Enhanced remyelination during late pregnancy: involvement of the GABAergic system

Samah Kalakh 1, Abdeslam Mouihate 2

Affiliations

22 May 2019

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doi: 10.1038/s41598-019-44050-4

Abstract

Pregnant women with MS experience fewer relapses, especially during the third trimester. In this study, we explore the cellular and molecular events that bring about the protective effect of late pregnancy on the course of de/remyelination in rats. Using cellular, molecular, and ultrastructural methods, we explored remyelination in response to a focal demyelination in the corpus callosum of late pregnant, virgin, and postpartum rats. We further explored the role of GABAA receptor (GABAAR) in the promyelinating effect observed during late pregnancy. Remyelination in response to a gliotoxin-induced demyelination in the corpus callosum was enhanced in late pregnant rats when compared to that seen in virgin and postpartum rats. This pregnancy-associated promyelinating effect was lost when either the GABAAR was blocked or when 5α-reductase, the rate limiting enzyme for the endogenous GABAAR activator allopregnanolone, was inhibited. Taken together, these data suggest that the pregnancy-associated pro-myelination operates, at least in part, through a GABAergic activated system.

Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1 Evaluation of lesion size and axonal integrity 7 days following lysolecithin-induced demyelination. (A–C) show representative images of LFB staining in saline-injected corpora callosa of virgin, pregnant, and postpartum animals respectively. (D–F) show representative images of LFB staining in lysolecithin-injected corpora callosa. (G) The bar graph shows the demyelination lesion size in the three lysolecithin-injected groups. Pregnant animals had a smaller lesion size compared to both the virgin group (Lyso-Vir: n = 6, Lyso-Preg: n = 6, p < 0.01) and the postpartum group (Lyso-PP: n = 5, p < 0.05). (H–J) show immunofluorescent images of NF (green) and MBP (red) at the edge of the demyelination lesion in virgin, pregnant, and postpartum animals respectively. Arrowheads indicate unmyelinated axons while arrows indicate myelinated ones. There was no significant difference in either the percentage area covered by NF+ fibers (K) or the percentage area covered by MBP+ fibers (L) between the experimental groups (Lyso-Vir: n = 5, Lyso-Preg: n = 4, Lyso-PP: n = 4, p > 0.05). (M) Pregnant animals had a significantly higher percentage of juxtaposed NF+ and MBP+ fibers compared to both virgin and postpartum animals (p < 0.05). (N) Pregnant animals had a significantly higher myelination index compared to virgin and postpartum animals (p < 0.05). Data are represented as mean ± SEM. Scale bar in LFB data = 200 µm. Scale bar in immunofluorescence data = 50 µm.

Figure 1 Evaluation of lesion size and axonal integrity 7 days following lysolecithin-induced demyelination. (A–C) show representative images of LFB staining in saline-injected corpora callosa of virgin, pregnant, and postpartum animals respectively. (D–F) show representative images of LFB staining in lysolecithin-injected corpora callosa. (G) The bar graph shows the demyelination lesion size in the three lysolecithin-injected groups. Pregnant animals had a smaller lesion size compared to both the virgin group (Lyso-Vir: n = 6, Lyso-Preg: n = 6, p < 0.01) and the postpartum group (Lyso-PP: n = 5, p < 0.05). (H–J) show immunofluorescent images of NF (green) and MBP (red) at the edge of the demyelination lesion in virgin, pregnant, and postpartum animals respectively. Arrowheads indicate unmyelinated axons while arrows indicate myelinated ones. There was no significant difference in either the percentage area covered by NF+ fibers (K) or the percentage area covered by MBP+ fibers (L) between the experimental groups (Lyso-Vir: n = 5, Lyso-Preg: n = 4, Lyso-PP: n = 4, p > 0.05). (M) Pregnant animals had a significantly higher percentage of juxtaposed NF+ and MBP+ fibers compared to both virgin and postpartum animals (p < 0.05). (N) Pregnant animals had a significantly higher myelination index compared to virgin and postpartum animals (p < 0.05). Data are represented as mean ± SEM. Scale bar in LFB data = 200 µm. Scale bar in immunofluorescence data = 50 µm.

