10.002 CrossRefPubMedGoogle Scholar
  23. Hoppe JB, Frozza RL, Horn AP, Comiran RA, Bernardi A, Campos MM, Battastini AMO, Salbego C (2010) Amyloid-beta neurotoxicity in organotypic culture is attenuated by melatonin: involvement of GSK-3beta, tau and neuroinflammation. J Pineal Res 48:230–238.  https://doi.org/10.1111/j.1600-079X.2010.00747.x CrossRefPubMedGoogle Scholar
  24. Hou XQ et al (2014) BushenYizhi formula ameliorates cognition deficits and attenuates oxidative stressrelated neuronal apoptosis in scopolamineinduced senescence in mice. Int J Mol Med 34:429–439.  https://doi.org/10.3892/ijmm.2014.1801 CrossRefPubMedPubMedCentralGoogle Scholar
  25. Hui Y, Wang D, Li W, Zhang L, Jin J, Ma N, Zhou L, Nakajima O, Zhao W, Gao X (2011) Long-term overexpression of heme oxygenase 1 promotes tau aggregation in mouse brain by inducing tau phosphorylation. Journal of Alzheimer's disease : JAD 26:299–313.  https://doi.org/10.3233/JAD-2011-102061 CrossRefPubMedGoogle Scholar
  26. Itoh K, Tong KI, Yamamoto M (2004) Molecular mechanism activating Nrf2-Keap1 pathway in regulation of adaptive response to electrophiles. Free Radic Biol Med 36:1208–1213.  https://doi.org/10.1016/j.freeradbiomed.2004.02.075 CrossRefPubMedGoogle Scholar
  27. Jahanshahi M, Nickmahzar EG, Babakordi F (2013) Effect of Gingko biloba extract on scopolamine-induced apoptosis in the hippocampus of rats. Anat Sci Int 88:217–222.  https://doi.org/10.1007/s12565-013-0188-8 CrossRefPubMedGoogle Scholar
  28. Jana A, Modi KK, Roy A, Anderson JA, van Breemen RB, Pahan K (2013) Up-regulation of neurotrophic factors by cinnamon and its metabolite sodium benzoate: therapeutic implications for neurodegenerative disorders. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 8:739–755.  https://doi.org/10.1007/s11481-013-9447-7 CrossRefGoogle Scholar
  29. Kadowaki H, Nishitoh H, Urano F, Sadamitsu C, Matsuzawa A, Takeda K, Masutani H, Yodoi J, Urano Y, Nagano T, Ichijo H (2005) Amyloid beta induces neuronal cell death through ROS-mediated ASK1 activation. Cell Death Differ 12:19–24.  https://doi.org/10.1038/sj.cdd.4401528 CrossRefPubMedGoogle Scholar
  30. Kamalvand G, Pinard G, Ali-Khan Z (2003) Heme-oxygenase-1 response, a marker of oxidative stress, in a mouse model of AA amyloidosis. Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis 10:151–159CrossRefGoogle Scholar
  31. Kanninen K, White AR, Koistinaho J, Malm T (2011) Targeting glycogen synthase kinase-3beta for therapeutic benefit against oxidative stress in Alzheimer's disease: involvement of the Nrf2-ARE pathway. Int J Alzheimers Dis 2011:985085:1–9.  https://doi.org/10.4061/2011/985085 CrossRefGoogle Scholar
  32. Karasek M, Reiter RJ (2002) Melatonin and aging. Neuro endocrinology letters 23(Suppl 1):14–16PubMedGoogle Scholar
  33. Khan MS, Ali T, Abid MN, Jo MH, Khan A, Kim MW, Yoon GH, Cheon EW, Rehman SU, Kim MO (2017) Lithium ameliorates lipopolysaccharide-induced neurotoxicity in the cortex and hippocampus of the adult rat brain. Neurochem Int 108:343–354.  https://doi.org/10.1016/j.neuint.2017.05.008 CrossRefPubMedGoogle Scholar
  34. Khan M, Shah SA, Kim MO (2018) 17beta-Estradiol via SIRT1/Acetyl-p53/NF-kB Signaling Pathway Rescued Postnatal Rat Brain Against Acute Ethanol Intoxication. Mol Neurobiol 55:3067–3078.  https://doi.org/10.1007/s12035-017-0520-8 CrossRefPubMedGoogle Scholar
