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Hydrogen Sulfide Attenuates the Neurotoxicity in the Animal Model of Fetal Alcohol Spectrum Disorders

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Abstract

Fetal alcohol spectrum disorder (FASD), which is caused by prenatal alcohol exposure, can result in cell death in specific brain regions. Alcohol-induced neurocognitive defects offspring’s are included with activation of oxidative-inflammatory cascade followed with wide apoptotic neurodegeneration in many brain’s regions such as hippocampus. According to the latest studies, H2S (hydrogen sulfide) can protect neuronal cells via antioxidant, anti-inflammatory, and anti-apoptotic mechanisms in different animal models. Therefore, we aimed to evaluate the protective effects of H2S on ethanol-induced neuroinflammation and neuronal apoptosis in pup hippocampus with postnatal alcohol exposure. Administration of ethanol (5.27 g/kg) in milk solution (27.8 mL/kg) for each rat pups was performed through intragastric intubation on 2 to 10 postnatal days and NaHS as H2S donor (1 mg/kg) was injected on similar time, subcutaneously. For examining the antioxidant and anti-inflammatory effects, ELISA assay was performed to determine the levels of TNF-α, IL1β, and antioxidant enzymes. Immunohistochemical staining was performed to evaluate the expression levels of GFAP and caspase-3 also Nissl staining was done for necrotic cell death evaluation. H2S treatment could significantly increase the activity of total superoxide dismutase, catalase, and glutathione (P < 0.05). It also decreased the levels of TNF-α, IL1β, and malondialdehyde, compared with the ethanol group (P < 0.05). Moreover, the number of hippocampal caspase-3, GFAP-positive cells, and necrotic cells death reduced in the H2S group (P < 0.01). Based on the findings, H2S can inhibit apoptotic signaling that is mediated by the oxidative-inflammatory cascade following ethanol exposure of rat pups on postnatal period.

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References

  • Abbott CW, Rohac DJ, Bottom RT, Patadia S, Huffman KJ (2017) Prenatal ethanol exposure and neocortical development: a transgenerational model of FASD. Cereb Cortex 28:2908–2921

    PubMed Central  Google Scholar 

  • Abe K, Kimura H (1996) The possible role of hydrogen sulfide as an endogenous neuromodulator. J Neurosci 16:1066–1071

    CAS  PubMed  PubMed Central  Google Scholar 

  • Amin FU, Shah SA, Kim MO (2016) Glycine inhibits ethanol-induced oxidative stress, neuroinflammation and apoptotic neurodegeneration in postnatal rat brain. Neurochem Int 96:1–12

    CAS  PubMed  Google Scholar 

  • Aski ML, Rezvani ME, Khaksari M, Hafizi Z, Pirmoradi Z, Niknazar S, Mehrjerdi FZ (2018) Neuroprotective effect of berberine chloride on cognitive impairment and hippocampal damage in experimental model of vascular dementia. Iran J Basic Med Sci 21:53

    PubMed  PubMed Central  Google Scholar 

  • Berman RF, Hannigan JH (2000) Effects of prenatal alcohol exposure on the hippocampus: spatial behavior, electrophysiology, and neuroanatomy. Hippocampus 10:94–110

    CAS  PubMed  Google Scholar 

  • Boitard C, Cavaroc A, Sauvant J, Aubert A, Castanon N, Layé S, Ferreira G (2014) Impairment of hippocampal-dependent memory induced by juvenile high-fat diet intake is associated with enhanced hippocampal inflammation in rats. Brain Behav Immun 40:9–17

    CAS  PubMed  Google Scholar 

  • Brocardo PS, Gil-Mohapel J, Wortman R, Noonan A, Mcginnis E, Patten AR, Christie BR (2017) The effects of ethanol exposure during distinct periods of brain development on oxidative stress in the adult rat brain. Alcohol Clin Exp Res 41:26–37

    CAS  PubMed  Google Scholar 

  • Brooks P (1997) DNA damage, DNA repair, and alcohol toxicity—a review. Alcohol Clin Exp Res 21:1073–1082

    CAS  PubMed  Google Scholar 

  • Calvert JW, Jha S, Gundewar S, Elrod JW, Ramachandran A, Pattillo CB, Kevil CG, Lefer DJ (2009) Hydrogen sulfide mediates cardioprotection through Nrf2 signaling. Circ Res 105:365–374

    CAS  PubMed  PubMed Central  Google Scholar 

  • Carloni S, Mazzoni E, Balduini W (2004) Caspase-3 and calpain activities after acute and repeated ethanol administration during the rat brain growth spurt. J Neurochem 89:197–203

