Abstract
To elucidate the impact of maternal seizures in the developing rat brain, pregnant Wistar rats were subjected to the pilocarpine-induced seizures and pups from different litters were studied at different ages. In the first 24 h of life, blood glucose and blood gases were analyzed. 14C-leucine [14C-Leu] incorporation was used to analyze protein synthesis at PN1, and Western Blot method was used to analyze protein levels of Bax, Bcl-2 and Poly(ADP-ribose) polymerase-1 (PARP-1) in the hippocampus (PN3-PN21). During the first 22 days of postnatal life, body weight gain, length, skull measures, tooth eruption, eye opening and righting reflex have been assessed. Pups from naive mothers were used as controls. Experimental pups showed a compensated metabolic acidosis and hyperglycemia. At PN1, the [14C-Leu] incorporation into different studied areas of experimental pups was lower than in the control pups. During development, the protein levels of Bax, Bcl-2 and PARP-1 in the hippocampus of experimental pups were altered when compared with control pups. A decreased level of pro- and anti-apoptotic proteins was verified in the early postnatal age (PN3), and an increased level of pro-apoptotic proteins concomitant with a reduced level of anti-apoptotic protein was observed at the later stages of the development (PN21). Experimental pups had a delay in postnatal growth and development beyond disturb in protein synthesis and some protein expression during development. These changes can be result from hormonal alterations linked to stress and/or hypoxic events caused by maternal epileptic seizures during pregnancy.
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Albrecht J, Smiatek M (1975) Effect of hypoxia, ischemia and carbon monoxide intoxication on in vivo protein synthesis in neuron and glia cell enriched fractions from rat brain. Acta Neuropath (Berl) 31:257–262
Amado D, Cavalheiro EA (1998) Hormonal and gestational parameters in female rats submitted to the pilocarpine model of epilepsy. Epilepsy Res 32:266–274
Austin MP, Leader LR, Reilly N (2005) Prenatal stress, the hypothalamic-pituitary-adrenal axis, and fetal and infant neurobehavior. Early Hum Dev 81:917–926
Autret A, Martin SJ (2009) Emerging role for members of the bcl-2 family in mitochondrial morphogenesis. Mol Cell 36:355–363
Autret A, Martin SJ (2010) Bcl-2 family proteins and mitochondrial fission/fusion dynamics. Cell Mol Life Sci 67:1599–1606
Cavalheiro EA, Silva DF, Turski WA, Calderazzo-Filho LS, Bortolotto ZA, Turski L (1987) The susceptibility of rats to pilocarpine-induced seizures is age-dependent. Dev Brain Res 37:43–58
Challis JRG, Matthews SG, Gibb W (2000) Endocrine and paracrine regulation of birth at term and preterm. Endocr Rev 21:514–555
CIOMS/OMS (1985) Council for International Organizations of Medical Services. WHO Distribution and sales service, 1211 Geneva 27, Switzerland, International Guiding Principles for Biomedical Research Involving Animals.
Clemens MJ, Bushell M, Jeffrey IW, Pain VM, Morley SJ (2000) Translation initiation factor modifications and the regulation of protein synthesis in apoptotic cells. Cell Death Differ 7(7):603–615
Cosmi EV, Luzi G, Gori F, Chiodi A (1990) Response of utero-placental fetal blood flow to stress situation and drugs. Eur J Obstet Gynecol Reprod Biol 36:239–245
Ha HC, Snyder SH (2000) Poly (ADP-ribose) polymerase-1 in the nervous system. Neurobiol Dis 7:225–239
Hawkins AJS (1991) Protein turnover: a functional appraisal. Funct Ecol 5:222–233
Herceg Z, Wang ZQ (2001) Functions of poly (ADP-ribose) polymerase (PARP) in DNA repair, genomic integrity and cell death. Mutat Res 477:97–110
Hossmann K-A, Widmann R, Wiessner C, Dux E, Djuricic B, Röhn G (1992) Protein synthesis after global cerebral ischemia and selective vulnerability. In J pharmacology of cerebral ischemia, edited by Krieglstein. H. Oberpichler-Schwenk, Wissenschaftliche Verlagsgesellschaft, Stuttgart, p. 289
Hvas C, Henriksen T, Ostergaard J, Dam M (2000) Epilepsy and pregnancy: effect of antiepileptic drugs and lifestyle on birthweight. Br J Obstet Gynaecol 107:896–902
Korsmeyer SJ (1999) BCL-2 gene family and the regulation of programmed cell. Death Cancer Res 59:1693s–1700s
Krause GS, Whithe BC, Aust SD, Nayini NR, Kumar KL (1988) Brain cell death following ischemia and reperfusion: a proposed biochemical consequence. Crit Care Med 16:714–726
Lagercrantz H, Bistoletti P (1977) Cathecolamine release in the newborn infant at birth. Pediatr Res 11:889–893