Figure 2 Division of OPCs is enhanced in the vicinity of the corpus callosum 7 days following lysolecithin-induced demyelination in pregnant rats. (A–C) are immunofluorescent staining images of PCNA (green) and NG2 (red) in lysolecithin-injected corpora callosa of virgin, pregnant, and postpartum animals respectively. (D) The bar graph shows that there was no significant difference in the cell density of dividing OPCs (NG2+/PCNA+, arrowheads), non-dividing OPCs (NG2+/PCNA−, arrows) (E), or the total number of NG2+ cells (F) between the three experimental groups (Lyso-Vir: n = 6, Lyso-Preg: n = 5, Lyso-PP: n = 4, p > 0.05). (G) The bar graph shows that focally demyelinated corpus callosa of pregnant animals have a significantly higher percentage of NG2+/PCNA+ cells when compared to those seen in either virgin or postpartum animals (p < 0.05). (H) The bar graph shows that demyelinated corpus callosa of pregnant animals had a significantly lower percentage of NG2+/PCNA− cells compared to those seen in either virgin or postpartum animals (p < 0.05). Data are presented as mean ± SEM. Scale bar = 50 µm.

Figure 2 Division of OPCs is enhanced in the vicinity of the corpus callosum 7 days following lysolecithin-induced demyelination in pregnant rats. (A–C) are immunofluorescent staining images of PCNA (green) and NG2 (red) in lysolecithin-injected corpora callosa of virgin, pregnant, and postpartum animals respectively. (D) The bar graph shows that there was no significant difference in the cell density of dividing OPCs (NG2+/PCNA+, arrowheads), non-dividing OPCs (NG2+/PCNA−, arrows) (E), or the total number of NG2+ cells (F) between the three experimental groups (Lyso-Vir: n = 6, Lyso-Preg: n = 5, Lyso-PP: n = 4, p > 0.05). (G) The bar graph shows that focally demyelinated corpus callosa of pregnant animals have a significantly higher percentage of NG2+/PCNA+ cells when compared to those seen in either virgin or postpartum animals (p < 0.05). (H) The bar graph shows that demyelinated corpus callosa of pregnant animals had a significantly lower percentage of NG2+/PCNA− cells compared to those seen in either virgin or postpartum animals (p < 0.05). Data are presented as mean ± SEM. Scale bar = 50 µm.

Figure 3 Axonal myelination is increased 7 days post-lysolecithin-induced demyelination in the corpus callosum of pregnant rats. (A–C) show representative TEM images of the corpus callosum post-lysolecithin injection. Green arrows indicate unmyelinated axons while yellow arrowheads indicate the myelinated ones. (D) Graph shows comparison of the g-ratio between the three experimental groups. The axons seen in the corpus callosum of pregnant rats had a significantly lower g-ratio when compared to those seen in virgin and postpartum animals (Lyso-Vir: n = 4, Lyso-Preg: n = 4, Lyso-PP: n = 3, p < 0.01). (E) Representative figures of western blot for the different myelin proteins. No significant difference was detected in the expression of S-MAG (F) or L-MAG (G) in demyelinated corpora callosa of the three experimental groups (Lyso-Vir: n = 6, Lyso-Preg: n = 5, Lyso-PP: n = 4, p > 0.05). The expression of both MOG (H) and CNPase (I) were significantly higher in the pregnant rats when compared to those seen in either virgin or postpartum rats (p < 0.05). The expression of the 21.5 kDa MBP isoform (J) was not different between the three experimental groups (p > 0.05). Pregnant rats had a significantly higher expression of 18.5 + 17 kDa isoforms (K) when compared to either virgin or postpartum rats (p < 0.01). The expression of the 14 kDa MBP isoform (L) was significantly increased in pregnant rats when compared to either virgin (p < 0.01) or postpartum (p < 0.05) rats. Results are presented as mean ± SEM. Scale bar = 1 µm.

