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Administration of 17β-Estradiol Improves Motoneuron Survival and Down-regulates Inflammasome Activation in Male SOD1(G93A) ALS Mice

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An Erratum to this article was published on 19 January 2017

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Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease manifested by the progressive loss of upper and lower motoneurons. The pathomechanism of ALS is complex and not yet fully understood. Neuroinflammation is believed to significantly contribute to disease progression. Inflammasome activation was recently shown in the spinal cord of human sporadic ALS patients and in the SOD1(G93A) mouse model for ALS. In the present study, we investigated the neuroprotective and anti-inflammatory effects of 17β-estradiol (E2) treatment in pre-symptomatic and symptomatic male SOD1(G93A) mice. Symptomatic mice with E2 substitution exhibited improved motor performance correlating with an increased survival of motoneurons in the lumbar spinal cord. Expression of NLRP3 inflammasome proteins and levels of activated caspase 1 and mature interleukin 1 beta were significantly reduced in SOD1(G93A) mice supplemented with E2.

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Change history

  • 19 January 2017

    An erratum to this article has been published.

Abbreviations

ASC:

Apoptosis-associated speck-like protein containing a caspase 1 recruitment domain

ALS:

Amyotrophic lateral sclerosis

ATP:

Adenosine triphosphate

CARD:

Caspase recruitment domain

ChAT:

Choline acetyltransferase

CNS:

Central nervous system

C9ORF72:

Chromosome 9 open reading frame 72

DAB:

3,3′-Diaminobenzidine

DAMP:

Danger-associated molecular pattern

DMT:

Dimethoate

EAE:

Experimental autoimmune encephalomyelitis

ER:

Estrogen receptor

ERE:

Estrogen response element

E2:

17β-Estradiol

GFAP:

Glial fibrillary acidic protein

GPR30:

G protein-coupled estrogen receptor

HMGB1:

High-mobility group protein B1

Iba1:

Ionized calcium-binding adapter molecule 1

IL1β:

Interleukin 1 beta

IL18:

Interleukin 18

IFN-γ:

Interferon gamma

ROS:

Reactive oxygen species

MAP 2:

Microtuble-associated protein 2

MS:

Multiple sclerosis

NeuN:

Neuronal nuclei

NF-κB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

NLR:

Nod-like receptor

NLRP1:

Nod-like receptor protein 1

NLRP3:

Nod-like receptor protein 3

Olig2:

Oligodendrocyte lineage transcription factor 2

OVX:

Ovariectomized

P2X7R:

P2X purinoceptor 7

PBS:

Phosphate-buffered saline

PCR:

Polymerase chain reaction

PRR:

Pattern recognition receptor

SCI:

Spinal cord injury

Serpinb9:

Serine proteinase inhibitor 9

SOD1:

Superoxide dismutase 1

TBI:

Traumatic brain injury

TDP43:

TAR DNA-binding protein

WT:

Wild type

References

  1. Chen S, Sayana P, Zhang X, Le W (2013) Genetics of amyotrophic lateral sclerosis: an update. Mol Neurodegener 8:28. doi:10.1186/1750-1326-8-28

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Poppe L, Rue L, Robberecht W, Van Den Bosch L (2014) Translating biological findings into new treatment strategies for amyotrophic lateral sclerosis (ALS). Exp Neurol 262(Pt B):138–151. doi:10.1016/j.expneurol.2014.07.001

    Article  PubMed  Google Scholar 

  3. Turner MR et al (2013) Mechanisms, models and biomarkers in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener 14(Suppl 1):19–32. doi:10.3109/21678421.2013.778554

    Article  PubMed  PubMed Central  Google Scholar 

  4. Moisse K, Strong MJ (2006) Innate immunity in amyotrophic lateral sclerosis. Biochim Biophys Acta 1762:1083–1093. doi:10.1016/j.bbadis.2006.03.001

