Skip to main content
SpringerLink
Log in

Melatonin regulates neurodegenerative complications associated with NAFLD via enhanced neurotransmission and cellular integrity: a correlational study

  • Original Article
  • Published:
Metabolic Brain Disease Aims and scope Submit manuscript

Abstract

Nonalcoholic fatty liver disease (NAFLD) is recognized globally as the leading cause of chronic liver diseases whose patients are asymptomatic and are diagnosed incidentally. It increases the rate of mortality which is usually related to cardiovascular events; however, scarce attention has been addressed to brain damage. This study was designed to investigate the impact of melatonin (MEL; 10 mg/kg) on overcoming the hepato and neuro-complications associated with high fat, high fructose (HFHF) diet induced-NAFLD in rats. NAFLD was induced by HFHF diet for 8 consecutive weeks. MEL was given orally for the last 10 days. Rats’ general behavior was assessed by; open field test (OFT) and forced swimming test (FST). On biochemical level; serum levels of glucose, insulin, alanine transaminase and aspartate transaminase as well as the hepatic levels of triglycerides and total cholesterol were evaluated. Monoamines’ brain levels, their metabolites in addition to the brain level of 8-hydroxyguanosine (8-OHdG) were evaluated. Moreover, the levels of tumor necrosis factor-α (TNF-α), malondialdehyde (MDA), reduced glutathione (GSH) and nitric oxide (NOx) were measured in both the liver and brain tissues. Oral treatment of NAFLD induced rats with MEL for ten consecutive days managed to increase the activity of the rats in the OFT and decrease the immobility period in the FST. Moreover, MEL reduced monoamines turnover and elevated brain 8-OHdG level. It also had the ability to counteract the elevated levels of GSH, NOx, MDA, and TNF- α in liver and brain tissues. MEL can be suggested to be a promising candidate for treating the neuronal side effects related to NAFLD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Ahmed R, Abdel-Rahman R, Abdallah H, Saleh D, Farid O, Hessin A (2014) Antidepressant-like effect of resveratrol in a subchronic model of depression. Journal of The Arab Society for Medical Research 9:48–53

    Google Scholar 

  • Ahmed R, El Awdan S, Abdel Jaleel G, Saleh D, Ahmed Farid O (2020) Correlation between brain neurotransmitters and insulin sensitivity: Neuro-preservative role of resveratrol against high fat, high fructose-induced insulin resistance. Journal of Applied Pharmaceutical Science 10:26–36

    CAS  Google Scholar 

  • Ahmed-Farid OA, Ahmed RF, Saleh DO (2016) Combination of resveratrol and fluoxetine in an acute model of depression in mice: prevention of oxidative DNA fragmentation and monoamines degradation. Journal of Applied Pharmaceutical Science 6:1–7

    CAS  Google Scholar 

  • Amin M, Ahmed RF, Saleh DO (2017) Methionine and choline deficient diet-induced non-alcoholic Steatohepatitis in rats: role of melatonin. Journal of Applied Pharmaceutical Science 7:012–019

    CAS  Google Scholar 

  • Arendt J (1998) Melatonin and the pineal gland: influence on mammalian seasonal and circadian physiology. Rev Reprod 3:13–22

    PubMed  CAS  Google Scholar 

  • Bonavida B (1991) Immunomodulatory effect of tumor necrosis factor. Biotherapy 3:127–133

    PubMed  CAS  Google Scholar 

  • Bonomini F, Borsani E, Favero G, Rodella LF, Rezzani R (2018) Dietary melatonin supplementation could be a promising preventing/therapeutic approach for a variety of liver diseases. Nutrients 10

  • Chao HW, Chao SW, Lin H, Ku HC, Cheng CF (2019) Homeostasis of glucose and lipid in non-alcoholic fatty liver disease. Int J Mol Sci 20

  • Chen Z, Yu R, Xiong Y, Du F, Zhu S (2017) A vicious circle between insulin resistance and inflammation in nonalcoholic fatty liver disease. Lipids Health Dis 16:203

    PubMed  PubMed Central  Google Scholar 

  • Cholankeril G, Patel R, Khurana S, Satapathy SK (2017) Hepatocellular carcinoma in non-alcoholic steatohepatitis: current knowledge and implications for management. World J Hepatol 9:533–543

