Abstract
Our objective was to determine if progesterone pretreatment could ameliorate the detrimental effects of lipopolysaccharide (LPS)-induced inflammation on cortical neurogenesis. Timed pregnant mouse dams (n = 8) were given intraperitoneal injections of progesterone (42 mg/kg) or vehicle on embryonic day 17.5. Two hours later, mice were given intraperitoneal LPS (140 μg/kg) or vehicle. Mice were sacrificed 16 hours later on embryonic day 18. Two-color immunofluorescence was performed with primary antibodies T-box transcription factor 2 (Tbr2), ionized calcium binding adapter molecule 1 (Iba1), cleaved caspase 3 (CC3), and 5-bromo-2′-deoxyuridine (BrdU). Cells were counted, and statistical analysis was determined using analysis of variance and Tukey-Kramer method. The Tbr2 intermediate neural progenitor cell density decreased after LPS exposure (P = .0022). Pre-exposure to progesterone statistically increased Tbr2 intermediate neural progenitors compared to LPS treatment alone and was similar to controls (P = .0022). After LPS exposure, microglia displayed an activated phenotype, and cell density was increased (P < .001). Cell death rates were low among study groups but was increased in LPS exposure groups compared to progesterone alone (P = .0015). Lipopolysaccharide-induced systemic inflammation reduces prenatal neurogenesis in mice. Pre-exposure with progesterone is associated with increased neurogenesis. Progesterone may protect the preterm brain from defects of neurogenesis induced by inflammation.
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Romero R, Dey SK, Fisher SJ. Preterm labor: one syndrome, many causes. Science. 2014;345(6198):760–765.
Breen K, Brown A, Burd I, Chai J, Friedman A, Elovitz MA. TLR-4-dependent and -independent mechanisms of fetal brain injury in the setting of preterm birth. Reprod Sci. 2012;19(8): 839–850.
Burd I, Chai J, Gonzalez J, et al. Beyond white matter damage: fetal neuronal injury in a mouse model of preterm birth. Am J Obstet Gynecol. 2009;201(3):279. e271–e278.
Elovitz MA, Brown AG, Breen K, Anton L, Maubert M, Burd I. Intrauterine inflammation, insufficient to induce parturition, still evokes fetal and neonatal brain injury. Int J Dev Neurosci. 2011; 29(6):663–671.
Ofek-Shlomai N, Berger I. Inflammatory injury to the neonatal brain - what can we do? Front Pediatr. 2014;2:30.
Rees S, Harding R, Walker D. The biological basis of injury and neuroprotection in the fetal and neonatal brain. Int J Dev Neurosci. 2011;29(6):551–563.
Cunningham CL, Martinez-Cerdeno V, Noctor SC. Microglia regulate the number of neural precursor cells in the developing cerebral cortex. J Neurosci. 2013;33(10):4216–4233.
Malik S, Vinukonda G, Vose LR, et al. Neurogenesis continues in the third trimester of pregnancy and is suppressed by premature birth. J Neurosci. 2013;33(2):411–423.
McAdams RM, Juul SE. The role of cytokines and inflammatory cells in perinatal brain injury. Neurol Res Int. 2012;2012: 561494.
Hagberg H, Gressens P, Mallard C. Inflammation during fetal and neonatal life: implications for neurologic and neuropsychiatric disease in children and adults. Ann Neurol. 2012;71(4):444–457.
Hevner RF, Hodge RD, Daza RA, Englund C. Transcription factors in glutamatergic neurogenesis: conserved programs in neocortex, cerebellum, and adult hippocampus. Neurosci Res. 2006; 55(3):223–233.
Martinez-Cerdeno V, Noctor SC, Kriegstein AR. Estradiol stimulates progenitor cell division in the ventricular and subventricular zones of the embryonic neocortex. Eur J Neurosci. 2006;24(12): 3475–3488.
Stein DG. Progesterone exerts neuroprotective effects after brain injury. Brain Res Rev. 2008;57(2):386–397.
Kipp M, Amor S, Krauth R, Beyer C. Multiple sclerosis: neuroprotective alliance of estrogen-progesterone and gender. Front Neuroendocrinol. 2012;33(1):1–16.
