Advertisement

Hippocampal Up-Regulation of Apolipoprotein D in a Rat Model of Maternal Hypo- and Hyperthyroidism: Implication of Oxidative Stress

  • Marziyeh Salami
  • Ahmad Reza Bandegi
  • Hamid Reza Sameni
  • Abbas Ali Vafaei
  • Abbas PakdelEmail author
Original Paper
  • 30 Downloads

Abstract

Thyroid disorders impair various functions of the hippocampus where thyroid hormone receptors are localized in the brain. Hyper and hypothyroidism are associated with large changes in brain oxidative stress. Apolipoprotein D (APOD) is a conserved glycoprotein that increased in response to oxidative stress in the brain and has been suggested function as an antioxidant in the brain. Thus, the goal of this work was to explore the effect of maternal hypo- and hyperthyroidism on the Apod expression in the pup’s brain regarding changes in oxidative stress. For induction hypo and hyperthyroidism in adult female rats, 100 ppm propylthiouracil (PTU) and 8 ppm levothyroxine administrated 1 month before copulation to the week 3 after delivery in drinking water. The hippocampal region of rat pups was isolated and used for immunohistochemistry and quantitative RT-PCR on postnatal day (PND)5, PND10 and PND20. Results revealed that APOD over-expressed in both hypo- and hyperthyroid groups on PND5, PND10, and PND20. There was a proportional increase between the Apod expression and oxidative stress in the hyperthyroid group but not the hypothyroid in different days. Regarding the wide functions of thyroid hormones, oxidative stress does not suggest to be the only mechanism that involves Apod gene expression in thyroid disturbances.

Keywords

Apolipoproteins D Hyperthyroidism Hypothyroidism Oxidative stress Hippocampus Thyroid hormones 

Abbreviations

THs

Thyroid hormones

Apod

Apolipoprotein D mRNA

APOD

Apolipoprotein D protein

PND

Postnatal day

PTU

Propylthiouracil

TAC

Total antioxidant capacity

MDA

Malondialdehyde

OS

Oxidative stress

TBA

Thiobarbituric acid

PBS

Phosphate buffered saline

TBS

Tris-buffered saline

BSA

Bovine serum albumin

DAB

3,3-Diaminobenzidine

HRP

Horseradish peroxidase

DG

Dentate gyrus

Notes

Acknowledgements

The research presented in this article is part of the dissertation of Marziyeh Salami, to receive a master’s degree in biochemistry. Semnan University of Medical Sciences sponsored this project under the project no. 1190.

Compliance with Ethical Standards

Conflict of interest

We declare that there are no conflicts of interests exist.

Ethical Approval

The ethics committee of Semnan university of medical sciences accredited the study (approval ID: IR. SEMUMS. REC.1395. 215). All experiments and animal care performed based on approved international and national guidelines.

Research Involving Human and Animal Participants

Authors have performed no studies on the human participants in this study.