    PubMed  PubMed Central  Google Scholar 

  • Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ (2005) Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest 115:1343–1351

    PubMed  PubMed Central  CAS  Google Scholar 

  • El-Baz FK, Saleh DO, Abdel Jaleel GA, Hussein RA (2020) Attenuation of age-related hepatic Steatosis by Dunaliella salina microalgae in senescence rats through the regulation of redox status, inflammatory indices, and apoptotic biomarkers. Advances in pharmacological and pharmaceutical sciences 2020:3797218

    PubMed  PubMed Central  Google Scholar 

  • Ertunc ME, Hotamisligil GS (2016) Lipid signaling and lipotoxicity in metaflammation: indications for metabolic disease pathogenesis and treatment. J Lipid Res 57:2099–2114

    PubMed  PubMed Central  CAS  Google Scholar 

  • Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ (2018) Mechanisms of NAFLD development and therapeutic strategies. Nat Med 24:908–922

    PubMed  PubMed Central  CAS  Google Scholar 

  • Grassi J, Pradelles P (1991) Compounds labelled by the acetylcholinesterase of electrophorus Electricus. Its preparation process and its use as a tracer or marquer in enzymo-immunological determinations. US Patent N1,047,330

  • Gray SM, Aylor KW, Barrett EJ (2017) Unravelling the regulation of insulin transport across the brain endothelial cell. Diabetologia 60:1512–1521

    PubMed  PubMed Central  CAS  Google Scholar 

  • Jayatilleke E, Shaw S (1993) A high-performance liquid chromatographic assay for reduced and oxidized glutathione in biological samples. Anal Biochem 214:452–457

    PubMed  CAS  Google Scholar 

  • Johnson LA, Edwards M, Gamboa A, Hall J, Robinson M, O'Bryant SE (2017) Depression, inflammation, and memory loss among Mexican Americans: analysis of the HABLE cohort. Int Psychogeriatr 29:1693–1699

    PubMed  PubMed Central  Google Scholar 

  • Joo DT, Xiong Z, MacDonald JF, Jia Z, Roder J, Sonner J, Orser BA (1999) Blockade of glutamate receptors and barbiturate anesthesia : increased sensitivity to pentobarbital-induced anesthesia despite reduced inhibition of AMPA receptors in GluR2 null mutant mice. Anesthesiology: The Journal of the American Society of Anesthesiologists 91:1329–1341

    CAS  Google Scholar 

  • Karatas F, Karatepe M, Baysar A (2002) Determination of free malondialdehyde in human serum by high-performance liquid chromatography. Anal Biochem 311:76–79

    PubMed  CAS  Google Scholar 

  • Karatepe M (2004) Simultaneous determination of ascorbic acid and free malondialdehyde in human serum by HPLC–UV. LCGC ASIA PACIFIC 7:36–38

    Google Scholar 

  • Karthikeyan R, Spence DW, Brown GM, Pandi-Perumal SR (2018) Are type 2 diabetes mellitus and depression part of a common clock genes network? J Circadian Rhythms 16:4

    PubMed  PubMed Central  Google Scholar 

  • Kim B, Feldman EL (2012) Insulin resistance in the nervous system. Trends Endocrinol Metab 23:133–141

    PubMed  PubMed Central  CAS  Google Scholar 

  • Koehler EM et al. (2016) Presence of diabetes mellitus and steatosis is associated with liver stiffness in a general population: The Rotterdam study. Hepatology 63(1):138–47

  • Lalanza JF, Caimari A, del Bas JM, Torregrosa D, Cigarroa I, Pallas M, Capdevila L, Arola L, Escorihuela RM (2014) Effects of a post-weaning cafeteria diet in young rats: metabolic syndrome, reduced activity and low anxiety-like behaviour. PLoS One 9:e85049

    PubMed  PubMed Central  Google Scholar 

  • Lazzarino G, Di Pierro D, Tavazzi B, Cerroni L, Giardina B (1991) Simultaneous separation of malondialdehyde, ascorbic acid, and adenine nucleotide derivatives from biological samples by ion-pairing high-performance liquid chromatography. Anal Biochem 197:191–196

