Protective effect of hot peppers against amyloid Aβ peptide and brain injury in AlCl3 induced Alzheimer’s disease in rats

Document Type : Original Article

Authors

1 Department of Toxicology and Narcotics, Medical Research, and Clinical Studies Institute, National Research Centre, Cairo, Egypt

2 Department of Medical Biochemistry, Medical Research, and Clinical Studies Institute, National Research Centre, Cairo, Egypt

3 Department of Pathology, Medical Research, and Clinical Studies Institute, National Research Centre, Cairo, Egypt

Abstract

Objective(s): This study investigated the therapeutic effect of red hot pepper (Capsicum annuum) methanolic extract in induced Alzheimer’s disease using AlCl3 in male rats. 
Materials and Methods: Rats were injected with AlCl3 intraperitoneally (IP) daily for two months. Starting from the 2nd month of AlCl3, rats received, in addition, IP treatments with Capsicum extract (25, 50 mg/kg) or saline. Other groups received only saline or Capsicum extract at 50 mg/kg for two months. Brain levels of reduced glutathione (GSH), nitric oxide (NO), and malondialdehyde (MDA) were determined.  Additionally, paraoxonase-1 (PON-1) activity, interleukin-6 (IL-6), Aβ-peptide, and acetylcholinesterase (AChE) concentrations in the brain were measured. Behavioral testing included wire-hanging tests for neuromuscular strength and memory tests such as Y-maze and Morris water maze. Histopathology of the brain was also done.  
Results: Compared with saline-treated rats, AlCl3 caused significant elevation of brain oxidative stress as GSH level and PON-1 activity were depleted along with MDA and NO level elevation in the brain. There were also significant increases in brain Aβ-peptide, IL-6, and AChE levels. Behavioral testing indicated that AlCl3 decreased neuromuscular strength and impaired memory performance. Capsicum extract given to AlCl3-treated rats significantly alleviated oxidative stress and decreased Aβ-peptide and IL-6 in the brain. It also improved grip strength and memory functioning and prevented neuronal degeneration in the cerebral cortex, hippocampus, and substantia nigra of AlCl3-treated rats. 
Conclusion: The study suggests beneficial effects for hot peppers through their anti-oxidant and anti-inflammatory actions in halting neurodegeneration in this model of Alzheimer’s disease.

