Abstract
Oxidative stress, cellular damage, and neuronal apoptosis are believed to underlie the progressive cognitive decline that accompanies natural aging and to be exacerbated in neurodegenerative diseases. Over the years, we have consistently demonstrated that iron neonatal treatment induces oxidative stress and memory deficits in adult rats, but the mechanisms underlying these effects remained undefined. The purpose of this study was to examine whether neonatal iron overload was associated with apoptotic cell death in adult and old rats. We analyzed Par-4 and caspase-3 immunoreactivity in specific brain areas including the hippocampus CA1, CA3 and dentate gyrus (DG), the adjacent cortex and the striatum in adult (3 months-old) and aged (24 months-old) rats from control (vehicle-treated) and neonatally iron-treated groups. Neonatal iron treatment consisted of a daily oral administration of 10 mg/kg of Fe+2, for three consecutive days, from post-natal 12–14. Control aged animals showed increased levels of both markers when compared to untreated adult animals. When adults were compared, iron-treated animals presented significantly higher Par-4 and caspase-3 immunoreactivities in CA1, CA3 and cortex. In the DG, this effect was statistically significant only for Par-4. Interestingly, when control and iron-treated aged animals were compared, a significant decrease in both apoptotic markers was observed in the later groups in the same areas. These results may be interpreted as an acceleration of aging progressive damages caused by iron overload and may contribute to a better understanding of the damaging potential of iron accumulation to brain function and the resulting increased susceptibility to neurodegeneration.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Adams JD, Mukherjee SK, Klaidman LK, Chang ML, Yasharel R (1996) Apoptosis and oxidative stress in the aging brain. Ann N Y Acad Sci 786:135–151
Anglade P, Vyas S, Hirsch EC, Agid Y (1997) Apoptosis in dopaminergic neurons of the human substantia nigra during normal aging. Histol Histopathol 12(3):603–610
Barja G (2004) Free radicals and aging. Trends Neurosci 10:595–600
Chan SL, Tammariello SP, Estus S, Mattson MP (1999) Prostate apoptosis response-4 mediates trophic factor withdrawal-induced apoptosis of hippocampal neurons: actions prior to mitochondrial dysfunction and caspase activation. J Neurochem 73(2):502–512
Connor JR, Pavlick G, Karli D, Menzies SL, Palmer C (1995) A histochemical study of iron-positive cells in the developing rat brain. J Comp Neurol 355(1):111–123
Dal-Pizzol F, Klamt F, Frota ML Jr, Andrades ME, Caregnato FF, Vianna MM et al (2001) Neonatal iron exposure induces oxidative stress in adult Wistar rat. Brain Res Dev Brain Res 130(1):109–114
de Lima MN, Polydoro M, Laranja DC, Bonatto F, Bromberg E, Moreira JC, Dal-Pizzol F, Schröder N (2005a) Recognition memory impairment and brain oxidative stress by postnatal iron administration. Eur J Neurosci 21:2521–2528
de Lima MN, Laranja DC, Caldana F, Grazziotin MM, Garcia VA, Dal-Pizzol F, Bromberg E, Schröder N (2005b) Selegiline protects against recognition memory impairments induced by neonatal iron treatment. Exp Neurol 196:177–183
de Lima MN, Laranja DC, Caldana F, Bromberg E, Roesler R, Schröder N (2005c) Reversal of age-related deficits in object recognition memory in rats with l-deprenyl. Exp Gerontol 40:506–511
de Lima MN, Presti-Torres J, Caldana F, Grazziotin MM, Scalco FS, Guimarães MR et al (2007) Desferoxamine reverses neonatal iron-induced recognition memory impairment in rats. Eur J Pharmacol 570:111–114
de Lima MN, Presti-Torres J, Garcia VA, Guimarães MR, Scalco FS, Roesler R, Schröder N (2008) Amelioration of recognition memory impairment associated with iron loading or aging by the type 4-specific phosphodiesterase inhibitor rolipram in rats. Neuropharmacology 55:788–792