    PubMed  CAS  Google Scholar 

  • Lindberg MC, Cunningham A, Lindberg NH (1992) Acute phenobarbital intoxication. South Med J 85:803–807

    PubMed  CAS  Google Scholar 

  • Lo CC, Lin SH, Chang JS, Chien YW (2017) Effects of melatonin on glucose homeostasis, antioxidant ability, and Adipokine secretion in ICR mice with NA/STZ-induced hyperglycemia. Nutrients 9

  • Lodovici M, Casalini C, Briani C, Dolara P (1997) Oxidative liver DNA damage in rats treated with pesticide mixtures. Toxicology 117:55–60

    PubMed  CAS  Google Scholar 

  • Lombardi R, Fargion S, Fracanzani AL (2019) Brain involvement in non-alcoholic fatty liver disease (NAFLD): a systematic review. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 51:1214–1222

    Google Scholar 

  • Malhi H, Gores GJ (2008) Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease. Semin Liver Dis 28:360–369

    PubMed  PubMed Central  CAS  Google Scholar 

  • Marchisello S, Di Pino A, Scicali R, Urbano F, Piro S, Purrello F, Rabuazzo AM (2019) Pathophysiological, molecular and therapeutic issues of nonalcoholic fatty liver disease: an overview. Int J Mol Sci 20

  • Marin V, Rosso N, Dal Ben M, Raseni A, Boschelle M, Degrassi C, Nemeckova I, Nachtigal P, Avellini C, Tiribelli C, Gazzin S (2016) An animal model for the juvenile non-alcoholic fatty liver disease and non-alcoholic Steatohepatitis. PLoS One 11:e0158817

    PubMed  PubMed Central  Google Scholar 

  • Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419

    CAS  Google Scholar 

  • Mirza S, Hossain M, Mathews C, Martinez P, Pino P, Gay JL, Rentfro A, McCormick JB, Fisher-Hoch SP (2012) Type 2-diabetes is associated with elevated levels of TNF-alpha, IL-6 and adiponectin and low levels of leptin in a population of Mexican Americans: a cross-sectional study. Cytokine 57:136–142

    PubMed  CAS  Google Scholar 

  • Mitra S, De A, Chowdhury A (2020) Epidemiology of non-alcoholic and alcoholic fatty liver diseases. Translational gastroenterology and hepatology 5:16

    PubMed  PubMed Central  Google Scholar 

  • Pagel P, Blome J, Wolf HU (2000) High-performance liquid chromatographic separation and measurement of various biogenic compounds possibly involved in the pathomechanism of Parkinson's disease. J Chromatogr B, Biomed Sci Appl 746:297–304

    CAS  Google Scholar 

  • Papadoyannis IN, Samanidou VF, Nitsos CC (1999) Simultaneous determination of nitrite and nitrate in drinking water and human serum by high performance anion-exchange chromatography and UV detection. J Liq Chromatogr Relat Technol 22:2023–2041

    CAS  Google Scholar 

  • Petersen MC, Shulman GI (2018) Mechanisms of Insulin Action and Insulin Resistance. Physiol Rev 98(4):2133–2223

  • Pincon A, De Montgolfier O, Akkoyunlu N, Daneault C, Pouliot P, Villeneuve L, Lesage F, Levy BI, Thorin-Trescases N, Thorin E, Ruiz M (2019) Non-alcoholic fatty liver disease, and the underlying altered fatty acid metabolism, reveals brain hypoperfusion and contributes to the cognitive decline in APP/PS1 mice. Metabolites 9

  • Porsolt RD, Le Pichon M, Jalfre M (1977) Depression: a new animal model sensitive to antidepressant treatments. Nature 266:730–732

    PubMed  CAS  Google Scholar 

  • Reitman S, Frankel S (1957) A colorimetric method for the determination of serum glutamic oxalacetic and glutamic pyruvic transaminases. Am J Clin Pathol 28:56–63

    PubMed  CAS  Google Scholar 

  • Saleh DO, Ahmed RF, Amin MM (2017) Modulatory role of Co-enzyme Q10 on methionine and choline deficient diet-induced non-alcoholic steatohepatitis (NASH) in albino rats. Appl Physiol Nutr Metab 42:243–249

