Abstract
Chronic fatigue syndrome (CFS) is a disorder characterized by persistent and relapsing fatigue along with long-lasting and debilitating fatigue, myalgia, cognitive impairment, and many other common symptoms. The present study was conducted to explore the protective effect of hemin on CFS in experimental mice. Male albino mice were subjected to stress-induced CFS in a forced swimming test apparatus for 21 days. After animals had been subjected to the forced swimming test, hemin (5 and 10 mg/kg; i.p.) and hemin (10 mg/kg) + tin(IV) protoporphyrin (SnPP), a hemeoxygenase-1 (HO-1) enzyme inhibitor, were administered daily for 21 days. Various behavioral tests (immobility period, locomotor activity, grip strength, and anxiety) and estimations of biochemical parameters (lipid peroxidation, nitrite, and GSH), mitochondrial complex dysfunctions (complexes I and II), and neurotransmitters (dopamine, serotonin, and norepinephrine and their metabolites) were subsequently assessed. Animals exposed to 10 min of forced swimming session for 21 days showed a fatigue-like behavior (as increase in immobility period, decreased grip strength, and anxiety) and biochemical alteration observed by increased oxidative stress, mitochondrial dysfunction, and neurotransmitter level alteration. Treatment with hemin (5 and 10 mg/kg) for 21 days significantly improved the decreased immobility period, increased locomotor activity, and improved anxiety-like behavior, oxidative defense, mitochondrial complex dysfunction, and neurotransmitter level in the brain. Further, these observations were reversed by SnPP, suggesting that the antifatigue effect of hemin is HO-1 dependent. The present study highlights the protective role of hemin against experimental CFS-induced behavioral, biochemical, and neurotransmitter alterations.
Similar content being viewed by others
Abbreviations
- CFS:
-
chronic fatigue stress
- DA:
-
dopamine
- DOPAC:
-
3,4-dihydroxyphenylacetic acid
- FST:
-
forced swimming test
- GSH:
-
reduced glutathione
- HO-1:
-
heme oxygenase
- HVA:
-
homovanillic acid
- LPO:
-
lipid peroxidation
- NE:
-
norepinephrine
- SnPP:
-
tin protoporphyrin
- 5-HT:
-
serotonin
- 5-HIAA:
-
5-hydroxyindoleacetic acid
References
Afari N, Buchwald D (2003) Chronic fatigue syndrome: a review. Am J Psychiatr 160(2):221–236
Alam J, Cook JL (2003) Transcriptional regulation of the heme oxygenase-1 gene via the stress response element pathway. Curr Pharm Des 9(30):2499–2511
Belzung C, El Hage W, Moindrot N, Griebel G (2001) Behavioral and neurochemical changes following predatory stress in mice. Neuropharmacology 41(3):400–408
Berman SB, Hastings TG (1999) Dopamine oxidation alters mitochondrial respiration and induces permeability transition in brain mitochondria: implications for Parkinson’s disease. J Neurochem 73(3):1127–1137
Dhir A, Kulkarni SK (2008) Venlafaxine reverses chronic fatigue-induced behavioral, biochemical and neurochemical alterations in mice. Pharmacol Biochem Behav 89(4):563–571
Eftekharzadeh B, Khodagholi F, Azadeh A, Nader M (2010) Alginate protects NT2 neurons against H2O2-induced neurotoxicity. Carbohydr Polym 79(4):1063–1072
Ellman G, Lysko H (1979) A precise method for the determination of whole blood and plasma sulfhydryl groups. Anal Biochem 93:98–102
Filler KL, Bennett D, McCain J, Elswick N et al (2014) Association of mitochondrial dysfunction and fatigue: a review of the literature. BBA Clin 1:12–23
Green LC, Wagner DA, Joseph G, Skipper PL, Wishnok JS et al (1982) Analysis of nitrate, nitrite, and [15N] nitrate in biological fluids. Anal Biochem 126(1):131–138
Jamwal S, Singh S, Kaur N, Kumar P (2015) Protective effect of spermidine against excitotoxic neuronal death induced by quinolinic acid in rats: possible neurotransmitters and neuroinflammatory mechanism. Neurotox Res 28(2):171–184
Jang JU, Lee SH, Choi CU, Song-Chull B, Taeg CH et al (2007) Effects of heme oxygenase-1 inducer and inhibitor on experimental autoimmune uveoretinitis. Korean J Ophthalmol 21(4):238–243
Kaizaki A, Sachiko T, Kumiko I, Satoshi N, Takemi Y (2006) The neuroprotective effect of heme oxygenase (HO) on oxidative stress in HO-1 siRNA-transfected HT22 cells. Brain Res 1108(1):39–44
Kennedy G, Spence Vance A, McLaren M, Hill A, Underwood C (2005) Oxidative stress levels are raised in chronic fatigue syndrome and are associated with clinical symptoms. Free Radic Biol Med 39(5):584–589