Figure 3 Axonal myelination is increased 7 days post-lysolecithin-induced demyelination in the corpus callosum of pregnant rats. (A–C) show representative TEM images of the corpus callosum post-lysolecithin injection. Green arrows indicate unmyelinated axons while yellow arrowheads indicate the myelinated ones. (D) Graph shows comparison of the g-ratio between the three experimental groups. The axons seen in the corpus callosum of pregnant rats had a significantly lower g-ratio when compared to those seen in virgin and postpartum animals (Lyso-Vir: n = 4, Lyso-Preg: n = 4, Lyso-PP: n = 3, p < 0.01). (E) Representative figures of western blot for the different myelin proteins. No significant difference was detected in the expression of S-MAG (F) or L-MAG (G) in demyelinated corpora callosa of the three experimental groups (Lyso-Vir: n = 6, Lyso-Preg: n = 5, Lyso-PP: n = 4, p > 0.05). The expression of both MOG (H) and CNPase (I) were significantly higher in the pregnant rats when compared to those seen in either virgin or postpartum rats (p < 0.05). The expression of the 21.5 kDa MBP isoform (J) was not different between the three experimental groups (p > 0.05). Pregnant rats had a significantly higher expression of 18.5 + 17 kDa isoforms (K) when compared to either virgin or postpartum rats (p < 0.01). The expression of the 14 kDa MBP isoform (L) was significantly increased in pregnant rats when compared to either virgin (p < 0.01) or postpartum (p < 0.05) rats. Results are presented as mean ± SEM. Scale bar = 1 µm.

Figure 4 Pregnancy does not affect the local inflammatory response following demyelination in the corpus callosum. (A–C) are representative immunofluorescent staining images of Iba1 in the corpus callosum in basal condition. (E–G) demonstrate microglial activation following of lysolecithin injection into the corpora callosa of virgin, pregnant, and postpartum animals respectively 7 days post-demyelination. (M) There was no difference in the density of Iba1+ cells in the lysolecithin-injected corpus callosum of virgin, pregnant, or postpartum animals (Lyso-Vir: n = 4, Lyso-Preg: n = 6, Lyso-PP: n = 5, p > 0.05). (G–I) are representative immunofluorescent staining images of GFAP in the corpus callosum in basal condition. (J–L) shows activated GFAP+ cells following of lysolecithin injection into the corpora callosa of virgin, pregnant, and postpartum animals respectively 7 days post-demyelination. (N) There was no significant difference in the OD of GFAP+ staining between virgin, pregnant, or postpartum animals (Lyso-Vir: n = 4, Lyso-Preg: n = 6, Lyso-PP: n = 5, p > 0.05). (O) The fraction area covered by GFAP+ cells was not different between the three experimental groups following demyelination (p > 0.05).

Figure 4 Pregnancy does not affect the local inflammatory response following demyelination in the corpus callosum. (A–C) are representative immunofluorescent staining images of Iba1 in the corpus callosum in basal condition. (E–G) demonstrate microglial activation following of lysolecithin injection into the corpora callosa of virgin, pregnant, and postpartum animals respectively 7 days post-demyelination. (M) There was no difference in the density of Iba1+ cells in the lysolecithin-injected corpus callosum of virgin, pregnant, or postpartum animals (Lyso-Vir: n = 4, Lyso-Preg: n = 6, Lyso-PP: n = 5, p > 0.05). (G–I) are representative immunofluorescent staining images of GFAP in the corpus callosum in basal condition. (J–L) shows activated GFAP+ cells following of lysolecithin injection into the corpora callosa of virgin, pregnant, and postpartum animals respectively 7 days post-demyelination. (N) There was no significant difference in the OD of GFAP+ staining between virgin, pregnant, or postpartum animals (Lyso-Vir: n = 4, Lyso-Preg: n = 6, Lyso-PP: n = 5, p > 0.05). (O) The fraction area covered by GFAP+ cells was not different between the three experimental groups following demyelination (p > 0.05).

Figure 5 Pharmacological blockade of GABAAR exacerbates demyelination lesion and reduces axonal integrity following 7 days lysolecithin-induced demyelination in the corpus callosum of pregnant rats. (A,B) show representative images of LFB staining in lysolecithin-injected corpora callosa of vehicle-treated and Bic-treated pregnant rats. Graph bar in (C) shows that administration of Bic resulted in a significantly larger demyelination lesion when compared to vehicle-treated rats (Lyso-Vehicle: n = 7, Lyso-Bic: n = 5, p < 0.05). (D,E) are immunofluorescent staining images of NF (green) and MBP (red) in the corpora callosa of vehicle-treated and Bic-treated animals respectively. Arrowheads indicate unmyelinated axons while arrows indicate myelinated ones. Bic treatment resulted in a significant reduction in the percentage area covered by NF+ fibers (p < 0.0002) (F), in the percentage area covered by MBP+ fibers (p < 0.002) (G), in the percentage area of juxtaposed NF+ and MBP+ fibers (p < 0.0002) (H), and in the myelination index (p < 0.002) (I) when compared to vehicle-treated animals (Lyso-Vehicle: n = 5, Lyso-Bic: n = 5). Results are presented as mean ± SEM. Scale bar in LFB micrograph = 200 µm. Scale bar in immunofluorescence micrograph = 50 µm.