    Article  CAS  PubMed  Google Scholar 

  5. Philips T, Robberecht W (2011) Neuroinflammation in amyotrophic lateral sclerosis: role of glial activation in motor neuron disease. Lancet Neurol 10:253–263. doi:10.1016/s1474-4422(11)70015-1

    Article  CAS  PubMed  Google Scholar 

  6. Rizzo F et al (2014) Cellular therapy to target neuroinflammation in amyotrophic lateral sclerosis. Cell Mol Life Sci 71:999–1015. doi:10.1007/s00018-013-1480-4

    Article  CAS  PubMed  Google Scholar 

  7. Brites D, Vaz AR (2014) Microglia centered pathogenesis in ALS: insights in cell interconnectivity. Front Cell Neurosci 8:117. doi:10.3389/fncel.2014.00117

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Thundyil J, Lim KL (2015) DAMPs and neurodegeneration. Ageing Res Rev 24:17–28. doi:10.1016/j.arr.2014.11.003

    Article  CAS  PubMed  Google Scholar 

  9. Schroder K, Tschopp J (2010) The inflammasomes. Cell 140:821–832. doi:10.1016/j.cell.2010.01.040

    Article  CAS  PubMed  Google Scholar 

  10. Walsh JG, Muruve DA, Power C (2014) Inflammasomes in the CNS. Nat Rev Neurosci 15:84–97. doi:10.1038/nrn3638

    Article  CAS  PubMed  Google Scholar 

  11. Johann S et al (2015) NLRP3 inflammasome is expressed by astrocytes in the SOD1 mouse model of ALS and in human sporadic ALS patients. Glia 63:2260–2273. doi:10.1002/glia.22891

    Article  PubMed  Google Scholar 

  12. Kadhim H, Deltenre P, Martin JJ, Sebire G (2016) In-situ expression of interleukin-18 and associated mediators in the human brain of sALS patients: hypothesis for a role for immune-inflammatory mechanisms. Med Hypotheses 86:14–17. doi:10.1016/j.mehy.2015.11.022

    Article  CAS  PubMed  Google Scholar 

  13. Meissner F, Molawi K, Zychlinsky A (2010) Mutant superoxide dismutase 1-induced IL-1beta accelerates ALS pathogenesis. Proc Natl Acad Sci U S A 107:13046–13050. doi:10.1073/pnas.1002396107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Pozzi S, Benedusi V, Maggi A, Vegeto E (2006) Estrogen action in neuroprotection and brain inflammation. Ann N Y Acad Sci 1089:302–323. doi:10.1196/annals.1386.035

    Article  CAS  PubMed  Google Scholar 

  15. Acaz-Fonseca E, Avila-Rodriguez M, Garcia-Segura LM, Barreto GE (2016) Regulation of astroglia by gonadal steroid hormones under physiological and pathological conditions. Prog Neurobiol. doi:10.1016/j.pneurobio.2016.06.002

    PubMed  Google Scholar 

  16. Habib P, Beyer C (2015) Regulation of brain microglia by female gonadal steroids. J Steroid Biochem Mol Biol 146:3–14. doi:10.1016/j.jsbmb.2014.02.018

    Article  CAS  PubMed  Google Scholar 

  17. Johann S, Beyer C (2013) Neuroprotection by gonadal steroid hormones in acute brain damage requires cooperation with astroglia and microglia. J Steroid Biochem Mol Biol 137:71–81. doi:10.1016/j.jsbmb.2012.11.006

    Article  CAS  PubMed  Google Scholar 

  18. Dodel RC, Du Y, Bales KR, Gao F, Paul SM (1999) Sodium salicylate and 17beta-estradiol attenuate nuclear transcription factor NF-kappaB translocation in cultured rat astroglial cultures following exposure to amyloid A beta(1-40) and lipopolysaccharides. J Neurochem 73:1453–1460

    Article  CAS  PubMed  Google Scholar 

  19. Habib P, Dreymueller D, Ludwig A, Beyer C, Dang J (2013) Sex steroid hormone-mediated functional regulation of microglia-like BV-2 cells during hypoxia. J Steroid Biochem Mol Biol 138:195–205. doi:10.1016/j.jsbmb.2013.06.003