Khan A, Jamwal S, Bijjem KRV, Prakash A, Kumar P (2015) Neuroprotective effect of hemeoxygenase-1/glycogen synthase kinase-3β modulators in 3-nitropropionic acid-induced neurotoxicity in rats. Neuroscience 287:66–77
King TE (1967) [58] Preparation of succinate dehydrogenase and reconstitution of succinate oxidase. in Methods in enzymology 322–331
King TE, Howard RL (1967) [52] Preparations and properties of soluble NADH dehydrogenases from cardiac muscle, in Methods in enzymology 275–294
Kravets Anatoliy, Hu Z, Tihomir M, Torno Michael D, Maines Mahin D (2004) Biliverdin reductase a novel regulator for induction of activating transcription factor-2 and heme oxygenase-1. J Biol Chem 279(19):19916–19923
Kumar P, Kalonia H, Kumar A (2012) Possible GABAergic mechanism in the neuroprotective effect of gabapentin and lamotrigine against 3-nitropropionic acid induced neurotoxicity. Eur J Pharmacol 674(2–3):265–274
Lim E-J, Ahn Y-C, Jang E-S, Lee S-W, Lee S-H (2020) Systematic review and meta-analysis of the prevalence of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). J Transl Med 18(1):1–15
Liu Y, Liu J, Tetzlaff W, Paty Donald W, Cynader Max S (2006) Biliverdin reductase a major physiologic cytoprotectant, suppresses experimental autoimmune encephalomyelitis. Free Radic Biol Med 40(6):960–967
Lowry OH, Rosebrough Nira J, Lewis FA, Randall Rose J (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275
Mitra A, Kumar ST, Sachhidananda U, Dipankar B, Jayram H (2017) Effect of Swarna Jibanti (Coelogyne cristata Lindley) in alleviation of chronic fatigue syndrome in aged Wistar rats. J Ayurveda Integr Med 30:1e6
Morse D, Choi AMK (2002) Heme oxygenase-1: the “emerging molecule” has arrived. Am J Respir Cell Mol Biol 27(1):8–16
Nunnari J, Suomalainen A (2012) Mitochondria: in sickness and in health. Cell. 148(6):1145–1159
Patel BA, Arundell M, Parker KH, Yeoman MS, O’Hare D (2005) Simple and rapid determination of serotonin and catecholamines in biological tissue using high-performance liquid chromatography with electrochemical detection. J Chromatogr B 818(2):269–276
Pizzigallo E, Racciatti D, Vecchiet J (1999) Clinical and pathophysiological aspects of chronic fatigue syndrome. J Musculoskelet Pain 7(1–2):217–224
Ragy M, Ali F, Ramzy MM (2016) Effect of hemin on brain alterations and neuroglobin expression in water immersion restraint stressed rats. Scientifica (Cairo) Hindawi 2016
Rivera C, Mastronardi M, Silva-Aldana C, Arcos-Burgos CT, Lidbury M et al (2019) Myalgic encephalomyelitis/chronic fatigue syndrome: a comprehensive review. Diagnostics 9(3):91
Sarvaiya K, Goswami S (2016) Investigation of the effects of vanilloids in chronic fatigue syndrome. Brain Res Bull 127:187–194
Schenck JF, Zimmerman EA (2004) High-field magnetic resonance imaging of brain iron: birth of a biomarker? NMR Biomed 17(7):433–445
Singh A, Naidu Pattipati S, Saraswati G, Kulkarni Shrinivas K (2002) Effect of natural and synthetic antioxidants in a mouse model of chronic fatigue syndrome. J Med Food 5(4):211–220
Son Y, Lee JH, Chung H-T, Pae H-O (2013) Therapeutic roles of heme oxygenase-1 in metabolic diseases: curcumin and resveratrol analogues as possible inducers of heme oxygenase-1. Oxidative Med Cell Longev 2013
Surapaneni DK, Adapa SRSS, Preeti K, Teja GR, Veeraragavan M et al (2012) Shilajit attenuates behavioral symptoms of chronic fatigue syndrome by modulating the hypothalamic–pituitary–adrenal axis and mitochondrial bioenergetics in rats. J Ethnopharmacol 143(1):91–99
Wills E (1966) Mechanisms of lipid peroxide formation in animal tissues. Biochem J 99(3):667–676
Zhang B, Wei X, Cui X, Kobayashi T, Li W (2008) Effects of heme oxygenase 1 on brain edema and neurologic outcome after cardiopulmonary resuscitation in rats. Anesthesiology 109(2):260–268
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
The authors declare that they have no conflict of interest.
Ethical Statement
The protocol of the study was approved by the Institutional Animal Ethics Committee (IAEC) Approval No. IAEC/CPCSEA/M14/P246 and was carried out in accordance with guidelines for the use and care of experimental animals. All the experiments for a given treatment were performed using age-matched animals to avoid variability between experimental groups.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Thakur, V., Jamwal, S., Kumar, M. et al. Protective Effect of Hemin Against Experimental Chronic Fatigue Syndrome in Mice: Possible Role of Neurotransmitters. Neurotox Res 38, 359–369 (2020). https://doi.org/10.1007/s12640-020-00231-y
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12640-020-00231-y