  35. Khodagholi F, Eftekharzadeh B, Maghsoudi N, Rezaei PF (2010) Chitosan prevents oxidative stress-induced amyloid beta formation and cytotoxicity in NT2 neurons: involvement of transcription factors Nrf2 and NF-kappaB. Mol Cell Biochem 337:39–51.  https://doi.org/10.1007/s11010-009-0284-1 CrossRefPubMedGoogle Scholar
  36. Kim EA, Choi J, Han AR, Cho CH, Choi SY, Ahn JY, Cho SW (2014) 2-Cyclopropylimino-3-methyl-1,3-thiazoline hydrochloride inhibits microglial activation by suppression of nuclear factor-kappa B and mitogen-activated protein kinase signaling. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 9:461–467.  https://doi.org/10.1007/s11481-014-9542-4 CrossRefGoogle Scholar
  37. Kim KY, Park KI, Kim SH, Yu SN, Park SG, Kim Y, Seo YK, Ma JY, Ahn SC (2017) Inhibition of autophagy promotes Salinomycin-induced apoptosis via reactive oxygen species-mediated PI3K/Akt/mTOR and ERK/p38 MAPK-dependent signaling in human prostate Cancer cells. Int J Mol Sci 18.  https://doi.org/10.3390/ijms18051088 CrossRefGoogle Scholar
  38. Koh EJ, Seo YJ, Choi J, Lee HY, Kang DH, Kim KJ, Lee BY (2017) Spirulina maxima extract prevents neurotoxicity via promoting activation of BDNF/CREB signaling pathways in neuronal cells and mice. Molecules 22.  https://doi.org/10.3390/molecules22081363 CrossRefGoogle Scholar
  39. Konar A, Shah N, Singh R, Saxena N, Kaul SC, Wadhwa R, Thakur MK (2011) Protective role of Ashwagandha leaf extract and its component withanone on scopolamine-induced changes in the brain and brain-derived cells. PLoS One 6:e27265.  https://doi.org/10.1371/journal.pone.0027265 CrossRefPubMedPubMedCentralGoogle Scholar
  40. Lee M, Kwon BM, Suk K, McGeer E, McGeer PL (2012) Effects of obovatol on GSH depleted glia-mediated neurotoxicity and oxidative damage. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 7:173–186.  https://doi.org/10.1007/s11481-011-9300-9 CrossRefGoogle Scholar
  41. Lee JE, Song HS, Park MN, Kim SH, Shim BS, Kim B (2018) Ethanol extract of Oldenlandia diffusa Herba attenuates scopolamine-induced cognitive impairments in mice via activation of BDNF, P-CREB and inhibition of acetylcholinesterase. Int J Mol Sci 19.  https://doi.org/10.3390/ijms19020363 CrossRefGoogle Scholar
  42. Li MM, Jiang T, Sun Z, Zhang Q, Tan CC, Yu JT, Tan L (2014) Genome-wide microRNA expression profiles in hippocampus of rats with chronic temporal lobe epilepsy. Sci Rep 4:4734.  https://doi.org/10.1038/srep04734 CrossRefPubMedPubMedCentralGoogle Scholar
  43. Ling ZQ, Tian Q, Wang L, Fu ZQ, Wang XC, Wang Q, Wang JZ (2009) Constant illumination induces Alzheimer-like damages with endoplasmic reticulum involvement and the protection of melatonin. Journal of Alzheimer's disease : JAD 16:287–300.  https://doi.org/10.3233/JAD-2009-0949 CrossRefPubMedGoogle Scholar
  44. Liu RY, Zhou JN, van Heerikhuize J, Hofman MA, Swaab DF (1999) Decreased melatonin levels in postmortem cerebrospinal fluid in relation to aging, Alzheimer's disease, and apolipoprotein E-epsilon4/4 genotype. J Clin Endocrinol Metab 84:323–327.  https://doi.org/10.1210/jcem.84.1.5394 CrossRefPubMedGoogle Scholar
  45. Lu J, Wu DM, Zheng YL, Hu B, Zhang ZF (2010) Purple sweet potato color alleviates D-galactose-induced brain aging in old mice by promoting survival of neurons via PI3K pathway and inhibiting cytochrome C-mediated apoptosis. Brain Pathol 20:598–612.  https://doi.org/10.1111/j.1750-3639.2009.00339.x CrossRefPubMedGoogle Scholar
  46. Maqbool A, Lattke M, Wirth T, Baumann B (2013) Sustained, neuron-specific IKK/NF-kappaB activation generates a selective neuroinflammatory response promoting local neurodegeneration with aging. Mol Neurodegener 8:40.  https://doi.org/10.1186/1750-1326-8-40 CrossRefPubMedPubMedCentralGoogle Scholar