    Article  CAS  PubMed  Google Scholar 

  20. Kipp M, Karakaya S, Johann S, Kampmann E, Mey J, Beyer C (2007) Oestrogen and progesterone reduce lipopolysaccharide-induced expression of tumour necrosis factor-alpha and interleukin-18 in midbrain astrocytes. J Neuroendocrinol 19:819–822. doi:10.1111/j.1365-2826.2007.01588.x

    Article  CAS  PubMed  Google Scholar 

  21. Valles SL et al (2010) Estradiol or genistein prevent Alzheimer’s disease-associated inflammation correlating with an increase PPAR gamma expression in cultured astrocytes. Brain Res 1312:138–144. doi:10.1016/j.brainres.2009.11.044

    Article  CAS  PubMed  Google Scholar 

  22. Chiappetta O et al (2007) Evidence to implicate early modulation of interleukin-1beta expression in the neuroprotection afforded by 17beta-estradiol in male rats undergone transient middle cerebral artery occlusion. Int Rev Neurobiol 82:357–372. doi:10.1016/s0074-7742(07)82019-8

    Article  CAS  PubMed  Google Scholar 

  23. Lammerding L, Slowik A, Johann S, Beyer C, Zendedel A (2015) Post-stroke inflammasome expression and regulation in the peri-infarct area by gonadal steroids after transient focal ischemia in the rat brain. Neuroendocrinology. doi:10.1159/000439435

    PubMed  Google Scholar 

  24. Zhao TZ, Ding Q, Hu J, He SM, Shi F, Ma LT (2016) GPER expressed on microglia mediates the anti-inflammatory effect of estradiol in ischemic stroke. Brain Behav 6:e00449. doi:10.1002/brb3.449

    Article  PubMed  PubMed Central  Google Scholar 

  25. Cuzzocrea S et al (2008) Effect of 17beta-estradiol on signal transduction pathways and secondary damage in experimental spinal cord trauma. Shock 29:362–371. doi:10.1097/shk.0b013e31814545dc

    CAS  PubMed  Google Scholar 

  26. Khaksari M, Soltani Z, Shahrokhi N, Moshtaghi G, Asadikaram G (2011) The role of estrogen and progesterone, administered alone and in combination, in modulating cytokine concentration following traumatic brain injury. Can J Physiol Pharmacol 89:31–40. doi:10.1139/y10-103

    Article  CAS  PubMed  Google Scholar 

  27. Sarkaki AR, Khaksari Haddad M, Soltani Z, Shahrokhi N, Mahmoodi M (2013) Time- and dose-dependent neuroprotective effects of sex steroid hormones on inflammatory cytokines after a traumatic brain injury. J Neurotrauma 30:47–54. doi:10.1089/neu.2010.1686

    Article  PubMed  Google Scholar 

  28. de Rivero Vaccari JP, Patel HH, Brand FJ 3rd, Perez-Pinzon MA, Bramlett HM, Raval AP (2016) Estrogen receptor beta signaling alters cellular inflammasomes activity after global cerebral ischemia in reproductively senescence female rats. J Neurochem 136:492–496. doi:10.1111/jnc.13404

    Article  PubMed  CAS  Google Scholar 

  29. Slowik A, Beyer C (2015) Inflammasomes are neuroprotective targets for sex steroids. J Steroid Biochem Mol Biol 153:135–143. doi:10.1016/j.jsbmb.2015.02.013

    Article  CAS  PubMed  Google Scholar 

  30. Logroscino G et al (2010) Incidence of amyotrophic lateral sclerosis in Europe. J Neurol Neurosurg Psychiatry 81:385–390. doi:10.1136/jnnp.2009.183525

    Article  PubMed  Google Scholar 

  31. McCombe PA, Henderson RD (2010) Effects of gender in amyotrophic lateral sclerosis. Gend Med 7:557–570. doi:10.1016/j.genm.2010.11.010