Dang J, Mitkari B, Kipp M, Beyer C. Gonadal steroids prevent cell damage and stimulate behavioral recovery after transient middle cerebral artery occlusion in male and female rats. Brain Behav Immun. 2011;25(4):715–726.
Meffre D, Labombarda F, Delespierre B, et al. Distribution of membrane progesterone receptor alpha in the male mouse and rat brain and its regulation after traumatic brain injury. Neuroscience. 2013;231:111–124.
Gottfried-Blackmore A, Sierra A, Jellinck PH, McEwen BS, Bulloch K. Brain microglia express steroid-converting enzymes in the mouse. J Steroid Biochem Mol Biol. 2008;109(1–2):96–107.
Habib P, Beyer C. Regulation of brain microglia by female gonadal steroids. J Steroid Biochem Mol Biol. 2015;146:3–14.
Aisemberg J, Vericelli CA, Bariani MV, Billi SC, Wolfson ML, et al. Progesterone Is Essential for Protecting against LPS-Induced Pregnancy Loss. LIF as a Potential Mediator of the Anti-inflammatory Effect of Progesterone. PLoS ONE. 2013;8(2): e56161.
Mouihate A. TLR4-mediated brain inflammation halts neurogenesis: impact of hormonal replacement therapy. Front Cell Neurosci. 2014;8:146.
Hevner RF, Daza RAM, Englund C, Kohntz J, Fink A. Postnatal shifts of interneuron position in the neocortex of normal and reeler mice: evidence for inward migration. Neuroscience. 2004;124: 605–618.
Baburamani AA, Supramaniam VG, Hagberg H, Mallard C. Microglia toxicity in preterm brain injury. Reprod Toxicol. 2014;48:106–112.
Wright DW, Kellermann AL, Hertzberg VS, et al. ProTECT: a randomized clinical trial of progesterone for acute traumatic brain injury. Ann Emerg Med. 2007;49(4):391–402, 402 e391–392.
Habib P, Slowik A, Zendedel A, Johann S, Dang J, Beyer C. Regulation of hypoxia-induced inflammatory responses and M1–M2 phenotype switch of primary rat microglia by sex steroids. J Mol Neurosci. 2014;52(2):277–285.
Bronte V, Serafini P, Mazzoni A, Segal DM, Zanovello P. L-arginine metabolism in myeloid cells controls T-lymphocyte functions. Trends Immunol. 2003;24(6):302–306.
Bajramovic JJ. Regulation of innate immune responses in the central nervous system. CNS Neurol Disord Drug Targets. 2011; 10(1):4–24.
Hirst JJ, Palliser HK, Yates DM, Yawno T, Walker DW. Neurosteroids in the fetus and neonate: potential protective role in compromised pregnancies. Neurochem Int. 2008;52(4–5):602–610.
Nguyen PN, Billiards SS, Walker DW, Hirst JJ. Changes in 5alpha-pregnane steroids and neurosteroidogenic enzyme expression in the perinatal sheep. Pediatr Res. 2003;53(6):956–964.
Gravett MG, Hitti J, Hess DL, Eschenbach DA. Intrauterine infection and preterm delivery: evidence for activation of the fetal hypothalamic-pituitary-adrenal axis. Am J Obstet Gynecol. 2000;182(6):1404–1413.
Schwarz JM, Bilbo SD. Sex, Glia, and Development: interactions in health and disease. Horm Behav. 2012;62(3):243–253.
Trotter A, Maier L, Grill HJ, Kohn T, Heckmann M, Pohlandt F. Effects of postnatal estradiol and progesterone replacement in extremely preterm infants. J Clin Endocrinol Metab. 1999; 84(12):4531–4535.
Trotter A, Steinmacher J, Kron M, Pohlandt F. Neurodevelopmental follow-up at five years corrected age of extremely low birth weight infants after postnatal replacement of 17beta-estradiol and progesterone. J Clin Endocrinol Metab. 2012; 97(3):1041–1047.
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Tronnes, A.A., Koschnitzky, J., Daza, R. et al. Effects of Lipopolysaccharide and Progesterone Exposures on Embryonic Cerebral Cortex Development in Mice. Reprod. Sci. 23, 771–778 (2016). https://doi.org/10.1177/1933719115618273
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DOI: https://doi.org/10.1177/1933719115618273