References

  1. 1.
    Moog NK, Entringer S, Heim C, Wadhwa PD, Kathmann N, Buss C (2017) Influence of maternal thyroid hormones during gestation on fetal brain development. Neuroscience 342:68–100Google Scholar
  2. 2.
    Göbel A, Heldmann M, Göttlich M, Dirk A-L, Brabant G, Münte TF (2015) Effect of experimental thyrotoxicosis on brain gray matter: a voxel-based morphometry study. Eur Thyr J 4(Suppl 1):113–118Google Scholar
  3. 3.
    Rami A, Patel A, Rabie A (1986) Thyroid hormone and development of the rat hippocampus: morphological alterations in granule and pyramidal cells. Neuroscience 19(4):1217–1226Google Scholar
  4. 4.
    O'Shaughnessy KL, Thomas SE, Spring SR, Ford JL, Ford RL, Gilbert ME (2019) A transient window of hypothyroidism alters neural progenitor cells and results in abnormal brain development. Sci Rep 9(1):4662–4662.  https://doi.org/10.1038/s41598-019-40249-7 Google Scholar
  5. 5.
    Gilbert M, Sui L, Walker M, Anderson W, Thomas S, Smoller S, Schon J, Phani S, Goodman J (2007) Thyroid hormone insufficiency during brain development reduces parvalbumin immunoreactivity and inhibitory function in the hippocampus. Endocrinology 148(1):92–102Google Scholar
  6. 6.
    Madeira MD, Paula-Barbosa MM (1993) Reorganization of mossy fiber synapses in male and female hypothyroid rats: a stereological study. J Comp Neurol 337(2):334–352.  https://doi.org/10.1002/cne.903370213 Google Scholar
  7. 7.
    Markowski VP, Zareba G, Stern S, Cox C, Weiss B (2001) Altered operant responding for motor reinforcement and the determination of benchmark doses following perinatal exposure to low-level 2,3,7,8-tetrachlorodibenzo-p-dioxin. Environ Health Perspect 109(6):621–622Google Scholar
  8. 8.
    Madeira M, Sousa N, Lima-Andrade M, Calheiros F, Cadete-Leite A, Paula-Barbosa M (1992) Selective vulnerability of the hippocampal pyramidal neurons to hypothyroidism in male and female rats. J Comp Neurol 322(4):501–518Google Scholar
  9. 9.
    Lavado-Autric R, Ausó E, García-Velasco JV, del Carmen Arufe M, del Rey FE, Berbel P, de Escobar GM (2003) Early maternal hypothyroxinemia alters histogenesis and cerebral cortex cytoarchitecture of the progeny. J Clinic Investig 111(7):1073–1082Google Scholar
  10. 10.
    Taşkın E, Artis AS, Bitiktas S, Dolu N, Liman N, Süer C (2011) Experimentally induced hyperthyroidism disrupts hippocampal long-term potentiation in adult rats. Neuroendocrinology 94(3):218–227Google Scholar
  11. 11.
    Ahmed OM, El-Gareib A, El-Bakry A, El-Tawab SA, Ahmed R (2008) Thyroid hormones states and brain development interactions. Int J Dev Neurosci 26(2):147–209Google Scholar
  12. 12.
    Rego AC, Oliveira CR (2003) Mitochondrial dysfunction and reactive oxygen species in excitotoxicity and apoptosis: implications for the pathogenesis of neurodegenerative diseases. Neurochem Res 28(10):1563–1574Google Scholar
  13. 13.
    Mayer L, Romic Ž, Škreb F, Bačic-Vrća V, Čepelak I, Žanic-Grubišić T, Kirin M (2004) Antioxidants in patients with hyperthyroidism. Clin Chem Lab Med 42(2):154–158Google Scholar
  14. 14.
    Cano-Europa E, Perez-Severiano F, Vergara P, Ortiz-Butron R, Rios C, Segovia J, Pacheco-Rosado J (2008) Hypothyroidism induces selective oxidative stress in amygdala and hippocampus of rat. Metab Brain Dis 23(3):275–287.  https://doi.org/10.1007/s11011-008-9099-0 Google Scholar
  15. 15.