    Article  PubMed  Google Scholar 

  32. Choi CI, Lee YD, Gwag BJ, Cho SI, Kim SS, Suh-Kim H (2008) Effects of estrogen on lifespan and motor functions in female hSOD1 G93A transgenic mice. J Neurol Sci 268:40–47. doi:10.1016/j.jns.2007.10.024

    Article  CAS  PubMed  Google Scholar 

  33. Blasco H et al (2012) Amyotrophic lateral sclerosis: a hormonal condition? Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases 13:585–588. doi:10.3109/17482968.2012.706303

    Article  Google Scholar 

  34. de Jong S et al (2013) Endogenous female reproductive hormones and the risk of amyotrophic lateral sclerosis. J Neurol 260:507–512. doi:10.1007/s00415-012-6665-5

    Article  CAS  PubMed  Google Scholar 

  35. Groeneveld GJ, Van Muiswinkel FL, Sturkenboom JM, Wokke JH, Bar PR, Van den Berg LH (2004) Ovariectomy and 17beta-estradiol modulate disease progression of a mouse model of ALS. Brain Res 1021:128–131. doi:10.1016/j.brainres.2004.06.024

    Article  CAS  PubMed  Google Scholar 

  36. Gurney ME (1994) Transgenic-mouse model of amyotrophic lateral sclerosis. N Engl J Med 331(25):1721–2

  37. Foster HL, Small JD, Fox JG (1983) The mouse in biomedical research: normative biology, immunology, and husbandry. Academic Press, Orlando, p. 138

    Google Scholar 

  38. Scott S et al (2008) Design, power, and interpretation of studies in the standard murine model of ALS. Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases 9:4–15. doi:10.1080/17482960701856300

    Article  CAS  Google Scholar 

  39. Johann S, Dahm M, Kipp M, Beyer C, Arnold S (2010) Oestrogen regulates mitochondrial respiratory chain enzyme transcription in the mouse spinal cord. J Neuroendocrinol 22:926–935. doi:10.1111/j.1365-2826.2010.02006.x

    CAS  PubMed  Google Scholar 

  40. Johann S, Dahm M, Kipp M, Zahn U, Beyer C (2011) Regulation of choline acetyltransferase expression by 17 beta-oestradiol in NSC-34 cells and in the spinal cord. J Neuroendocrinol 23:839–848. doi:10.1111/j.1365-2826.2011.02192.x

    Article  CAS  PubMed  Google Scholar 

  41. Dhandapani KM, Brann DW (2002) Protective effects of estrogen and selective estrogen receptor modulators in the brain. Biol Reprod 67:1379–1385

    Article  CAS  PubMed  Google Scholar 

  42. Cho J, Kim L, Li Z, Rose NR, Talor MV, Njoku DB (2013) Sex bias in experimental immune-mediated, drug-induced liver injury in BALB/c mice: suggested roles for Tregs, estrogen, and IL-6. PLoS One 8:e61186. doi:10.1371/journal.pone.0061186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Saito T, Ciobotaru A, Bopassa JC, Toro L, Stefani E, Eghbali M (2009) Estrogen contributes to gender differences in mouse ventricular repolarization. Circ Res 105:343–352. doi:10.1161/circresaha.108.190041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Cousins SW, Marin-Castano ME, Espinosa-Heidmann DG, Alexandridou A, Striker L, Elliot S (2003) Female gender, estrogen loss, and sub-RPE deposit formation in aged mice. Invest Ophthalmol Vis Sci 44:1221–1229

    Article  PubMed  Google Scholar 

  45. Haisenleder DJ, Schoenfelder AH, Marcinko ES, Geddis LM, Marshall JC (2011) Estimation of estradiol in mouse serum samples: evaluation of commercial estradiol immunoassays. Endocrinology 152:4443–4447. doi:10.1210/en.2011-1501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Alves CJ et al (2011) Early motor and electrophysiological changes in transgenic mouse model of amyotrophic lateral sclerosis and gender differences on clinical outcome. Brain Res 1394:90–104. doi:10.1016/j.brainres.2011.02.060