    PubMed  CAS  Google Scholar 

  • Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, Neuschwander-Tetri BA, Lavine JE, Tonascia J, Unalp A, Van Natta M, Clark J, Brunt EM, Kleiner DE, Hoofnagle JH, Robuck PR, Nash CRN (2010) Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 362:1675–1685

    PubMed  PubMed Central  CAS  Google Scholar 

  • Sharma AN, Elased KM, Lucot JB (2012) Rosiglitazone treatment reversed depression- but not psychosis-like behavior of db/db diabetic mice. J Psychopharmacol 26:724–732

    PubMed  Google Scholar 

  • Singh M, Jadhav HR (2014) Melatonin: functions and ligands. Drug Discov Today 19:1410–1418

    PubMed  CAS  Google Scholar 

  • Son SM, Song H, Byun J, Park KS, Jang HC, Park YJ, Mook-Jung I (2012) Altered APP processing in insulin-resistant conditions is mediated by autophagosome accumulation via the inhibition of mammalian target of rapamycin pathway. Diabetes 61:3126–3138

    PubMed  PubMed Central  CAS  Google Scholar 

  • Trinder P (1969) Determination of blood glucose using an oxidase-peroxidase system with a non-carcinogenic chromogen. J Clin Pathol 22:158–161

    PubMed  PubMed Central  CAS  Google Scholar 

  • Ucar F, Sezer S, Erdogan S, Akyol S, Armutcu F, Akyol O (2013) The relationship between oxidative stress and nonalcoholic fatty liver disease: its effects on the development of nonalcoholic steatohepatitis. Redox report : communications in free radical research 18:127–133

    PubMed  CAS  Google Scholar 

  • Van Herck MA, Vonghia L, Francque SM (2017) Animal models of nonalcoholic fatty liver disease-a starter's guide. Nutrients 9

  • Vazquez-Medina JP, Zenteno-Savin T, Forman HJ, Crocker DE, Ortiz RM (2011) Prolonged fasting increases glutathione biosynthesis in postweaned northern elephant seals. J Exp Biol 214:1294–1299

    PubMed  PubMed Central  CAS  Google Scholar 

  • Yang P, Wang Y, Tang W, Sun W, Ma Y, Lin S, Jing J, Jiang L, Shi H, Song Z, Yu L (2020) Western diet induces severe nonalcoholic steatohepatitis, ductular reaction, and hepatic fibrosis in liver CGI-58 knockout mice. Sci Rep 10:4701

    PubMed  PubMed Central  CAS  Google Scholar 

  • Yoshida T (1996) Determination of reduced and oxidized glutathione in erythrocytes by high-performance liquid chromatography with ultraviolet absorbance detection. J Chromatogr B Biomed Appl 678:157–164

    PubMed  CAS  Google Scholar 

  • Younossi ZM et al. (2016) The economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe. Hepatology 64(5):1577–1586

Download references

Author information

Authors and Affiliations

  1. Pharmacology Department, National Research Centre (NRC), 33 El Buhouth St. (Former El Tahrir St.), Dokki, Giza, P.O. 12622, Egypt

    Gehad A. Abdel Jaleel, Sally A. Al-Awdan, Rania F. Ahmed & Dalia O. Saleh

  2. Department of Physiology, National Organization for Drug Control and Research, Giza, Egypt

    Omar A.H. Ahmed-Farid

Authors
  1. Gehad A. Abdel Jaleel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sally A. Al-Awdan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rania F. Ahmed
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Omar A.H. Ahmed-Farid
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dalia O. Saleh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dalia O. Saleh.

Ethics declarations

Conflict of interest

Authors declare no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(PDF 354 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

A. Abdel Jaleel, G., A. Al-Awdan, S., F. Ahmed, R. et al. Melatonin regulates neurodegenerative complications associated with NAFLD via enhanced neurotransmission and cellular integrity: a correlational study. Metab Brain Dis 35, 1251–1261 (2020). https://doi.org/10.1007/s11011-020-00593-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11011-020-00593-4

Keywords

Search

Navigation