    Domingues JT, Cattani D, Cesconetto PA, Nascimento de Almeida BA, Pierozan P, dos Santos K, Razzera G, Silva FRMB, Pessoa-Pureur R, Zamoner A (2018) Reverse T3 interacts with αvβ3 integrin receptor and restores enzyme activities in the hippocampus of hypothyroid developing rats: insight on signaling mechanisms. Mol Cell Endocrinol 470:281–294.  https://doi.org/10.1016/j.mce.2017.11.013 Google Scholar
  16. 16.
    Butler TR, Smith KJ, Self RL, Braden BB, Prendergast MA (2011) Neurodegenerative effects of recombinant HIV-1 Tat(1–86) are associated with inhibition of microtubule formation and oxidative stress-related reductions in microtubule-associated protein-2(a, b). Neurochem Res 36(5):819–828.  https://doi.org/10.1007/s11064-011-0409-2 Google Scholar
  17. 17.
    Salazar P, Cisternas P, Codocedo JF (1863) Inestrosa NC (2017) Induction of hypothyroidism during early postnatal stages triggers a decrease in cognitive performance by decreasing hippocampal synaptic plasticity. Biochim Biophys Acta (BBA)-Mol Basis Dis 4:870–883.  https://doi.org/10.1016/j.bbadis.2017.01.002 Google Scholar
  18. 18.
    Rassart E, Bedirian A, Do Carmo S, Guinard O, Sirois J, Terrisse L, Milne R (2000) Apolipoprotein d. Biochim Biophys Acta (BBA)-Protein Struct Mol Enzymol 1482(12):185–198Google Scholar
  19. 19.
    Bajo-Grañeras R, Sanchez D, Gutierrez G, González C, Do Carmo S, Rassart E, Ganfornina MD (2011) Apolipoprotein D alters the early transcriptional response to oxidative stress in the adult cerebellum. J Neurochem 117(6):949–960Google Scholar
  20. 20.
    Bhatia S, Jenner AM, Li H, Ruberu K, Spiro AS, Shepherd CE, Kril JJ, Kain N, Don A, Garner B (2013) Increased apolipoprotein D dimer formation in Alzheimer's disease hippocampus is associated with lipid conjugated diene levels. J Alzheimer's Dis 35(3):475–486Google Scholar
  21. 21.
    Zhou Y, Wang L, Li R, Liu M, Li X, Su H, Xu Y, Wang H (2018) Secreted glycoprotein BmApoD1 plays a critical role in anti-oxidation and anti-apoptosis in Bombyx mori. Biochem Biophys Res Commun 495(1):839–845Google Scholar
  22. 22.
    Dassati S, Waldner A, Schweigreiter R (2014) Apolipoprotein D takes center stage in the stress response of the aging and degenerative brain. Neurobiol Aging 35(7):1632–1642Google Scholar
  23. 23.
    Ganfornina MD, Do Carmo S, Lora JM, Torres-Schumann S, Vogel M, Allhorn M, González C, Bastiani MJ, Rassart E, Sanchez D (2008) Apolipoprotein D is involved in the mechanisms regulating protection from oxidative stress. Aging Cell 7(4):506–515Google Scholar
  24. 24.
    Bhatia S, Knoch B, Wong J, Kim WS, Else PL, Oakley AJ, Garner B (2012) Selective reduction of hydroperoxyeicosatetraenoic acids to their hydroxy derivatives by apolipoprotein D: implications for lipid antioxidant activity and Alzheimer's disease. Biochem J 442(3):713–721Google Scholar
  25. 25.
    Li H, Ruberu K, Muñoz SS, Jenner AM, Spiro A, Zhao H, Rassart E, Sanchez D, Ganfornina MD, Karl T (2015) Apolipoprotein D modulates amyloid pathology in APP/PS1 Alzheimer's disease mice. Neurobiol Aging 36(5):1820–1833Google Scholar
  26. 26.
    Do Carmo S, Levros LC Jr, Rassart E (2007) Modulation of apolipoprotein D expression and translocation under specific stress conditions. Biochim Biophys Acta 1773(6):954–969.  https://doi.org/10.1016/j.bbamcr.2007.03.007 Google Scholar
  27. 27.
    Alvarez ML, Barbón JJ, González LO, Abelairas J, Boto A, Vizoso FJ (2003) Apolipoprotein D expression in retinoblastoma. Ophthalmic Res 35(2):111–116Google Scholar
