Inhibition of aluminum chloride-induced amyloid Aβ peptide accumulation and brain neurodegeneration by Bougainvillea spectabilis flower decoction

Document Type : Original Article


1 Department of Toxicology and Narcotics, National Research Centre, Cairo, Egypt

2 Department of Medical Biochemistry, National Research Centre, Cairo, Egypt

3 Department of Pathology, National Research Centre, Cairo, Egypt


Objective(s): To investigate the potential therapeutic effect of Bougainvillea spectabilis flower decoction on aluminum chloride (AlCl3)-induced neurotoxicity. 
Materials and Methods: Rats received daily intraperitoneal injections of AlCl3 at 10 mg/kg for two months and were treated with B. spectabilis decoction at 50 or 100 mg/kg or saline during the 2nd month of the study. The control group received saline. Brain malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH), acetylcholinesterase (AChE), amyloid Aβ peptide, and interleukin-6 (IL-6) concentrations and paraoxonase-1 (PON-1) activity were determined and brain histology was done. Behavioral and neurological testing included Morris water maze (WMZ), Y maze, and wire hanging. 
Results: Compared with saline controls, AlCl3 significantly increased brain MDA and NO along with decreased GSH and PON-1 activity. It also increased AChE, IL-6, and amyloid Aβ concentrations. AlCl3 impaired motor strength and memory performance and caused brain neurodegeneration. B. spectabilis decoction given at 50 or 100 mg/kg protected against the biochemical and histopathological alterations evoked by AlCl3 by alleviating the increase in MDA and NO, and decrease in GSH and PON-1 activity.  B. spectabilis decoction showed no significant effect on AChE but markedly decreased IL-6 and amyloid Aβ in the brain of AlCl3-treated rats. It also restored memory performance and motor strength, and protected against AlCl3-induced neurodegeneration.
Conclusion: These results suggest that B. spectabilis flower decoction might prove of value in the treatment of Alzheimer’s disease.