Lautier D, Lagueux J, Thibodeau J, Menard L, Poirier GG (1993) Molecular and biochemical features of poly (ADP-ribose) metabolism. Mol Cell Biochem 122:171–193
Lee HY, Naha N, Kim JH, Jo MJ, Min KS, Seong HH, et al. (2008) Age- and area-dependent distinct effects of ethanol on bax and bcl-2 expression in prenatal rat brain. J Microbiol Biotechnol 18(9):1590–1598
Lima DC, Vale TG, Arganãraz GA, Varella PP, Frussa-Filho R, Cavalheiro EA, et al. (2010) Behavioral evaluation of adult rats exposed in utero to maternal epileptic seizures. Epilepsy Behav 18:45–49
Lima DC, Cossa AC, Perosa SR, Oliveira EM, Junior JAS, Fernandes MJS, et al. (2011) Neuroglobin is up regulated in cerebellum of pups exposed to maternal epileptic seizures. Int J Dev Neurosci 29(8):891–897
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193:265–275
Meador KJ, Baker GA, Finnell RH, Kalayjian LA, Liporace JD, Loring DW, et al. (2006) In utero antiepileptic drug exposure: fetal death and malformations. Neurology 67:407–412
Merry DE, Korsmeyer SJ (1997) Bcl-2 gene family in the nervous system. Annu Rev Neurosci 20:245–267
Minkoff H, Schaffer R, Delke I, Grunevaum A (1985) Diagnosis of intracranial hemorrhage in utero after a maternal seizure. Obstet Gynecol 65:22S–24S
Northington FJ, Ferriero DM, Graham EM, Traystman RJ, Martin LJ (2001) Early neurodegeneration after hypoxia–ischemia in neonatal rat is necrosis while delayed neuronal death is apoptosis. Neurobiol Dis 8:207–219
Nowak JTS, Fried RL, Lust D, Passonneau JV (1985) Changes in brain energy metabolism and protein synthesis following transient bilateral ischemia in the gerbil. J Neurochem 44:487–494
Oltvai ZN, Milliman CL, Korsmeyer SJ (1993) Bcl-2 heterodimerizes in vivo with a conserved homolog, bax, that accelerates programed cell death. Cell 74:609–619
Pospisilik JA, Knauf C, Joza N, Benit P, Orthofer M, Cani PD, et al. (2007) Targeted deletion of AIF decreases mitochondrial oxidative phosphorylation and protects from obesity and diabetes. Cell 131:476–491
Procianoy RS, Silveira RC (2001) Hypoxic-ischemic syndrome. J Pediatr 77:S63–S70
Racine R (1972) Modification of seizure activity by electrical stimulation II. Motor seizure. Electroencephalogr Clin Neurophysiol 32:281–294
Ramachandra R, Subramanian T (2011) Atlas of the neonatal rat brain, 1st edn. CRC Press, Taylor & Francis Group, New York
Smulson ME, Simbulan-Rosenthal CM, Boulares AH, Yakovlev A, Stoica B, Iyer S, et al. (2000) Roles of poly(ADP-ribosyl)ation and PARP in apoptosis, DNA repair, genomic stability and functions of p53 and E2F-1. Adv Enzym Regul 40:183–215
Tuor UI, Manley JJ, Fyfe CA, Bascaramurty S (1999) Dexamethasone effects on cerebral protein synthesis prior to and following hypoxia-ischemia in immature rat. Brain Res Bull 48(1):61–64
Vale, TG (2007) Efeito de crises epilépticas maternas sobre o desenvolvimento da prole. PhD Thesis. Universidade Federal de São Paulo, Departamento de Neurologia e Neurocirurgia, Unpublished results.
Vale TG, Silva AV, Lima DC, Lima E, Torres LB, Cossa AC, et al. (2010) Seizures during pregnancy modify the development of hippocampal interneurons of the offspring. Epilepsy Behav 19:20–25
Valente SG, Naffah-Mazzacoratti MG, Pereira M, Silva I, Santos NF, Baracat EC, Cavalheiro EA, Amado D (2002) Castration in female rats modifies the development of pilocarpine model of epilepsy. Epilepsy Res 49:181–188
Wang Y, Dawson VL, Dawson TM (2009) Poly ADP-ribose signals to mitochondrial AIF: a key event in parthanatos. Exp Neurol 218(2):193–202
White E (1996) Life, death and the pursuit of apoptosis. Genes Dev 10:1–15
Yerby MS (2000) Quality of life, epilepsy advances, and the evolving role of anticonvulsants in women with epilepsy. Neurology 55:21–31
Yin XM, Oltvai ZN, Korsmeyer SJ (1994) BH1 and BH2 domains of bcl-2 are required for inhibition of apoptosis and heterodimerization with bax. Nature 369:321–323
Acknowledgments
The authors are grateful for Hilda da Silva Reis for technical assistance, and Iara Ribeiro Silva for assistance with autorradiography. The study was supported by grants from FAPESP, CAPES, CNPq, PRONEX, CInAPCe, and FAPESP/CNPq/MCT-Instituto Nacional de Neurosciência Translacional.
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Cossa, A.C., Lima, D.C., do Vale, T.G. et al. Maternal seizures can affect the brain developing of offspring. Metab Brain Dis 31, 891–900 (2016). https://doi.org/10.1007/s11011-016-9825-y
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DOI: https://doi.org/10.1007/s11011-016-9825-y