  47. Ohno M, Cole SL, Yasvoina M, Zhao J, Citron M, Berry R, Disterhoft JF, Vassar R (2007) BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice. Neurobiol Dis 26:134–145.  https://doi.org/10.1016/j.nbd.2006.12.008 CrossRefPubMedGoogle Scholar
  48. Pariyar R, Yoon CS, Svay T, Kim DS, Cho HK, Kim SY, Oh H, Kim YC, Kim J, Lee HS, Seo J (2017) Vitis labruscana leaf extract ameliorates scopolamine-induced impairments with activation of Akt, ERK and CREB in mice. Phytomedicine : international journal of phytotherapy and phytopharmacology 36:8–17.  https://doi.org/10.1016/j.phymed.2017.09.008 CrossRefGoogle Scholar
  49. Park SJ, Kim DH, Jung JM, Kim JM, Cai M, Liu X, Hong JG, Lee CH, Lee KR, Ryu JH (2012) The ameliorating effects of stigmasterol on scopolamine-induced memory impairments in mice. Eur J Pharmacol 676:64–70.  https://doi.org/10.1016/j.ejphar.2011.11.050 CrossRefPubMedGoogle Scholar
  50. Qian YF, Wang H, Yao WB, Gao XD (2008) Aqueous extract of the Chinese medicine, Danggui-Shaoyao-san, inhibits apoptosis in hydrogen peroxide-induced PC12 cells by preventing cytochrome c release and inactivating of caspase cascade. Cell Biol Int 32:304–311.  https://doi.org/10.1016/j.cellbi.2007.10.004 CrossRefPubMedGoogle Scholar
  51. Rangasamy SB, Dasarathi S, Pahan P, Jana M, Pahan K (2018) Low-dose aspirin upregulates tyrosine hydroxylase and increases dopamine production in dopaminergic neurons: implications for Parkinson's disease. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology.  https://doi.org/10.1007/s11481-018-9808-3
  52. Ray RS, Rai S, Katyal A (2014) Cholinergic receptor blockade by scopolamine and mecamylamine exacerbates global cerebral ischemia induced memory dysfunction in C57BL/6J mice. Nitric Oxide Biol Chem 43:62–73.  https://doi.org/10.1016/j.niox.2014.08.009 CrossRefGoogle Scholar
  53. Rodriguez C, Mayo JC, Sainz RM, Antolin I, Herrera F, Martin V, Reiter RJ (2004) Regulation of antioxidant enzymes: a significant role for melatonin. J Pineal Res 36:1–9CrossRefGoogle Scholar
  54. Sarubbo F, Ramis MR, Kienzer C, Aparicio S, Esteban S, Miralles A, Moranta D (2018) Chronic Silymarin, quercetin and Naringenin treatments increase monoamines synthesis and hippocampal Sirt1 levels improving cognition in aged rats. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 13:24–38.  https://doi.org/10.1007/s11481-017-9759-0 CrossRefGoogle Scholar
  55. Sattayasai J, Chaonapan P, Arkaravichie T, Soi-ampornkul R, Junnu S, Charoensilp P, Samer J, Jantaravinid J, Masaratana P, Suktitipat B, Manissorn J, Thongboonkerd V, Neungton N, Moongkarndi P (2013) Protective effects of mangosteen extract on H2O2-induced cytotoxicity in SK-N-SH cells and scopolamine-induced memory impairment in mice. PLoS One 8:e85053.  https://doi.org/10.1371/journal.pone.0085053 CrossRefPubMedPubMedCentralGoogle Scholar
  56. Schliebs R, Arendt T (2011) The cholinergic system in aging and neuronal degeneration. Behav Brain Res 221:555–563.  https://doi.org/10.1016/j.bbr.2010.11.058 CrossRefPubMedGoogle Scholar
  57. Scott Bitner R (2012) Cyclic AMP response element-binding protein (CREB) phosphorylation: a mechanistic marker in the development of memory enhancing. Alzheimer's disease therapeutics. Biochem Pharmacol 83:705–714.  https://doi.org/10.1016/j.bcp.2011.11.009 CrossRefPubMedGoogle Scholar