1. Cummings J, Aisen PS, DuBois B, Frölich L, Jack Jr CR, Jones RW,  et al. Drug development in Alzheimer’s disease: The path to 2025. Alzheimers Res Ther 2016; 8:39. 
2. Harrington CR. The aetiology of Alzheimer’s disease: Diverse routes into a common tau pathway. In Aluminium and Alzheimer’s disease: The science that describes the link. (Exley C, ed) 2001, pp 97-132, Elsevier Science BV.
3. Bird TD. Genetic aspects of Alzheimer disease. Genet Med 2008; 10:231-239. 
4. Khachaturian ZS. Diagnosis of Alzheimer’s disease. Arch Neurol 1985; 42: 1097-1105.
5. Abdel-Salam OME. Stem cell therapy for Alzheimer’s disease. CNS Neurol Disord Drug Targets 2011; 10: 459-485. 
6. Castellani RJ, Lee HG, Zhu X, Nunomura A, Perry G. Neuropathology of Alzheimer disease: Pathognomonic but not pathogenic. Acta Neuropathol 2006; 111: 503-509.
7. Rajmohan R, Reddy PH. Amyloid beta and phosphorylated tau accumulations cause abnormalities at synapses of Alzheimer’s disease neurons. J Alzheimer’s Dis 2017; 57: 975-999. 
8. Haass C, Selkoe DJ. Soluble protein oligomers in neurodegeneration: Lessons from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol 2007; 8:101–112. 
9. Whitehouse PJY, Price DL, Struble RG, Clark AW, Coyle JT, DeLong MR. Alzheimer’s disease and senile dementia: Loss of neurons in the basal forebrain. Science 1982; 215: 1237-1239.
10. O’Brien JT, Holmes C, Jones M, Jones R, Livingston G, McKeith I, et al. Clinical practice with anti-dementia drugs: A revised (third) consensus statement from the British Association for Psychopharmacology. J Psychopharmacol 2017; 31:147-168. 
11. Walton JR. An aluminum-based rat model for Alzheimer’s disease exhibits oxidative damage, inhibition of PP2A activity, hyperphosphorylated tau, and granulovacuolar degeneration. Inorg Biochem 2007; 101: 1275-1284.
12. Exley C, Clarkson E. Aluminium in human brain tissue from donors without neurodegenerative disease: A comparison with Alzheimer’s disease, multiple sclerosis and autism. Sci Rep 2020; 10:7770. 
13. Foster HD. How aluminum causes Alzheimer’s Disease: The implications for prevention and treatment of Foster’s multiple antagonist hypothesis. J Orthomolec Med 2000; 15: 21-51.
14. Yumoto S, Kakimi S, Ohsaki A, Ishikawa A.  Demonstration of aluminum in amyloid fibers in the cores of senile plaques in the brains of patients with Alzheimer’s disease. J Inorg Biochem 2009; 103:1579-1584. 
15. Walton JR, Wang MX. APP expression, distribution and accumulation are altered by aluminum in a rodent model for Alzheimer’s disease. J Inorg Biochem 2009; 103:1548–1554.
16. Rodella LF, Ricci F, Borsani E, Stacchiotti A, Foglio E. Aluminium exposure induces Alzheimer’s disease-like histopathological alterations in mouse brain. Histol Histopathol 2008; 23: 433-439.
17. Abdel-Salam OME, Hamdy SM, Seadawy SAM, Galal AF, Abouelfadl DM, Atrees SS. Effect of piracetam, vincamine, vinpocetine, and donepezil on oxidative stress and neurodegeneration induced by aluminum chloride in rats. Comp Clin Pathol 2016; 25: 305–318.
18. Shawa CA, Petrikc MS. Aluminum hydroxide injections lead to motor deficits and motor neuron degeneration. J Inorg Biochem 2009; 103: 1555. 
19. Yang WN, Han H, Hu XD, Feng GF, Qian YH. The effects of perindopril on cognitive impairment induced by d-galactose and aluminum trichloride via inhibition of acetylcholinesterase activity and oxidative stress. Pharmacol Biochem Behav 2003; 114–115:31–36.
20. Abdel-Salam OME, Youness ER, Morsy FA, Mahfouz MM, Kenawy SA. Study of the effect of antidepressant drugs and donepezil on aluminum-induced memory impairment and biochemical alterations in rats. Comp Clin Pathol 2015; 24: 847-860.
21. Massoulie J, Sussman J, Bon S, Silman I.  Structure and functions of acetylcholinesterase and butyrylcholinesterase. Prog Brain Res 1993; 98:139–146. 
22. Kawahara M. Effects of aluminum on the nervous system and its possible link with neurodegenerative diseases. J Alzheimer’s Dis 2005; 8:171–182.
23. Golby EV. History of Bougainvillea in Florida. In: Edwin AM, Editor. Flowering vines of the world: An Encyclopedia of Climbing Plants. Hearthside Press Inc., Publishers, New York; 1970. p. 138-145.
24. Abarca-Vargas R, Petricevich VL. Bougainvillea Genus: A review on phytochemistry, pharmacology, and toxicology. Evid Based Complement Alternat Med 2018; 2018:9070927.
25. Mandal G, Chatterjee C, Chatterjee M. Evaluation of anti-inflammatory activity of methanolic extract of leaves of Bougainvillea spectabilis in experimental animal models. Pharmacogn Res 2015; 7: 18-22.