Keywords

References

1. Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E. Alzheimer’s disease. Lancet 2011; 377: 1019–31.
2.    Khachaturian ZS. Diagnosis of Alzheimer’s disease. Arch Neurol 1985; 42: 1097-1105. 
3.    Abdel-Salam OME. Stem cell therapy for Alzheimer’s disease. CNS Neurol Disord Drug Targets 2011; 10: 459-485.
4.    Serrano-Pozo A, Frosch MP, Masliah E, Hyman BT. Neuropathological alterations in Alzheimer disease. Cold Spring Harb Perspect Med. 2011; 1: a006189.  
5.    Weintraub D, Dietz N, Duda JE, Wolk DA, Doshi J, Xie SX et al. Alzheimer’s disease pattern of brain atrophy predicts cognitive decline in Parkinson’s disease. Brain 2012; 135: 170–180. 
6.    Haam J, Yakel JL. Cholinergic modulation of the hippocampal region ad memory function. J Neurochem 2017; 142 (Suppl. 2): 111–121.
7.    Wilkinson DG, Francis PT, Schwam E, Payne-Parrish J. Cholinesterase inhibitors used in the treatment of Alzheimer’s disease.The relationship between pharmacological effects and clinical efficacy. Drugs & Aging 2004; 21: 453–478.
8.    Bali J, Gheinani AS, Zurbriggen S, Rajendran L. Role of genes linked to sporadic Alzheimer’s disease risk in the production of β-amyloid peptides. Proc Natl Acad Sci U S A 2012;109:15307-11.
9.    Ferreira PC, Tonani KA, Julião FC, Cupo P, Domingo JL, Segura-Muñoz SI. Aluminum concentrations in water of elderly people’s houses and retirement homes and its relation with elderly health. Bull Environ Contam Toxicol 2009; 83:565–569. 
10.    Bondy SC. Prolonged exposure to low levels of aluminum leads to changes associated with brain aging and neurodegeneration. Toxicology 2014; 315: 1-7.
11.    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
12.    Chen S-M, Fan C-C, Chiue M-S, Chou C, Chen J-H, Hseu R-S. Hemodynamic and neuropathological analysis in rats with aluminum trichloride-induced Alzheimer’s disease. PLoS One 2013; 8:e82561
13.    Tuppo EE, Arias HR. The role of inflammation in Alzheimer’s disease. Int J Biochem Cell Biol. 2005;37:289-305.
14.    Agostinho P, Cunha RA, Oliveira C. Neuroinflammation, oxidative stress and the pathogenesis of Alzheimers disease. Curr Pharm Des 2010;16:2766-2778.
15.    Christen Y. Oxidative stress and Alzheimer disease. Am J Clin Nutr 2000;71(suppl):621S–629S. 
16.    Crosby KM. Pepper. In: Vegetables II: Handbook of Plant Breeding (J Prohens, F Nuez). Springer, New York, NY, USA. 2008, p. 221–48. 
17.    Guzman I, Bosland PW, O’Connell MA. Heat, color, and flavor compounds in Capsicum fruit. In: The Biological Activity of Phytochemicals: Recent Advances in Phytochemistry 41 (DR Gang): Springer, New York, NY, USA. 2011; p. 109–126. 
18.    Jayaprakasha GK, Bae H, Crosby K, Jifon JL, Patil BS. Bioactive compounds in peppers and their antioxidant potential. In: Hispanic Foods: Chemistry and Bioactive Compounds (MH Tunick, EG de Mejia). American Chemical Society, Washington DC, USA. 2013, pp. 43–56. 
19.    Szolcsányi J. Capsaicin and sensory neurones: A historical perspective. In: Capsaicin as a Therapeutic Molecule (Progress in Drug Research 68) (Abdel-Salam OME, ed.). Springer, Basel, Switzerland. 2014, p. 1–37. 
20.    Abdel-Salam OME, Sleem AA, Youness ER, Yassen NN, Shaffie N, El-Toumy SA. Capsicum protects against rotenone-induced toxicity in mice brain via reduced oxidative stress and 5-lipoxygenase activation. J Pharm Pharmacol Res 2018; 2:60–77.
21.    Abdel-Salam OME, Sleem AA, Youness ER, Morsy FA, Shaffie NM, Souleman AMA. Hot pepper extract protects against hypoglycemia-induced brain and liver injury in mice. Reactive Oxygen Species 2019; 8:297–311.
22.    Liu CH, Bu XL, Wang J, Zhang T, Xiang Y, Shen LL, et al. The associations between a capsaicin-rich diet and blood amyloid-beta levels and cognitive function. J Alzheimers Dis 2016; 52: 1081–1088.