Figure 5 Pharmacological blockade of GABAAR exacerbates demyelination lesion and reduces axonal integrity following 7 days lysolecithin-induced demyelination in the corpus callosum of pregnant rats. (A,B) show representative images of LFB staining in lysolecithin-injected corpora callosa of vehicle-treated and Bic-treated pregnant rats. Graph bar in (C) shows that administration of Bic resulted in a significantly larger demyelination lesion when compared to vehicle-treated rats (Lyso-Vehicle: n = 7, Lyso-Bic: n = 5, p < 0.05). (D,E) are immunofluorescent staining images of NF (green) and MBP (red) in the corpora callosa of vehicle-treated and Bic-treated animals respectively. Arrowheads indicate unmyelinated axons while arrows indicate myelinated ones. Bic treatment resulted in a significant reduction in the percentage area covered by NF+ fibers (p < 0.0002) (F), in the percentage area covered by MBP+ fibers (p < 0.002) (G), in the percentage area of juxtaposed NF+ and MBP+ fibers (p < 0.0002) (H), and in the myelination index (p < 0.002) (I) when compared to vehicle-treated animals (Lyso-Vehicle: n = 5, Lyso-Bic: n = 5). Results are presented as mean ± SEM. Scale bar in LFB micrograph = 200 µm. Scale bar in immunofluorescence micrograph = 50 µm.

Figure 6 Impact of Bic on the number of OPCs 7 days following lysolecithin-induced demyelination in the corpus callosum of pregnant rats. (A) shows representative images of the proliferation marker PCNA (green) and the OPC marker NG2 (red), while (B) shows representative images of PCNA (green) and pan oligodendrocyte marker Olig2 (OPCs and mature oligodendrocytes; red) in the demyelinated corpus callosum of vehicle-treated and Bic-treated rats respectively. (C) Bic treatment resulted in a significant reduction in the number of NG2+/PCNA+ cells (arrowheads) in the vicinity of the demyelinated corpus callosum when compared to vehicle-treated animals (Lyso-Vehicle: n = 4, Lyso-Bic: n = 4, p < 0.01). (D) There was no significant difference in the cell density of NG2+/PCNA− cells (arrows) between vehicle-treated and Bic-treated animals (p > 0.05). (E) The total number of NG2+ cells was significantly reduced by Bic treatment in comparison to vehicle treatment (p < 0.01). There was no significant difference in the fraction of NG2+/PCNA+ (F), or the fraction of NG2+/PCNA− (G) cells (p > 0.05). (H) There was no significant difference in the density of Olig2+/PCNA+ cells (Olig2/red, PCNA/green) between vehicle-treated and Bic-treated animals (Lyso-Vehicle: n = 4, Lyso-Bic: n = 5, p > 0.05). Bic administration resulted in a significant reduction in the density of Olig2+/PCNA− cells (I) and total Olig2+ cells (J) in the vicinity of the demyelinated corpus callosum when compared to vehicle-treated animals (p < 0.05). There was no significant difference in the percentage of Olig2+/PCNA+ cells (K) or Olig2+/PCNA− cells (L) between vehicle-treated and Bic-treated animals (p > 0.05). Results are presented as mean ± SEM. Scale bar = 50 µ