26. Chauhan P, Mahajan S, Kulshrestha A, Shrivastava S, Sharma B, Goswamy HM, et al. Bougainvillea spectabilis exhibits antihyperglycemic and anti-oxidant activities in experimental diabetes. J Evid Based Complem Altern Med 2016; 21: 177-185.
27. Abdel-Salam OME, Youness ER, Ahmed NA, El-Toumy SA, Souleman AMA, Shaffie N. Bougainvillea spectabilis flowers extract protects against the rotenone-induced toxicity. Asian Pac J Trop Med 2017; 10:478-490. 
28. Ruiz-Larrea MB, Leal AM, Liza M, Lacort M, de Groot H. Anti-oxidant effects of estradiol and 2-hydroxyestradiol on iron-induced lipid peroxidation of rat liver microsomes. Steroids 1994; 59: 383-388.
28. Archer S. Measurement of nitric oxide in biological models. FASEB J 1997; 7: 340-360.
30. Ellman GL. Tissue sulfhydryl groups. Arch Biochem Biophys 1959; 82: 70-77.
31. Haagen L, Brock A.  A new automated method for phenotyping arylesterase (EC based upon inhibition of enzymatic hydrolysis of 4-nitrophenyl acetate by phenyl acetate. Eur J Clin Chem Clin Biochem 1992; 30: 391-395.
32. Morris R. Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 1984; 11: 47-60.
33. Arai K, Matsuki N, Ikegaya Y, Nishiyama N. Deterioration of spatial learning performances in lipopolysaccharide-treated mice. Jpn J Pharmacol  2001; 87: 195-201.
34. Crawley JN. What’s wrong with my mouse? Behavioral phenotyping of transgenic and knockout mice. 2nd ed. Hoboken: Wiley; 2017
35. Wu G, Fang YZ, Yang S, Lupton JR, Turner ND. Glutathione metabolism and its implications for health. J Nutr 2004; 134: 489–492.
36. Exley C. The pro-oxidant activity of aluminum. Free Radic Biol Med 2004; 36:380–387.
37. Li HQ, Ip SP, Zheng GQ, Xian YF, Lin ZX. Isorhynchophylline alleviates learning and memory impairments induced by aluminum chloride in mice. Chin Med 2018; 13:29
38. Gutteridge JM, Quinlan GJ, Clark I, Halliwell B. Aluminium salts accelerate peroxidation of membrane lipids stimulated by iron salts. Biochim Biophys Acta 1985; 835: 441-447.
39. Meglio L, Oteiza PI. Aluminum enhances melanin-induced lipid peroxidation. Neurochemical Res 1999; 24: 1001-1008.
40. Stevanović  ID, Jovanović  MD, Čolić M, Jelenkovic A, Bokonjić D. Nitric oxide synthase inhibitors protect cholinergic neurons against AlCl3 excitotoxicity in the rat brain. Brain Res Bull 2010; 81: 641-646.
41. Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev 2007; 87:315-424.
42. Menini T, Gugliucci A. Paraoxonase 1 in neurological disorders. Redox Rep 2014; 19:49–58.
43. Furlong CE, Marsillach J, Jarvika GP, Costa LG.  Paraoxonases-1, -2 and -3: What are their Functions? Chem Biol Interact 2016; 259:51–62.
44. Nguyen SD, Sok DE. Preferential inhibition of paraoxonase activity of human paraoxonase 1 by negatively charged lipids. J Lipid Res 2004; 45:2211-2220. 
45. Yang F, Lim GP, Begum AN, Ubeda OJ, Simmons MR, Ambegaokar SS, et al. Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem 2005; 280: 5892–5901.
46. Mori T, Rezai-Zadeh K, Koyama N, Arendash GW, Yamaguchi H, Kakuda N, et al. Tannic acid is a natural β-secretase inhibitor that prevents cognitive impairment and mitigates Alzheimer-like pathology in transgenic mice. J Biol Chem 2012; 287:6912-6927. 
47. Auld DS, Kornecook TJ, Bastianetto S, Quirion R. Alzheimer’s disease and the basal forebrain cholinergic system: Relations to beta-amyloid peptides, cognition, and treatment strategies. Prog Neurobiol 2002; 68:209-245.
48. Peng JH, Xu ZC, Xu ZX, Parker Jr JC, Friedlander ER, Tang JP, et al. Aluminum-induced acute cholinergic neurotoxicity in rat. Mol Chem Neuropathol 1992; 17:79-89.
49. Kaizer RR, Corrêa MC, Gris LRS, da Rosa CS, Bohrer D, Morsch VM, et al. Effect of long-term exposure to aluminum on the acetylcholinesterase activity in the central nervous system and erythrocytes. Neurochem Res 2008; 33:2294-2301.
50. Decker EA. Phenolics: Prooxidants or anti-oxidants? Nutr Rev 1997; 55:396-298.
51. Alink GM, Awad HM, Boersma MG, Cnubben NHP, De Haan L, Koeman JH, et al. The pro-oxidant chemistry of the natural anti-oxidants vitamin C, vitamin E, carotenoids and flavonoids. Environ Toxicol Pharmacol 2002; 11: 321-333.
52. Chan TS. Simultaneous detection of the anti-oxidant and pro-oxidant activity of dietary polyphenolics in a peroxidase system. Free Radical Research 2003; 37: 787-794.
53. de Roos B, Duthie GG. Role of dietary pro-oxidants in the maintenance of health and resilience to oxidative stress. Mol Nutr Food Res 2015; 59:1229-1248.
54. Lee-Hilz YY, Boerboom AM, Westphal AH, Berkel WJ, Aarts JM, Rietjens IM. Pro-oxidant activity of flavonoids induces EpRE-mediated gene expression. Chem Res Toxicol 2006; 19:1499-1505.