Dexter DT, Carayon A, Javoy-Agid F, Agid Y, Wells FR, Daniel SE et al (1991) Alterations in the levels of iron, ferritin and other trace metals in Parkinson’s disease and other neurodegenerative diseases affecting the basal ganglia. Brain 114(Pt4):1953–1975
Dorszewska J, Adamczewska-Goncerzewicz Z, Szczech J (2004) Apoptotic proteins in the course of aging of central nervous system in the rat. Respir Physiol Neurobiol 139(2):145–155
Duan W, Rangnekar VM, Mattson MP (1999) Par-4 production in synaptic compartments following apoptotic and excitotoxic insults: evidence for a pivotal role in mitochondrial dysfunction and neuronal degeneration. J Neurochem 72(6):2312–2322
Dwork AJ, Lawler G, Zybert PA, Durkin M, Osman M, Willson N et al (1990) An autoradiographic study of the uptake and distribution of iron by the brain of the young rat. Brain Res 518(1-2):31–39
Earnshaw WC, Martins LM, Kaufmann SH (1999) Mammalian caspases: structure, activation, substrates, and functions during apoptosis. Annu Rev Biochem 68:383–424
Eichenbaum H (2004) Hippocampus: cognitive processes and neural representations that underlie declarative memory. Neuron 44:109–120
El-Guendy N, Rangnekar VM (2003) Apoptosis by Par-4 in cancer and neurodegenerative diseases. Exp Cell Res 283(1):51–66
Fernandez LL, Carmona M, Portero-Otin M, Naudi A, Pamplona R, Schröder N et al (2009) Effects of increased iron intake during the neonatal period on the brain of adult AbetaPP/PS1 transgenic mice. J Alzheimers Dis 19:1069–1080
Fredriksson A, Schröder N, Eriksson P, Izquierdo I, Archer T (1999) Neonatal iron exposure induces neurobehavioural in adult mice. Toxicol Appl Pharmacol 159(1):25–30
Fredriksson A, Schröder N, Eriksson P, Izquierdo I, Archer T (2000) Maze learning and motor activity deficits in adult mice induced by iron exposure during a critical postnatal period. Brain Res Dev Brain Res 119(1):65–74
Friedlander RM (2003) Apoptosis and caspases in neurodegenerative diseases. N Engl J Med 348:1365–1375
Guo Q, Fu W, Xie J, Luo H, Sells SF, Geddes JW et al (1998) Par-4 is a mediator of neuronal degeneration associated with the pathogenesis of Alzheimer disease. Nat Med 4(8):957–962
Guo Q, Xie J, Chang X, Zhang X, Du H (2001) Par-4 is a synaptic protein that regulates neurite outgrowth by altering calcium homeostasis and transcription factor AP-1 activation. Brain Res 903(1–2):13–25
Kienzl E, Puchinger L, Jellinger K, Linert W, Stachelberger H, Jameson RF (1995) The role of transition metals in the pathogenesis of Parkinson’s disease. J Neurol Sci 134:69–78
Kooncumchoo P, Sharma S, Porter J, Govitrapong P, Ebadi M (2006) Coenzyme Q(10) provides neuroprotection in iron-induced apoptosis in dopaminergic neurons. J Mol Neurosci 28(2):125–141
Lacelle C, Xu S, Wang E (2002) Identification of high caspase-3 mRNA expression as a unique signature profile for extremely old individuals. Mech Ageing Dev 123(8):1133–1144
Lee DW, Andersen JK, Kaur D (2006) Iron dysregulation and neurodegeneration: the molecular connection. Mol Interven 6(2):89–97
Lynch AM, Lynch MA (2001) The age-related increase in IL-1 type I receptor in rat hippocampus is coupled with an increase in caspase-3 activation. Eur J Neurosci 15(11):1779–1788
Mansour H, Chamberlain CG, Weible MW II, Hughes S, Chu Y, Chan-Ling T (2008) Aging-related changes in astrocytes in the rat retina: imbalance between cell proliferation and cell death reduces astrocyte availability. Aging Cell 7(4):526–540
Mattson MP (2000) Apoptosis in neurodegenerative disorders. Nat Rev Mol Cell Biol 1(2):120–129
Mattson MP, Kroemer G (2003) Mitochondria in cell death: novel targets for neuroprotection and cardioprotection. Trends Mol Med 9(5):196–205
Mattson MP, Duan W, Chan SL, Camandola S (1999) Par-4: an emerging pivotal player in neuronal apoptosis and neurodegenerative disorders. J Mol Neurosci 13(1–2):17–30