  58. Shao BY, Xia Z, Xie Q, Ge XX, Zhang WW, Sun J, Jiang P, Wang H, le WD, Qiu ZB, Lu Y, Chen HZ (2014) Meserine, a novel carbamate AChE inhibitor, ameliorates scopolamine-induced dementia and alleviates amyloidogenesis of APP/PS1 transgenic mice. CNS neuroscience & therapeutics 20:165–171.  https://doi.org/10.1111/cns.12183 CrossRefGoogle Scholar
  59. Shintani EY, Uchida KM (1997) Donepezil: an anticholinesterase inhibitor for Alzheimer's disease. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists 54:2805–2810Google Scholar
  60. Skalicka-Wozniak K, Budzynska B, Biala G, Boguszewska-Czubara A (2018) Scopolamine-induced memory impairment is alleviated by Xanthotoxin: role of acetylcholinesterase and oxidative stress processes. ACS Chem Neurosci 9:1184–1194.  https://doi.org/10.1021/acschemneuro.8b00011 CrossRefPubMedGoogle Scholar
  61. Song JH, Yu JT, Tan L (2015) Brain-derived neurotrophic factor in Alzheimer's disease: risk, mechanisms, and therapy. Mol Neurobiol 52:1477–1493.  https://doi.org/10.1007/s12035-014-8958-4 CrossRefPubMedGoogle Scholar
  62. Spires-Jones TL, Hyman BT (2014) The intersection of amyloid beta and tau at synapses in Alzheimer's disease. Neuron 82:756–771.  https://doi.org/10.1016/j.neuron.2014.05.004 CrossRefPubMedPubMedCentralGoogle Scholar
  63. Terai K, Matsuo A, McGeer PL (1996) Enhancement of immunoreactivity for NF-kappa B in the hippocampal formation and cerebral cortex of Alzheimer's disease. Brain Res 735:159–168CrossRefGoogle Scholar
  64. Venkatesan R, Subedi L, Yeo EJ, Kim SY (2016) Lactucopicrin ameliorates oxidative stress mediated by scopolamine-induced neurotoxicity through activation of the NRF2 pathway. Neurochem Int 99:133–146.  https://doi.org/10.1016/j.neuint.2016.06.010 CrossRefPubMedGoogle Scholar
  65. Wen J, Ariyannur PS, Ribeiro R, Tanaka M, Moffett JR, Kirmani BF, Namboodiri AMA, Zhang Y (2016) Efficacy of N-Acetylserotonin and melatonin in the EAE model of multiple sclerosis. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 11:763–773.  https://doi.org/10.1007/s11481-016-9702-9 CrossRefGoogle Scholar
  66. Yan BC et al (2014) Long-term administration of scopolamine interferes with nerve cell proliferation, differentiation and migration in adult mouse hippocampal dentate gyrus, but it does not induce cell death. Neural Regen Res 9:1731–1739.  https://doi.org/10.4103/1673-5374.143415 CrossRefPubMedPubMedCentralGoogle Scholar
  67. Yan T, Zhao Y, Zhang X, Lin X (2016) Astaxanthin inhibits acetaldehyde-induced cytotoxicity in SH-SY5Y cells by modulating Akt/CREB and p38MAPK/ERK signaling pathways. Marine drugs 14.  https://doi.org/10.3390/md14030056 CrossRefGoogle Scholar
  68. Yu YZ, Liu S, Wang HC, Shi DY, Xu Q, Zhou XW, Sun ZW, Huang PT (2016) A novel Abeta B-cell epitope vaccine (rCV01) for Alzheimer's disease improved synaptic and cognitive functions in 3 x Tg-AD mice. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 11:657–668.  https://doi.org/10.1007/s11481-016-9678-5 CrossRefGoogle Scholar
  69. Zhou JN, Liu RY, Kamphorst W, Hofman MA, Swaab DF (2003) Early neuropathological Alzheimer's changes in aged individuals are accompanied by decreased cerebrospinal fluid melatonin levels. J Pineal Res 35:125–130CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Tahir Muhammad
    • 1
  • Tahir Ali
    • 1
  • Muhammad Ikram
    • 1
  • Amjad Khan
    • 1
  • Sayed Ibrar Alam
    • 1
  • Myeong Ok Kim
    • 1
    Email author
  1. 1.Division of Applied Life Science (BK 21), College of Natural SciencesGyeongsang National UniversityJinjuRepublic of Korea

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