23.    Wang J, Sun BL, Xiang Y, Tian DY, Zhu C, Li WW, et al. Capsaicin consumption reduces brain amyloid beta generation and attenuates Alzheimer’s disease-type pathology and cognitive deficits in APP/PS1 mice. Transl Psychiatry 2020; 10:230. 
24.    Walton  JR. An aluminum-based rat model for Alzheimer’s disease exhibits oxidative damage, inhibition of PP2A activity, hyperphosphorylated tau, and granulovacuolar degeneration. J Inorg Biochem. 2007; 101: 1275–1284.
25.    Ruiz-Larrea MB, Leal AM, Liza M, Lacort M, de Groot H. Antioxidant effects of estradiol and 2-hydroxyestradiol on iron-induced lipid peroxidation of rat liver microsomes. Steroids 1994; 59: 383-388.
26.    Archer S. Measurement of nitric oxide in biological models. FASEB J 1993; 7: 340-360.
27.    Ellman GL. Tissue sulfhydryl groups. Arch Biochem Biophys 1959; 82: 70-77.
28.    Teich AF, Patel M, Arancio O. A reliable way to detect endogenous murine β-amyloid. PLoS ONE 2013; 8: e55647. 
29.    Ponomarenko AI, Tyrtyshnaia AA, Pislyagin EA, Dyuizen IV, Sultanov RM, Manzhulo IV. N-docosahexaenoylethanolamine reduces neuroinflammation and cognitive impairment after mild traumatic brain injury in rats. Scientific Reports 2021; 11:756. 
30.    Haagen L, Brock A. A new automated method for phenotyping arylesterase (EC 3.1.1.2) based upon inhibition of enzymatic hydrolysis of 4-nitrophenyl acetate by phenyl acetate. Eur J Clin Chem Clin Biochem 1992; 30: 391-395. 
31.    Kaizer RR, Correa 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.
32.    Crawley JN. What’s wrong with my mouse? Behavioral phenotyping of transgenic and knockout mice. 2nd ed. Hoboken: Wiley; 2017.
33.    Morris R. Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 1984; 11: 47–60.
34.    Arai K, Matsuki N, Ikegaya Y, Nishiyama N. Deterioration of spatial learning performances in lipopolysaccharide-treated mice. Jpn  J Pharmacol 2001; 87: 195 – 201.
35.    Gutteridge JM. Lipid peroxidation and antioxidants as biomarkers of tissue damage. Clin Chem 1985; 41:1819–1828.
36.    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.
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.    Exley C. The pro-oxidant activity of aluminum. Free Radic Biol Med 2004; 36:380–387.
39.    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.
40.    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.
41.    Wink DA, Feelisch M, Vodovotz Y, Fukuto J, Grisham MB. The chemical biology of nitric oxide. In: Reactive Oxygen Species in Biological Systems (DL Gilbert, CA Colton). Kluwer Academic/Plenum Publishers, New York, NY, USA. 1999, pp. 245–91.
42.    Brown GC. Nitric oxide and neuronal death. Nitric Oxide 2010; 23:153–165. 
43.    Stevanović  ID, Jovanović  MD, Čolić M, Jelenkovic A, Bokonjić D, et al. Nitric oxide synthase inhibitors protect cholinergic neurons against AlCl3 excitotoxicity in the rat brain. Brain Res Bull 2010; 81: 641-646.
44.    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.
45.    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.
46.    Abdel-Salam OME, El-Shamarka MES, Youness ER, Shaffie N. Inhibition of aluminum chloride-induced amyloid Aβ peptide accumulation and brain neurodegeneration by Bougainvillea spectabilis flower decoction. Iran J Basic Med Sci 2021; 24:1437-1445. 
47.    La Du BN. Human serum paraoxonase/arylesterase. In: Pharmacogenetics of Drug Metabolism (Kalow W editor). Pergamon, New York, NY, USA. 1992, p. 51–91.
48.    Furlong CE, Marsillach J, Jarvik GP, Costa LG. Paraoxonases-1, -2 and -3: what are their functions? Chem Biol Interact 2016; 259(Pt B):51–62. 
49.    Nguyen SD, Sok DE. Preferential inhibition of paraoxonase activity of human paraoxonase 1 by negatively charged lipids. J Lipid Res 2004; 45:2211–2220. 
50.    Jarvik GP, Tsai NT, McKinstry LA, Wani R, Brophy VH, Richter RJ et al. Vitamin C and E intake is associated with increased paraoxonase activity. Arterioscler Thromb Vasc Biol 2002;22(8):1329–33.
