Anthony Tope OLOFINNADE, Adejoke Yetunde ONAOLAPO, Olakunle James ONAOLAPO

Anxiogenic, memory-impairing, pro-oxidant and pro-inflammatory effects of sodium benzoate in the mouse brain

Objective: Sodium benzoate (NaB), a commonly used food additive, is effective in preventing deterioration and/or spoilage of foods and drinks. While there have been reports suggesting its potential use as an adjunct in schizophrenia management; there is a lack of information on its effects on the brain, especially when added to dry foods. This study examined the effects of NaB added to rodent feed on neurobehavior, antioxidant status, anti-inflammatory and apoptotic markers in mouse brain. Method: Animals were divided into 4 groups of 10 mice each. Groups included normal control (fed with rodent chow) and 3 groups fed with NaB at 125, 250 and 500 mg/kg, respectively, for eight weeks. Open field, elevated plus maze (EPM), Y-maze, and radial-arm maze behaviors were assessed on day 57, following animals were euthanized 24 hours after the behavioral test. Whole-brain homogenate processed for the assessment of antioxidant status, inflammatory/apoptotic markers, and acetylcholinesterase activity. Results: The NaB diet altered body weight, open-field behaviors, working-memory, and anxiety indices. Brain antioxidant status, tumor necrosis factor-α and interleukin-10 decreased, while the malondialdehyde, caspase-3 level, and acetylcholinesterase activity increased. Conclusion: The results of this study revealed that the addition of NaB at these concentrations to rodent chow was associated with memory loss, anxiety, oxidative stress and increased inflammatory/apoptotic effects suggesting vigilance in its use.

PDF

___

1. Khoshnoud MJ, Siavashpour A, Bakhshizadeh M, Rashedinia M. Effects of sodium benzoate, a commonly used food preservative, on learning, memory, and oxidative stress in brain of mice. J Biochem Mol Toxicol 2018; 32:e22022.

2. Lucera A, Costa C, Conte A, Del Nobile MA. Food applications of natural antimicrobial compounds. Front Microbiol 2012; 3:287.

3. Pongsavee M. Effect of sodium benzoate preservative on micronucleus induction, chromosome break, and Ala40Thr superoxide dismutase gene mutation in lymphocytes. Biomed Res Int 2015; 2015:103512.

4. Yadav A, Kumar A, Das M, Tripathi A. Sodium benzoate, a food preservative, affects the functional and activation status of splenocytes at non cytotoxic dose. Food Chem Toxicol 2016; 88:40-47.

5. El-Shennawy L, Kamel MAE, Khalaf AHY, Yousef MI. Dose-dependent reproductive toxicity of sodium benzoate in male rats: Inflammation, oxidative stress and apoptosis. Reprod Toxicol 2020; 98:92-98.

6. Lennerz BS, Vafai SB, Delaney NF, Clish CB, Deik AA, Pierce KA, et al. Effects of sodium benzoate, a widely used food preservative, on glucose homeostasis and metabolic profiles in humans. Mol Genet Metab 2015; 114:73-79.

7. United States Food and Drug Administration. Data on benzene in soft drinks and other beverages. https://wayback.archive.it.org/7993/20170112012123/https:/www.fda.gov/Food/ FoodborneIllnessContaminants/ChemicalContaminants/ ucm055815.htm. Accessed January 12, 2021.

8. World Health Organization. Codex Alimentarius Commission Procedural Manual; JOINT FAO/WHO Food Standards Programme. http://www.fao.org/3/i3243e/i3243e.pdf. Accessed January 12, 2021.

9. Ifijeh M. NIFST Aligns with FG, Says Benzoate is Safe as Preservatives. https://www.thisdaylive.com/index. php/2017/04/06/nifst-aligns-with-fg-says-benzoate-is-safe-as-preservatives/. Accessed January 12, 2021.

10. Brahmachari S, Jana A, Pahan K. Sodium benzoate, a metabolite of cinnamon and a food additive, reduces microglial and astroglial inflammatory responses. J Immunol 2009; 183:5917-5927.

11. Yucel A, Ozyalcin S, Talu GK, Yucel EC, Erdine S. Intravenous administration of caffeine sodium benzoate for postdural puncture headache. Reg Anesth Pain Med 1999; 24:51-54.