Figure 6 Impact of Bic on the number of OPCs 7 days following lysolecithin-induced demyelination in the corpus callosum of pregnant rats. (A) shows representative images of the proliferation marker PCNA (green) and the OPC marker NG2 (red), while (B) shows representative images of PCNA (green) and pan oligodendrocyte marker Olig2 (OPCs and mature oligodendrocytes; red) in the demyelinated corpus callosum of vehicle-treated and Bic-treated rats respectively. (C) Bic treatment resulted in a significant reduction in the number of NG2+/PCNA+ cells (arrowheads) in the vicinity of the demyelinated corpus callosum when compared to vehicle-treated animals (Lyso-Vehicle: n = 4, Lyso-Bic: n = 4, p < 0.01). (D) There was no significant difference in the cell density of NG2+/PCNA− cells (arrows) between vehicle-treated and Bic-treated animals (p > 0.05). (E) The total number of NG2+ cells was significantly reduced by Bic treatment in comparison to vehicle treatment (p < 0.01). There was no significant difference in the fraction of NG2+/PCNA+ (F), or the fraction of NG2+/PCNA− (G) cells (p > 0.05). (H) There was no significant difference in the density of Olig2+/PCNA+ cells (Olig2/red, PCNA/green) between vehicle-treated and Bic-treated animals (Lyso-Vehicle: n = 4, Lyso-Bic: n = 5, p > 0.05). Bic administration resulted in a significant reduction in the density of Olig2+/PCNA− cells (I) and total Olig2+ cells (J) in the vicinity of the demyelinated corpus callosum when compared to vehicle-treated animals (p < 0.05). There was no significant difference in the percentage of Olig2+/PCNA+ cells (K) or Olig2+/PCNA− cells (L) between vehicle-treated and Bic-treated animals (p > 0.05). Results are presented as mean ± SEM. Scale bar = 50 µ