    CAS  PubMed  Google Scholar 

  • Connor PD, Sampson PD, Bookstein FL, Barr HM, Streissguth AP (2000) Direct and indirect effects of prenatal alcohol damage on executive function. Dev Neuropsychol 18:331–354

    CAS  PubMed  Google Scholar 

  • Crews F, Nixon K, Kim D, Joseph J, Shukitt-Hale B, Qin L, Zou J (2006) BHT blocks NF-κB activation and ethanol-induced brain damage. Alcohol Clin Exp Res 30:1938–1949

    CAS  PubMed  Google Scholar 

  • Cronise K, Marino MD, Tran TD, Kelly SJ (2001) Critical periods for the effects of alcohol exposure on learning in rats. Behav Neurosci 115:138

    CAS  PubMed  Google Scholar 

  • Erfani S, Moghimi A, Aboutaleb N, Khaksari M (2018) Nesfatin-1 improve spatial memory impairment following transient global cerebral ischemia/reperfusion via inhibiting microglial and caspase-3 activation. J Mol Neurosci 65:377–384

    CAS  PubMed  Google Scholar 

  • Ghanbari F, Khaksari M, Vaezi G, Hojati V, Shiravi A (2019) Hydrogen sulfide protects hippocampal neurons against methamphetamine neurotoxicity via inhibition of apoptosis and neuroinflammation. J Mol Neurosci 67:133–141

    CAS  PubMed  Google Scholar 

  • Gong J, Mullins CB (2008) Selective oxidation of ethanol to acetaldehyde on gold. J Am Chem Soc 130:16458–16459

    CAS  PubMed  Google Scholar 

  • Goodlett CR, Horn KH (2001) Mechanisms of alcohol-induced damage to the developing nervous system. Alcohol Res Health 25:175–184

    CAS  PubMed  PubMed Central  Google Scholar 

  • Guerri C, Pascual M (2010) Mechanisms involved in the neurotoxic, cognitive, and neurobehavioral effects of alcohol consumption during adolescence. Alcohol 44:15–26

    CAS  PubMed  Google Scholar 

  • Guidotti T (1996) Hydrogen sulphide. Occup Med 46:367–371

    CAS  Google Scholar 

  • Heaton MB, Paiva M, Madorsky I, Mayer J, Moore DB (2003) Effects of ethanol on neurotrophic factors, apoptosis-related proteins, endogenous antioxidants, and reactive oxygen species in neonatal striatum: relationship to periods of vulnerability. Dev Brain Res 140:237–252

    CAS  Google Scholar 

  • Helfer JL, Goodlett CR, Greenough WT, Klintsova AY (2009) The effects of exercise on adolescent hippocampal neurogenesis in a rat model of binge alcohol exposure during the brain growth spurt. Brain Res 1294:1–11

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ikegami Y, Goodenough S, Inoue Y, Dodd P, Wilce P, Matsumoto I (2003) Increased TUNEL positive cells in human alcoholic brains. Neurosci Lett 349:201–205

    CAS  PubMed  Google Scholar 

  • Johansen D, Ytrehus K, Baxter GF (2006) Exogenous hydrogen sulfide (H 2 S) protects against regional myocardial ischemia–reperfusion injury. Basic Res Cardiol 101:53–60

    CAS  PubMed  Google Scholar 

  • Kadiiska M, Gladen B, Baird D, Germolec D, Graham L, Parker C, Nyska A, Wachsman J, Ames B, Basu S (2005) Biomarkers of oxidative stress study II: are oxidation products of lipids, proteins, and DNA markers of CCl4 poisoning? Free Radic Biol Med 38:698–710

    CAS  PubMed  Google Scholar 

  • Kelly SJ, Goodlett CR, Hannigan JH (2009) Animal models of fetal alcohol spectrum disorders: impact of the social environment. Dev Disabil Res Rev 15:200–208

    PubMed  PubMed Central  Google Scholar 

  • Kempuraj D, Thangavel R, Natteru P, Selvakumar G, Saeed D, Zahoor H, Zaheer S, Iyer S, Zaheer A (2016) Neuroinflammation induces neurodegeneration. J Neurol Neurosurg Spine 1

  • Khaksari M, Mehrjerdi FZ, Rezvani ME, Safari F, Mirgalili A, Niknazar S (2017) The role of erythropoietin in remote renal preconditioning on hippocampus ischemia/reperfusion injury. J Physiol Sci 67:163–171

    CAS  PubMed  Google Scholar 

  • Kilburn KH, Warshaw RH (1995) Hydrogen sulfide and reduced-sulfur gases adversely affect neurophysiological functions. Toxicol Ind Health 11:185–197