12. Lane HY, Lin CH, Green MF, Hellemann G, Huang CC, Chen PW, et al. Add-on treatment of benzoate for schizophrenia: a randomized, double-blind, placebo-controlled trial of D-amino acid oxidase inhibitor. JAMA Psychiatry 2013; 70:1267-1275.

13. Yetuk G, Pandir D, Bas H. Protective role of catechin and quercetin in sodium benzoate-induced lipid peroxidation and the antioxidant system in human erythrocytes in vitro. ScientificWorldJournal 2014; 2014:874824.

14. Beezhold BL, Johnston CS, Nochta KA. Sodium benzoate-rich beverage consumption is associated with increased reporting of ADHD symptoms in college students: a pilot investigation. J Atten Disord 2014; 18:236-241.

15. Priya RJ, Sridhar R, Balachandran C, Manohar, BM. Effect of sodium benzoate treatment on body weight of Wistar rats. Indian Vet J 2010; 87:303-304.

16. Onaolapo AY, Ayeni OJ, Ogundeji MO, Ajao A, Onaolapo OJ, Owolabi AR. Subchronic ketamine alters behaviour, metabolic indices and brain morphology in adolescent rats: Involvement of oxidative stress, glutamate toxicity and caspase-3-mediated apoptosis. J Chem Neuroanat 2019; 96:22-33.

17. Onaolapo OJ, Onaolapo AY, Akanmu MA, Olayiwola G. Changes in spontaneous working-memory, memory-recall and approachavoidance following “low dose” monosodium Glutamate in mice. AIMS Neurosci 2016; 3:317-337.

18. Onaolapo AY, Onaolapo OJ, Nwoha PU. Aspartame and the hippocampus: Revealing a bi-directional, dose/time-dependent behavioural and morphological shift in mice. Neurobiol Learn Mem 2017; 139:76-88.

19. Olofinnade AT, Onaolapo TM, Oladimeji S, Fatoki AM, Balogun CI, Onaolapo AY, et al. An Evaluation of the effects of pyridoxal phosphate in chlorpromazineinduced parkinsonism using mice. Cent Nerv Syst Agents Med Chem 2020; 20:13-25.

20. Onaolapo AY, Onaolapo OJ, Nwoha PU. Methyl aspartylphenylalanine, the pons and cerebellum in mice: An evaluation of motor, morphological, biochemical, immunohistochemical and apoptotic effects. J Chem Neuroanat 2017; 86:67-77.

21. Onaolapo OJ, Onaolapo AY, Omololu TA, Oludimu AT, Segun-Busari T, Omoleke T. Exogenous testosterone, aging, and changes in behavioral response of gonadally ıntact male mice. J Exp Neurosci 2016; 10:59-70.

22. Onaolapo AY, Odetunde I, Akintola AS, Ogundeji MO, Ajao A, Obelawo AY, et al. Dietary composition modulates impact of food-added monosodium glutamate on behaviour, metabolic status and cerebral cortical morphology in mice. Biomed Pharmacother 2019; 109:417-428.

23. Onaolapo AY, Olawore OI, Yusuf FO, Adeyemo AM, Adewole IO, Onaolapo OJ. Oral monosodium glutamate administration differentially affects novelty-induced behaviors, behavioral despair and place preference in male and female mice. Current Psychopharmacol 2019; 8:130-145.

24. Onaolapo OJ, Adekola MA, Azeez TO, Salami K, Onaolapo AY. l-Methionine and silymarin: A comparison of prophylactic protective capabilities in acetaminophen-induced injuries of the liver, kidney and cerebral cortex. Biomed Pharmacother 2017; 85:323-333.

25. Onaolapo OJ, Ademakinwa OQ, Olalekan TO, Onaolapo AY. Ketamine-induced behavioural and brain oxidative changes in mice: an assessment of possible beneficial effects of zinc as mono- or adjunct therapy. Psychopharmacology (Berl) 2017; 234:2707-2725.

26. Onaolapo OJ, Paul TB, Onaolapo AY. Comparative effects of sertraline, haloperidol or olanzapine treatments on ketamine-induced changes in mouse behaviours. Metab Brain Dis 2017;32:1475-1489.

27. Onaolapo AY, Adebisi EO, Adeleye AE, Olofinnade AT, Onaolapo OJ. Dietary melatonin protects against behavioural, metabolic, oxidative, and organ morphological changes in mice that are fed high-fat, high- sugar diet. Endocr Metab Immune Disord Drug Targets 2020; 20:570-583.