  28. 28.
    Bradley DJ, Young WS, Weinberger C (1989) Differential expression of alpha and beta thyroid hormone receptor genes in rat brain and pituitary. Proc Natl Acad Sci 86(18):7250–7254.  https://doi.org/10.1073/pnas.86.18.7250 Google Scholar
  29. 29.
    Terrisse L, Seguin D, Bertrand P, Poirier J, Milne R, Rassart E (1999) Modulation of apolipoprotein D and apolipoprotein E expression in rat hippocampus after entorhinal cortex lesion. Brain Res Mol Brain Res 70(1):26–35Google Scholar
  30. 30.
    Shafiee SM, Vafaei AA, Rashidy-Pour A (2016) Effects of maternal hypothyroidism during pregnancy on learning, memory and hippocampal BDNF in rat pups: beneficial effects of exercise. Neuroscience 329:151–161Google Scholar
  31. 31.
    Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72(1–2):248–254Google Scholar
  32. 32.
    Ohkawa H, Ohishi N, Yagi K (1978) Reaction of linoleic acid hydroperoxide with thiobarbituric acid. J Lipid Res 19(8):1053–1057Google Scholar
  33. 33.
    Benzie IF, Strain JJ (1996) The ferric reducing ability of plasma (FRAP) as a measure of “antioxidant power”: the FRAP assay. Anal Biochem 239(1):70–76Google Scholar
  34. 34.
    Sanchez D, López-Arias B, Torroja L, Canal I, Wang X, Bastiani MJ, Ganfornina MD (2006) Loss of glial lazarillo, a homolog of apolipoprotein D, reduces lifespan and stress resistance in Drosophila. Curr Biol 16(7):680–686Google Scholar
  35. 35.
    Royland JE, Parker JS, Gilbert ME (2008) A genomic analysis of subclinical hypothyroidism in hippocampus and neocortex of the developing rat brain. J Neuroendocrinol 20(12):1319–1338.  https://doi.org/10.1111/j.1365-2826.2008.01793.x Google Scholar
  36. 36.
    Shiraki A, Saito F, Akane H, Akahori Y, Imatanaka N, Itahashi M, Yoshida T, Shibutani M (2016) Gene expression profiling of the hippocampal dentate gyrus in an adult toxicity study captures a variety of neurodevelopmental dysfunctions in rat models of hypothyroidism. J Appl Toxicol 36(1):24–34.  https://doi.org/10.1002/jat.3140 Google Scholar
  37. 37.
    Mutch DM, Berger A, Mansourian R, Rytz A, Roberts M-A (2002) The limit fold change model: a practical approach for selecting differentially expressed genes from microarray data. BMC Bioinform 3(1):17.  https://doi.org/10.1186/1471-2105-3-17 Google Scholar
  38. 38.
    Rahaman SO, Ghosh S, Mohanakumar K, Das S, Sarkar PK (2001) Hypothyroidism in the developing rat brain is associated with marked oxidative stress and aberrant intraneuronal accumulation of neurofilaments. Neurosc Res 40(3):273–279Google Scholar
  39. 39.
    Cano-Europa E, Pérez-Severiano F, Vergara P, Ortiz-Butrón R, Ríos C, Segovia J, Pacheco-Rosado J (2008) Hypothyroidism induces selective oxidative stress in amygdala and hippocampus of rat. Metab Brain Dis 23(3):275–287Google Scholar
  40. 40.
    Goswami K, Nandakumar DN, Koner BC, Bobby Z, Sen SK (2003) Oxidative changes and desialylation of serum proteins in hyperthyroidism. Clin Chimica acta 337(1–2):163–168Google Scholar
  41. 41.
    Guerra LN, de Molina MdCR, Miler EA, Moiguer S, Karner M, Burdman JA (2005) Antioxidants and methimazole in the treatment of Graves' disease: effect on urinary malondialdehyde levels. Clin Chimica Acta 352(1–2):115–120Google Scholar
  42. 42.