    CAS  PubMed  Google Scholar 

  • Kimura H (2013) Physiological role of hydrogen sulfide and polysulfide in the central nervous system. Neurochem Int 63:492–497

    CAS  PubMed  Google Scholar 

  • Komada M, Hara N, Kawachi S, Kawachi K, Kagawa N, Nagao T, Ikeda Y (2017) Mechanisms underlying neuro-inflammation and neurodevelopmental toxicity in the mouse neocortex following prenatal exposure to ethanol. Sci Rep 7:4934

    PubMed  PubMed Central  Google Scholar 

  • Kumar M, Ray RS, Sandhir R (2018) Hydrogen sulfide attenuates homocysteine-induced neurotoxicity by preventing mitochondrial dysfunctions and oxidative damage: in vitro and in vivo studies. Neurochem Int 120:87–98

    CAS  PubMed  Google Scholar 

  • Luo Y, Yang X, Zhao S, Wei C, Yin Y, Liu T, Jiang S, Xie J, Wan X, Mao M (2013) Hydrogen sulfide prevents OGD/R-induced apoptosis via improving mitochondrial dysfunction and suppressing an ROS-mediated caspase-3 pathway in cortical neurons. Neurochem Int 63:826–831

    CAS  PubMed  Google Scholar 

  • Marino MD, Cronise K, Lugo JN Jr, Kelly SJ (2002) Ultrasonic vocalizations and maternal–infant interactions in a rat model of fetal alcohol syndrome. Dev Psychobiol 41:341–351

    PubMed  Google Scholar 

  • Miki T, Harris SJ, Wilce PA, Takeuchi Y, Bedi KS (2004) Effects of age and alcohol exposure during early life on pyramidal cell numbers in the CA1-CA3 region of the rat hippocampus. Hippocampus 14:124–134

    CAS  PubMed  Google Scholar 

  • Moreno E, Yan M, Basler K (2002) Evolution of TNF signaling mechanisms: JNK-dependent apoptosis triggered by Eiger, the Drosophila homolog of the TNF superfamily. Curr Biol 12:1263–1268

    CAS  PubMed  Google Scholar 

  • Pascual M, Blanco AM, Cauli O, Miñarro J, Guerri C (2007) Intermittent ethanol exposure induces inflammatory brain damage and causes long-term behavioural alterations in adolescent rats. Eur J Neurosci 25:541–550

    PubMed  Google Scholar 

  • Peake BF, Nicholson CK, Lambert JP, Hood RL, Amin H, Amin S, Calvert JW (2013) Hydrogen sulfide preconditions the db/db diabetic mouse heart against ischemia-reperfusion injury by activating Nrf2 signaling in an Erk-dependent manner. Am J Phys Heart Circ Phys 304:H1215–H1224

    CAS  Google Scholar 

  • Pla A, Pascual M, Guerri C (2017) Role of TLR4 in the ethanol-induced modulation of the autophagy pathway in the brain. Elsevier, Addictive Substances and Neurological Disease

    Google Scholar 

  • Raghunathan R, Wu C, Singh M, Liu CH, Miranda RC, Larin KV (2018) Evaluating the effects of maternal alcohol consumption on murine fetal brain vasculature using optical coherence tomography. J Biophotonics 11:e201700238

    PubMed  PubMed Central  Google Scholar 

  • Riley EP, Mcgee CL (2005) Fetal alcohol spectrum disorders: an overview with emphasis on changes in brain and behavior. Exp Biol Med 230:357–365

    CAS  Google Scholar 

  • Seifert HA, Pennypacker KR (2014) Molecular and cellular immune responses to ischemic brain injury. Transl Stroke Res 5:543–553

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shafahi M, Vaezi G, Shajiee H, Sharafi S, Khaksari M (2018) Crocin inhibits apoptosis and astrogliosis of hippocampus neurons against methamphetamine neurotoxicity via antioxidant and anti-inflammatory mechanisms. Neurochem Res 43:2252–2259

    CAS  PubMed  Google Scholar 

  • Shah SA, Yoon GH, Kim MO (2015) Protection of the developing brain with anthocyanins against ethanol-induced oxidative stress and neurodegeneration. Mol Neurobiol 51:1278–1291

    CAS  PubMed  Google Scholar 

  • Siler-Marsiglio KI, Shaw G, Heaton MB (2004) Pycnogenol® and vitamin E inhibit ethanol-induced apoptosis in rat cerebellar granule cells. J Neurobiol 59:261–271