51.    Yang HJ, Kwon DY, Kim MJ, Kang S, Moon NR, Daily JW, et al. Red peppers with moderate and severe pungency prevent the memory deficit and hepatic insulin resistance in diabetic rats with Alzheimer’s disease. Nutr Metab (Lond) 2015; 12:9. 
52.    Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 2002; 297: 353–356.
53.    Steenland HW, Ko SW, Wu LJ, Zhuo M. Hot receptors in the brain. Mol Pain 2006; 2:34. 
54.    Nagy I, Friston D, Valente JS, Perez JVT, Andreou AP. Pharmacology of the capsaicin receptor, transient receptor potential vanilloid type-1 ion channel. In: Capsaicin as a Therapeutic Molecule (Progress in Drug Research 68) (Abdel-Salam OME, editor). Springer, Basel, Switzerland. 2014, p. 39–76.
55.    Edwards JG. TRPV1 in the central nervous system: Synaptic plasticity, function, and pharmacological implications. In: Capsaicin as a Therapeutic Molecule (Progress in Drug Research 68) (Abdel-Salam OME, editor). Springer, Basel, Switzerland. 2014, p. 77-104.
56.    Abdel-Salam OM, Szolcsanyi J, Mozsik G. Capsaicin and the stomach: a review of experimental and clinical data. J Physiol Paris 1997; 91:151–171.
57.    Saria A, Skofitsch G, Lembeck F. Distribution of capsaicin in rat tissues after systemic administration. J Pharm Pharmacol 1982; 34:273–275. 
58.    Pegorini S, Braida D, Verzoni C, Guerini-Rocco C, Consalez GG, Croci L, Sala M. Capsaicin exhibits neuroprotective effects in a model of transient global cerebral ischemia in Mongolian gerbils. Br J Pharmacol 2005; 144:727–735.
59.    Chung YC, Baek JY, Kim SR, Ko HW, Bok E, Shin WH, et al. Capsaicin prevents degeneration of dopamine neurons by inhibiting glial activation and oxidative stress in the MPTP model of Parkinson’s disease. Exp Mol Med 2017; 49:e298. 
60.    Demirbilek S, Ersoy MO, Demirbilek S, Karaman A, Gurbuz N, Bayraktar N,  et al. Small-dose capsaicin reduces systemic inflammatory responses in septic rats. Anesth Analg 2004; 99:1501-7.
61.    Abdel-Salam OME, Abdel-Rahman RF, Sleem AA et al. Modulation of lipopolysaccharide-induced oxidative stress by capsaicin. Infnlammopharmacology 2021; 20: 207-217.
62.    Arimboor R, Natarajan RB, Menon KR, Chandrasekhar LP, et al. Red pepper (Capsicum annuum) carotenoids as a source of natural food colors: analysis and stability-a review. J Food Sci Technol 2015; 52:1258-1271.
63.    Charles DJ. Capsicum. In: Anti-oxidant Properties of Spices, Herbs and Other Sources, Springer, New York, 2013, p.189-197.
64.    Bridgemohan P, Mohammed M, Bridgemohan RSH. Capsicums. In: Fruit and Vegetable Phytochemicals: Chemistry and Human Health,Volume II, 2nd ed. (Yahia EM, editor), JohnWiley & Sons Ltd. 2018, p. 957-968.
65.    Mullan K, Williams MA, Cardwell CR, McGuinness B, Passmore P, Silvestri G, Woodside JV, McKay GJ. Serum concentrations of vitamin E and carotenoids are altered in Alzheimer’s disease: A case-control study. Alzheimers Dement (N Y) 2017; 3: 432-439.
66.    Morris MC, Evans DA, Bienias JL Tangney CC, Wilson RS. Vitamin E and cognitive decline in older persons. Arch Neurol. 2002;59:1125-1132. 
67.    Power R, Coen RF, Beatty S, Mulcahy R, Moran R, Stack J, Howard  AN, Nolan JM. Supplemental retinal carotenoids enhance memory in healthy individuals with low levels of macular pigment in a randomized, double-blind, placebo-controlled clinical trial. J Alzheimers Dis 2018;61:947-961. 
68.    Yuan C, Chen H, Wang Y, Schneider JA, Willett WC, Morris MC. Dietary carotenoids related to risk of incident Alzheimer dementia (AD) and brain AD neuropathology: A community-based cohort of older adults. Am J Clin Nutr 2021;113:200–208.
Iranian Journal of Basic Medical Sciences
Volume 26, Issue 3
March 2023
Pages 335-342

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