28. Onaolapo OJ, Odeniyi AO, Jonathan SO, Samuel MO, Amadiegwu D, Olawale A, et al. An investigation of the anti-Parkinsonism potential of co-enzyme Q10 and co-enzyme Q10 /levodopa-carbidopa combination in mice. Curr Aging Sci 2019. doi: 10.2174/1874609812666191023153724

29. Miller NJ, Rice-Evans C, Davies MJ, Gopinathan V, Milner A. A novel method for measuring antioxidant capacity and its application to monitoring the antioxidant status in premature neonates. Clin Sci (Lond) 1993; 84:407-412.

30. Ghiselli A, Serafini M, Natella F, Scaccini C. Total antioxidant capacity as a tool to assess redox status: critical view and experimental data. Free RadicBiol Med 2000; 29:1106.

31. Bartosz G. Non-enzymatic antioxidant capacity assays: limitations of use in biomedicine. Free Radic Res 2010; 44:711-720.

32. Pinchuk I, Shoval H, Dotan Y, Lichtenberg D. Evaluation of antioxidants: scope, limitations and relevance of assays. Chem Phys Lipids. 2012; 165:638-647.

33. Re R, Pellegrini N, Proteggente A, Pannala A, Yang M, Rice-Evans C. Antioxidant activity applying an improved ABTS radical cation decolorization assay. Free Radic Biol Med 1999; 26:1231-1237.

34. Shea TB, Rogers E, Ashline D, Ortiz D, Sheu MS. Quantification of antioxidant activity in brain tissue homogenates using the 'total equivalent antioxidant capacity'. J Neurosci Methods 2003; 125:55-58.

35. Griffith WH. Nutritional factors affecting growth of rats on diets containing sodium benzoate. Exp Biol Med 1929; 26:858-860.

36. Saatci C, Erdem Y, Bayramov R, Akalın H, Tascioglu N, Ozkul Y. Effect of sodium benzoate on DNA breakage, micronucleus formation and mitotic index in peripheral blood of pregnant rats and their newborns. Biotechnol Biotechnol Equip 2016; 30:1179- 1183.

37. Nair B. Final report on the safety assessment of Benzyl Alcohol, Benzoic Acid, and Sodium Benzoate. Int J Toxicol 2001; 20(Suppl.3):23-50.

38. Khasnavis S, Pahan K. Sodium benzoate, a metabolite of cinnamon and a food additive, upregulates neuroprotective Parkinson disease protein DJ-1 in astrocytes and neurons. J Neuroimmune Pharmacol 2012; 7:424-435.

39. Noorafshan A, Erfanizadeh M, Karbalay-Doust S. Sodium benzoate, a food preservative, induces anxiety and motor impairment in rats. Neurosciences (Riyadh) 2014; 19:24-28.

40. Modi KK, Roy A, Brahmachari S, Rangasamy SB, Pahan K. Cinnamon and ıts metabolite sodium benzoate attenuate the activation of p21rac and protect memory and learning in an animal model of alzheimer's disease. PLoS One 2015; 10:e0130398.

41. Crane SC, Lachance.PA The effect of chronic sodium benzoate consumption on brain monamines and spontaneous activity in rats. Nutr Rep Int 1985; 31:169-177.

42. Chen Q, Huang NN, Huang JT, Chen S, Fan J, Li C, et al. Sodium benzoate exposure downregulates the expression of tyrosine hydroxylase and dopamine transporter in dopaminergic neurons in developing zebrafish. Birth Defects Res B Dev Reprod Toxicol 2009; 86:85-91.

43. Tsay HJ, Wang YH, Chen WL, Huang MY, Chen YH. Treatment with sodium benzoate leads to malformation of zebrafish larvae. Neurotoxicol Teratol 2007; 29:562-569.

44. Fukui K, Onodera K, Shinkai T, Suzuki S, Urano S. Impairment of learning and memory in rats caused by oxidative stress and aging, and changes in antioxidative defense systems. Ann N Y Acad Sci 2001; 928:168-175.

45. Kandlur A, Satyamoorthy K, Gangadharan G. Oxidative stress in cognitive and epigenetic aging: a retrospective glance. Front Mol Neurosci 2020; 13:41.