    CAS  PubMed  Google Scholar 

  • Sivarajah A, Collino M, Yasin M, Benetti E, Gallicchio M, Mazzon E, Cuzzocrea S, Fantozzi R, Thiemermann C (2009) Anti-apoptotic and anti-inflammatory effects of hydrogen sulfide in a rat model of regional myocardial I/R. Shock 31:267–274

    CAS  PubMed  Google Scholar 

  • Swart PC, Currin CB, Russell VA, Dimatelis JJ (2017) Early ethanol exposure and vinpocetine treatment alter learning-and memory-related proteins in the rat hippocampus and prefrontal cortex. J Neurosci Res 95:1204–1215

    CAS  PubMed  Google Scholar 

  • Tiwari V, Chopra K (2013) Resveratrol abrogates alcohol-induced cognitive deficits by attenuating oxidative–nitrosative stress and inflammatory cascade in the adult rat brain. Neurochem Int 62:861–869

    CAS  PubMed  Google Scholar 

  • Toosi A, Shajiee H, Khaksari M, Vaezi G, Hojati V (2019) Obestatin improve spatial memory impairment in a rat model of fetal alcohol spectrum disorders via inhibiting apoptosis and neuroinflammation. Neuropeptides

  • Tran TD, Kelly SJ (2003) Critical periods for ethanol-induced cell loss in the hippocampal formation. Neurotoxicol Teratol 25:519–528

    CAS  PubMed  Google Scholar 

  • Vallés SL, Blanco AM, Pascual M, Guerri C (2004) Chronic ethanol treatment enhances inflammatory mediators and cell death in the brain and in astrocytes. Brain Pathol 14:365–371

    PubMed  Google Scholar 

  • Verkhratsky A, Zorec R, Parpura V (2017) Stratification of astrocytes in healthy and diseased brain. Brain Pathol 27:629–644

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang X, Michaelis EK (2010) Selective neuronal vulnerability to oxidative stress in the brain. Front Aging Neurosci 2:12

    PubMed  PubMed Central  Google Scholar 

  • West JR, Hamre KM, Pierce DR (1984) Delay in brain growth induced by alcohol in artificially reared rat pups. Alcohol 1:213–222

    CAS  PubMed  Google Scholar 

  • Wright JW, Masino AJ, Reichert JR, Turner GD, Meighan SE, Meighan PC, Harding JW (2003) Ethanol-induced impairment of spatial memory and brain matrix metalloproteinases. Brain Res 963:252–261

    CAS  PubMed  Google Scholar 

  • Xuan A, Long D, Li J, Ji W, Zhang M, Hong L, Liu J (2012) Hydrogen sulfide attenuates spatial memory impairment and hippocampal neuroinflammation in beta-amyloid rat model of Alzheimer’s disease. J Neuroinflammation 9:202

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yin J, Tu C, Zhao J, Ou D, Chen G, Liu Y, Xiao X (2013) Exogenous hydrogen sulfide protects against global cerebral ischemia/reperfusion injury via its anti-oxidative, anti-inflammatory and anti-apoptotic effects in rats. Brain Res 1491:188–196

    CAS  PubMed  Google Scholar 

  • Zare Mehrjerdie F, Shoshtari A, Mohseni F, Khastar H, Norouzi P, Asadi Y, Dadkhah M, Khaksari M (2018) Sulfur dioxide reduces hippocampal cells death and improves learning and memory deficits in rat model of transient global ischemia/reperfusion. Iran J Basic Med Scis 21:998–1003

    Google Scholar 

  • Zeng T, Zhang C-L, Zhao N, Guan M-J, Xiao M, Yang R, Zhao X-L, Yu L-H, Zhu Z-P, Xie K-Q (2018) Impairment of Akt activity by CYP2E1 mediated oxidative stress is involved in chronic ethanol-induced fatty liver. Redox Biol 14:295–304

    CAS  PubMed  Google Scholar 

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Funding

This study was supported by grant No: 96167 from Shahroud University of Medical Sciences.

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Authors and Affiliations

  1. Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran

    Fahimeh Mohseni

  2. School of Biology, Damghan University, Damghan, Iran

    Farzaneh Bagheri

  3. Addiction Research Center, Shahroud University of Medical Sciences, Shahroud, Iran

    Mehdi Khaksari

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  1. Fahimeh Mohseni
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  2. Farzaneh Bagheri
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  3. Mehdi Khaksari
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Correspondence to Mehdi Khaksari.

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Mohseni, F., Bagheri, F. & Khaksari, M. Hydrogen Sulfide Attenuates the Neurotoxicity in the Animal Model of Fetal Alcohol Spectrum Disorders. Neurotox Res 37, 977–986 (2020). https://doi.org/10.1007/s12640-019-00152-5

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