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KMEL References

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References

  1.  
    1. Franklin RJ, Gallo V. The translational biology of remyelination: Past, present, and future. Glia. 2014;62:1905–1915. doi: 10.1002/glia.22622. - DOI - PubMed
  2.  
    1. van Walderveen MA, et al. Magnetic resonance evaluation of disease activity during pregnancy in multiple sclerosis. Neurology. 1994;44:327–329. doi: 10.1212/WNL.44.2.327. - DOI - PubMed
  3.  
    1. Patas K, Engler JB, Friese MA, Gold SM. Pregnancy and multiple sclerosis: feto-maternal immune cross talk and its implications for disease activity. J. Reprod. Immunol. 2013;97:140–146. doi: 10.1016/j.jri.2012.10.005. - DOI - PubMed
  4.  
    1. Paty DW, Li DK. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. UBC MS/MRI Study Group and the IFNB Multiple Sclerosis Study Group. Neurology. 1993;43:662–667. doi: 10.1212/WNL.43.4.662. - DOI - PubMed
  5.  
    1. Johnson KP, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology. 1995;45:1268–1276. doi: 10.1212/WNL.45.7.1268. - DOI - PubMed
  6.  
    1. Jacobs LD, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG) Ann. Neurol. 1996;39:285–294. doi: 10.1002/ana.410390304. - DOI - PubMed
  7.  
    1. Brunton PJ, Russell JA, Hirst JJ. Allopregnanolone in the brain: protecting pregnancy and birth outcomes. Prog. Neurobiol. 2014;113:106–136. doi: 10.1016/j.pneurobio.2013.08.005. - DOI - PubMed
  8.  
    1. Concas A, et al. Role of brain allopregnanolone in the plasticity of gamma-aminobutyric acid type A receptor in rat brain during pregnancy and after delivery. Proc. Natl. Acad. Sci. USA. 1998;95:13284–13289. doi: 10.1073/pnas.95.22.13284. - DOI - PMC - PubMed
  9.  
    1. Hoppe D, Kettenmann H. GABA triggers a Cl- efflux from cultured mouse oligodendrocytes. Neurosci. Lett. 1989;97:334–339. doi: 10.1016/0304-3940(89)90620-4. - DOI - PubMed
  10.  
    1. Paul AM, et al. GABA transport and neuroinflammation are coupled in multiple sclerosis: regulation of the GABA transporter-2 by ganaxolone. Neuroscience. 2014;273:24–38. doi: 10.1016/j.neuroscience.2014.04.037. - DOI - PubMed
  11.  
    1. Demakova, E. V., Korobov, V. P. & Lemkina, L. M. [Determination of gamma-aminobutyric acid concentration and activity of glutamate decarboxylase in blood serum of patients with multiple sclerosis]. Klin. Lab Diagn. 15–17 (2003). - PubMed
  12.  
    1. Xiao BG, Link H. Is there a balance between microglia and astrocytes in regulating Th1/Th2-cell responses and neuropathologies? Immunol. Today. 1999;20:477–479. doi: 10.1016/S0167-5699(99)01501-7. - DOI - PubMed
  13.  
    1. Nair A, Frederick TJ, Miller SD. Astrocytes in multiple sclerosis: a product of their environment. Cell Mol. Life Sci. 2008;65:2702–2720. doi: 10.1007/s00018-008-8059-5. - DOI - PMC - PubMed
  14.  
    1. Cherry JD, Olschowka JA, O’Banion MK. Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. J. Neuroinflammation. 2014;11(98):98–11. doi: 10.1186/1742-2094-11-98. - DOI - PMC - PubMed
  15.  
    1. Domingues, H. S., Portugal, C. C., Socodato, R. & Relvas, J. B. Corrigendum: Oligodendrocyte, Astrocyte and Microglia Crosstalk in Myelin Development, Damage, and Repair. Front Cell Dev. Biol. 4, 10.3389/fcell.2016.00079 (2016). - PMC - PubMed
  16.  
    1. Miron VE, et al. M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat. Neurosci. 2013;16:1211–1218. doi: 10.1038/nn.3469. - DOI - PMC - PubMed
  17.  
    1. Hosli E, Otten U, Hosli L. Expression of GABA(A) receptors by reactive astrocytes in explant and primary cultures of rat CNS. Int. J. Dev. Neurosci. 1997;15:949–960. doi: 10.1016/S0736-5748(97)00041-5. - DOI - PubMed
  18.  
    1. Bhat R, et al. Inhibitory role for GABA in autoimmune inflammation. Proc. Natl. Acad. Sci. USA. 2010;107:2580–2585. doi: 10.1073/pnas.0915139107. - DOI - PMC - PubMed
  19.  
    1. Harauz G, Boggs JM. Myelin management by the 18.5-kDa and 21.5-kDa classic myelin basic protein isoforms. J. Neurochem. 2013;125:334–361. doi: 10.1111/jnc.12195. - DOI - PMC - PubMed
  20.  
    1. Lindner M, et al. Sequential myelin protein expression during remyelination reveals fast and efficient repair after central nervous system demyelination. Neuropathol. Appl. Neurobiol. 2008;34:105–114. - PubMed