    Cetinkaya A, Kurutas EB, Buyukbese MA, Kantarceken B (2005) Bulbuloglu E (2005) Levels of malondialdehyde and superoxide dismutase in subclinical hyperthyroidism. Mediat Inflamm 1:57–59Google Scholar
  43. 43.
    Kowalczyk E, Kopff M, Kopff A, Rudnicka M, Błaszczyk J (2003) The influence of hyperthyroidism on selected parameters of oxidant-antioxidant balance on animal model. Polskie Arch Med Wewn 110(2):837–841Google Scholar
  44. 44.
    Mogulkoc R, Baltaci A, Aydin L, Oztekin E, Sivrakaya A (2005) The effect of thyroxine administration on lipid peroxidation in different tissues of rats with hypothyroidism. Acta Physiol Hung 92(1):39–46Google Scholar
  45. 45.
    Pascua Maestro R, González E, Lillo C, Ganfornina MD, Falcon-Perez JM, Sanchez D (2018) Extracellular vesicles secreted by astroglial cells transport Apolipoprotein D to neurons and mediate neuronal survival upon oxidative stress. Frontiers in cellular neuroscience 12:526Google Scholar
  46. 46.
    Do Carmo S, Séguin D, Milne R, Rassart E (2002) Modulation of apolipoprotein D and apolipoprotein E mRNA expression by growth arrest and identification of key elements in the promoter. J Biol Chem 277(7):5514–5523Google Scholar
  47. 47.
    Kim WS, Wong J, Weickert CS, Webster MJ, Bahn S, Garner B (2009) Apolipoprotein-D expression is increased during development and maturation of the human prefrontal cortex. J Neurochem 109(4):1053–1066.  https://doi.org/10.1111/j.1471-4159.2009.06031.x Google Scholar
  48. 48.
    Najyb O, Do Carmo S, Alikashani A, Rassart E (2017) Apolipoprotein D overexpression protects against kainate-induced neurotoxicity in mice. Mol Neurobiol 54(6):3948–3963.  https://doi.org/10.1007/s12035-016-9920-4 Google Scholar
  49. 49.
    Desmarais F, Bergeron KF, Lacaille M, Lemieux I, Bergeron J, Biron S, Rassart E, Joanisse DR, Mauriege P, Mounier C (2018) High ApoD protein level in the round ligament fat depot of severely obese women is associated with an improved inflammatory profile. Endocrine 61(2):248–257.  https://doi.org/10.1007/s12020-018-1621-5 Google Scholar
  50. 50.
    Nam SM, Kim JW, Yoo DY, Jung HY, Chung JY, Kim DW, Hwang IK, Yoon YS (2018) Hypothyroidism increases cyclooxygenase-2 levels and pro-inflammatory response and decreases cell proliferation and neuroblast differentiation in the hippocampus. Mol Med Rep 17(4):5782–5788.  https://doi.org/10.3892/mmr.2018.8605 Google Scholar
  51. 51.
    Levros LC Jr, Labrie M, Charfi C, Rassart E (2013) Binding and repressive activities of apolipoprotein E3 and E4 isoforms on the human ApoD promoter. Mol Neurobiol 48(3):669–680.  https://doi.org/10.1007/s12035-013-8456-0 Google Scholar
  52. 52.
    Roman C, Fuior EV, Trusca VG, Kardassis D, Simionescu M, Gafencu AV (2015) Thyroid hormones upregulate apolipoprotein E gene expression in astrocytes. Biochem Biophys Res Commun 468(1–2):190–195.  https://doi.org/10.1016/j.bbrc.2015.10.132 Google Scholar
  53. 53.
    Lim W, Bae H, Song G (2016) Differential expression of apolipoprotein D in male reproductive system of rats by high-fat diet. Andrology 4(6):1115–1122.  https://doi.org/10.1111/andr.12250 Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Nervous System Stem Cells Research CenterSemnan University of Medical SciencesSemnanIran
  2. 2.Department of Biochemistry, Faculty of MedicineSemnan University of Medical SciencesSemnanIran
  3. 3.Research Center of PhysiologySemnan University of Medical SciencesSemnanIran

Personalised recommendations