McKay SE, Purcell AL, Carew TJ (1999) Regulation of synaptic function by neurotrophic factors in vertebrates and invertebrates: implications for development and learning. Learn Mem 6(3):193–215
Morrison JH, Hof PR (1997) Life and death of neurons in the aging brain. Science 278(5337):412–419
Paxinos G, Watson C (2005) The rat brain:in stereotaxic coordinates, 6th edn. Academic Press, San Diego
Polla AS, Polla LL, Polla BS (2003) Iron as the malignant spirit in successful ageing. Ageing Res Rev 2(1):25–37
Reichmann H, Janetzky B, Riederer P (1995) Iron-dependent enzymes in Parkinson’s disease. J Neural Transm Suppl 46:157–164
Rohn TT (2008) Caspase-cleaved TAR DNA-binding protein-43 is a major pathological finding in Alzheimer’s disease. Brain Res 1228:189–198
Salvesen GS (2002) Caspases: opening the boxes and interpreting the arrows. Cell Death Differ 9(1):3–5
Schipper HM (2004) Brain iron deposition and the free radical-mitochondrial theory of ageing. Ageing Res Rev 3(3):265–301
Schröder N, Fredriksson A, Vianna MRM, Roesler R, Izquierdo I, Archer T (2001) Memory deficits in adult rats following post natal iron administration. Behav Brain Res 124:77–85
Sells SF, Wood DP Jr, Joshi-Barve SS, Muthukumar S, Jacob RJ, Crist SA et al (1994) Commonality of the gene programs induced by effectors of apoptosis in androgen dependent and independent prostate cells. Cell Growth Differ 5(4):457–466
Shimohama S, Tanino H, Fujimoto S (1999) Changes in caspase expression in Alzheimer’s disease: comparison with development and aging. Biochem Biophys Res Commun 256(2):381–384
Stefanis L (2005) Caspase-dependent and -independent neuronal death: two distinct pathways to neuronal injury. Neuroscientist 11(1):50–62
Swaiman KF (1991) Hallervorden-Spatz syndrome and brain iron metabolism. Arch Neurol 48(12):1285–1293
Taglialatela G, Gegg M, Perez-Polo JR, Williams LR, Rose GM (1996) Evidence for DNA fragmentation in the CNS of aged Fischer-344 rats. Neuroreport 7(5):977–980
Tatton WG, Chalmers-Redman R, Brown D, Tatton N (2003) Apoptosis in Parkinson’s disease: signals for neuronal degradation. Ann. Neurol 53(Suppl 3): S61–S72
Taylor EM, Morgan EH (1990) Developmental changes in transferrin and iron uptake by the brain in the rat. Brain Res Dev Brain Res 55(1):35–42
Taylor EM, Crowe A, Morgan EH (1991) Tranferrin and iron uptake by the brain: effects of altered iron status. J Neurochem 57:1584–1592
Troy CM, Salvesen GS (2002) Caspases on the brain. J Neurosci Res 69(2):145–150
Youdim MB, Ben-Shachar D, Riederer P (1993) The possible role of iron in the etiopathology of Parkinson’s disease. Mov Disord 8(1):1–12
Yuan J, Yankner BA (2000) Apoptosis in the nervous system. Nature 407(6805):802–809
Zecca L, Gallorini M, Schunemann V, Trautwein AX, Gerlach M, Riederer P et al (2001) Iron, neuromelanin and ferritin content in the substantia nigra of normal subjects at different ages: consequences for iron storage and neurodegenerative processes. J Neurochem 76(6):1766–1773
Zecca L, Youdim MB, Riederer P, Connor JR, Crichton RR (2004) Iron, brain ageing and neurodegenerative disorders. Nat Rev Neurosci 5(11):863–873
Zhang S, Wang J, Song N, Xie J, Jiang H (2009) Up-regulation of divalent metal transporter 1 is involved in 1-methyl-4-phenylpyridinium (MPP(+)-induced apoptosis in MES23.5 cells. Neurobiol Aging 30(9):1466–1476
Acknowledgments
This research was partially funded by CNPq grant 476316/2006-5 and FAPERGS PROADE3 0521807 to Monica Vianna. Monica Vianna is supported by CNPq 312137/2006-0 fellowship, Nadja Schröder is supported by 301368/2006-6 fellowship, and Clivia Miwa is supported by CAPES-MEC fellowship.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Miwa, C.P., de Lima, M.N.M., Scalco, F. et al. Neonatal Iron Treatment Increases Apoptotic Markers in Hippocampal and Cortical Areas of Adult Rats. Neurotox Res 19, 527–535 (2011). https://doi.org/10.1007/s12640-010-9181-3
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12640-010-9181-3