  21.  
    1. Lai C, et al. Two forms of 1B236/myelin-associated glycoprotein, a cell adhesion molecule for postnatal neural development, are produced by alternative splicing. Proc. Natl. Acad. Sci. USA. 1987;84:4337–4341. doi: 10.1073/pnas.84.12.4337. - DOI - PMC - PubMed
  22.  
    1. Schumacher, M. et al. Progesterone synthesis in the nervous system: implications for myelination and myelin repair. Front Neurosci. 8, 10.3389/fnins.2012.00010 (2012). - PMC - PubMed
  23.  
    1. Noorbakhsh, F., Baker, G. B. & Power, C. Allopregnanolone and neuroinflammation: a focus on multiple sclerosis. Front Cell Neurosci. 8, 10.3389/fncel.2014.00134. (2014). - PMC - PubMed
  24.  
    1. Belelli D, Casula A, Ling A, Lambert JJ. The influence of subunit composition on the interaction of neurosteroids with GABA(A) receptors. Neuropharmacology. 2002;43:651–661. doi: 10.1016/S0028-3908(02)00172-7. - DOI - PubMed
  25.  
    1. Haddady S, Low HP, Billings-Gagliardi S, Riskind PN, Schwartz WJ. Pregnancy modulates precursor cell proliferation in a murine model of focal demyelination. Neuroscience. 2010;19(167):656–664. doi: 10.1016/j.neuroscience.2010.02.061. - DOI - PubMed
  26.  
    1. Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T. Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group. N. Engl. J. Med. 1998;339:285–291. doi: 10.1056/NEJM199807303390501. - DOI - PubMed
  27.  
    1. Langer-Gould A, Garren H, Slansky A, Ruiz PJ, Steinman L. Late pregnancy suppresses relapses in experimental autoimmune encephalomyelitis: evidence for a suppressive pregnancy-related serum factor. J. Immunol. 2002;169:1084–1091. doi: 10.4049/jimmunol.169.2.1084. - DOI - PubMed
  28.  
    1. McClain MA, et al. Pregnancy suppresses experimental autoimmune encephalomyelitis through immunoregulatory cytokine production. J. Immunol. 2007;179:8146–8152. doi: 10.4049/jimmunol.179.12.8146. - DOI - PubMed
  29.  
    1. Lambert JJ, Cooper MA, Simmons RD, Weir CJ, Belelli D. Neurosteroids: endogenous allosteric modulators of GABA(A) receptors. Psychoneuroendocrinology. 2009;34:S48–S58. doi: 10.1016/j.psyneuen.2009.08.009. - DOI - PubMed
  30.  
    1. Neumann ID, et al. Attenuated neuroendocrine responses to emotional and physical stressors in pregnant rats involve adenohypophysial changes. J. Physiol. 1998;508:289–300. doi: 10.1111/j.1469-7793.1998.289br.x. - DOI - PMC - PubMed
  31.  
    1. Langer-Gould A, et al. Exclusive breastfeeding and the risk of postpartum relapses in women with multiple sclerosis. Arch. Neurol. 2009;66:958–963. doi: 10.1001/archneurol.2009.132. - DOI - PubMed
  32.  
    1. Grota LJ, Eik-Nes KB. Plasma progesterone concentrations during pregnancy and lactation in the rat. J. Reprod. Fertil. 1967;13:83–91. doi: 10.1530/jrf.0.0130083. - DOI - PubMed
  33.  
    1. Gravel M, et al. Overexpression of 2′,3′-cyclic nucleotide 3′-phosphodiesterase in transgenic mice alters oligodendrocyte development and produces aberrant myelination. Mol. Cell Neurosci. 1996;7:453–466. doi: 10.1006/mcne.1996.0033. - DOI - PubMed
  34.  
    1. Schachner M, Bartsch U. Multiple functions of the myelin-associated glycoprotein MAG (siglec-4a) in formation and maintenance of myelin. Glia. 2000;29:154–165. doi: 10.1002/(SICI)1098-1136(20000115)29:2<154::AID-GLIA9>3.0.CO;2-3. - DOI - PubMed
  35.  
    1. Pronker, M. F. et al. Structural basis of myelin-associated glycoprotein adhesion and signalling. Nat. Commun. 7, 10.1038/ncomms13584 (2016). - PMC - PubMed
  36.  
    1. Franklin RJ, Ffrench-Constant C. Remyelination in the CNS: from biology to therapy. Nat. Rev. Neurosci. 2008;9:839–855. doi: 10.1038/nrn2480. - DOI - PubMed
  37.  
    1. Gago N, et al. 3alpha,5alpha-Tetrahydroprogesterone (allopregnanolone) and gamma-aminobutyric acid: autocrine/paracrine interactions in the control of neonatal PSA-NCAM+ progenitor proliferation. J. Neurosci. Res. 2004;78:770–783. doi: 10.1002/jnr.20348. - DOI - PubMed
  38.  
    1. Ghoumari AM, Baulieu EE, Schumacher M. Progesterone increases oligodendroglial cell proliferation in rat cerebellar slice cultures. Neuroscience. 2005;135:47–58. doi: 10.1016/j.neuroscience.2005.05.023. - DOI - PubMed
  39.  
    1. Brinton RD. Neurosteroids as regenerative agents in the brain: therapeutic implications. Nat. Rev. Endocrinol. 2013;9:241–250. doi: 10.1038/nrendo.2013.31. - DOI - PubMed
  40.  
    1. Wang JM, Johnston PB, Ball BG, Brinton RD. The neurosteroid allopregnanolone promotes proliferation of rodent and human neural progenitor cells and regulates cell-cycle gene and protein expression. J. Neurosci. 2005;25:4706–4718. doi: 10.1523/JNEUROSCI.4520-04.2005. - DOI - PMC - PubMed
  41.  
    1. Rawji, K. S. & Yong, V. W. The benefits and detriments of macrophages/microglia in models of multiple sclerosis. Clin. Dev. Immunol. 2013, 10.1155/2013/948976 (2013). - PMC - PubMed
  42.  
    1. Al-Shammri S, et al. Th1/Th2 cytokine patterns and clinical profiles during and after pregnancy in women with multiple sclerosis. J. Neurol. Sci. 2004;222:21–27. doi: 10.1016/j.jns.2004.03.027. - DOI - PubMed
  43.  
    1. Takahashi K, Rochford CD, Neumann H. Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J. Exp. Med. 2005;201:647–657. doi: 10.1084/jem.20041611. - DOI - PMC - PubMed
  44.  
    1. Manyam NV, Katz L, Hare TA, Gerber JC, III, Grossman MH. Levels of gamma-aminobutyric acid in cerebrospinal fluid in various neurologic disorders. Arch. Neurol. 1980;37:352–355. doi: 10.1001/archneur.1980.00500550054006. - DOI - PubMed
  45.  
    1. Kalakh S, Mouihate A. Promyelinating properties of androstenediol in gliotoxin-induced demyelination in rat corpus callosum. Neuropathol. Appl. Neurobiol. 2015;41:964–982. doi: 10.1111/nan.12237. - DOI - PubMed
  46.  
    1. Jeffery ND, Blakemore WF. Remyelination of mouse spinal cord axons demyelinated by local injection of lysolecithin. J. Neurocytol. 1995;24:775–781. doi: 10.1007/BF01191213. - DOI - PubMed
  47.  
    1. Merrill JE. In vitro and in vivo pharmacological models to assess demyelination and remyelination. Neuropsychopharmacology. 2009;34:55–73. doi: 10.1038/npp.2008.145. - DOI - PMC - PubMed
  48.  
    1. Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat. Methods. 2012;9:671–675. doi: 10.1038/nmeth.2089. - DOI - PMC - PubMed
  49.  
    1. Kalakh S, Mouihate A. Demyelination-Induced Inflammation Attracts Newly Born Neurons to the White Matter. Mol. Neurobiol. 2017;54:5905–5918. doi: 10.1007/s12035-016-0127-5. - DOI - PubMed
  50.  
    1. Zhang H, Jarjour AA, Boyd A, Williams A. Central nervous system remyelination in culture–a tool for multiple sclerosis research. Exp. Neurol. 2011;230:138–148. doi: 10.1016/j.expneurol.2011.04.009. - DOI - PMC - PubMed
  51.  
    1. Canchi S, et al. Simulated blast overpressure induces specific astrocyte injury in an ex vivo brain slice model. PLoS. One. 2017;12:e0175396. doi: 10.1371/journal.pone.0175396. - DOI - PMC - PubMed
  52.  
    1. Kalakh, S. & Mouihate, A. Androstenediol Reduces Demyelination-Induced Axonopathy in the Rat Corpus Callosum: Impact on Microglial Polarization. Front Cell Neurosci. 11, 10.3389/fncel.2017.00049 (2017). - PMC - PubMed
  53.  
    1. Binder MD, et al. Gas6 increases myelination by oligodendrocytes and its deficiency delays recovery following cuprizone-induced demyelination. PLoS. One. 2011;6:e17727. doi: 10.1371/journal.pone.0017727. - DOI - PMC - PubMed
  54.  
    1. Gregg C, et al. White matter plasticity and enhanced remyelination in the maternal CNS. J. Neurosci. 2007;27:1812–1823. doi: 10.1523/JNEUROSCI.4441-06.2007. - DOI - PMC - PubMed
  55.  
    1. Ishikawa A, et al. Development of a method for the determination of gamma-aminobutyric acid in foodstuffs. J. Nutr. Sci. Vitaminol. (Tokyo). 2009;55:292–295. doi: 10.3177/jnsv.55.292. - DOI - PubMed
  56.  
    1. Ugale RR, Hirani K, Morelli M, Chopde CT. Role of neuroactive steroid allopregnanolone in antipsychotic-like action of olanzapine in rodents. Neuropsychopharmacology. 2004;29:1597–1609. doi: 10.1038/sj.npp.1300460. - DOI - PubMed
  57.  
    1. Brunton PJ, et al. Central opioid inhibition of neuroendocrine stress responses in pregnancy in the rat is induced by the neurosteroid allopregnanolone. J. Neurosci. 2009;20(29):6449–6460. doi: 10.1523/JNEUROSCI.0708-09.2009. - DOI - PMC - PubMed

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