    Article  CAS  PubMed  Google Scholar 

  47. Knippenberg S, Thau N, Dengler R, Petri S (2010) Significance of behavioural tests in a transgenic mouse model of amyotrophic lateral sclerosis (ALS). Behav Brain Res 213:82–87. doi:10.1016/j.bbr.2010.04.042

    Article  PubMed  Google Scholar 

  48. Mead RJ et al (2011) Optimised and rapid pre-clinical screening in the SOD1(G93A) transgenic mouse model of amyotrophic lateral sclerosis (ALS). PLoS One 6:e23244. doi:10.1371/journal.pone.0023244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Enns DL, Tiidus PM (2010) The influence of estrogen on skeletal muscle: sex matters. Sports medicine (Auckland, NZ) 40:41–58. doi:10.2165/11319760-000000000-00000

    Article  Google Scholar 

  50. Lowe DA, Baltgalvis KA, Greising SM (2010) Mechanisms behind estrogen’s beneficial effect on muscle strength in females. Exerc Sport Sci Rev 38:61–67. doi:10.1097/JES.0b013e3181d496bc

    Article  PubMed  PubMed Central  Google Scholar 

  51. Das A, Smith JA, Gibson C, Varma AK, Ray SK, Banik NL (2011) Estrogen receptor agonists and estrogen attenuate TNF-alpha-induced apoptosis in VSC4.1 motoneurons. J Endocrinol 208:171–182. doi:10.1677/joe-10-0338

    Article  CAS  PubMed  Google Scholar 

  52. Kim HJ, Magrane J, Starkov AA, Manfredi G (2012) The mitochondrial calcium regulator cyclophilin D is an essential component of oestrogen-mediated neuroprotection in amyotrophic lateral sclerosis. Brain : a journal of neurology 135:2865–2874. doi:10.1093/brain/aws208

    Article  Google Scholar 

  53. Chen J et al (2015) G-protein-coupled receptor 30-mediated antiapoptotic effect of estrogen on spinal motor neurons following injury and its underlying mechanisms. Mol Med Rep 12:1733–1740. doi:10.3892/mmr.2015.3601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Krieg AJ, Krieg SA, Ahn BS, Shapiro DJ (2004) Interplay between estrogen response element sequence and ligands controls in vivo binding of estrogen receptor to regulated genes. J Biol Chem 279:5025–5034. doi:10.1074/jbc.M307076200

    Article  CAS  PubMed  Google Scholar 

  55. Fischer LR et al (2004) Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man. Exp Neurol 185:232–240

    Article  PubMed  Google Scholar 

  56. Rocha MC, Pousinha PA, Correia AM, Sebastiao AM, Ribeiro JA (2013) Early changes of neuromuscular transmission in the SOD1(G93A) mice model of ALS start long before motor symptoms onset. PLoS One 8:e73846. doi:10.1371/journal.pone.0073846

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kitajima Y, Ono Y (2016) Estrogens maintain skeletal muscle and satellite cell functions. J Endocrinol 229:267–275. doi:10.1530/joe-15-0476

    Article  CAS  PubMed  Google Scholar 

  58. Velders M, Schleipen B, Fritzemeier KH, Zierau O, Diel P (2012) Selective estrogen receptor-beta activation stimulates skeletal muscle growth and regeneration. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 26:1909–1920. doi:10.1096/fj.11-194779

    Article  CAS  Google Scholar 

  59. Pollanen E et al (2010) Effects of combined hormone replacement therapy or its effective agents on the IGF-1 pathway in skeletal muscle. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society 20:372–379. doi:10.1016/j.ghir.2010.07.003

    Article  CAS  Google Scholar 

  60. Boland R, Vasconsuelo A, Milanesi L, Ronda AC, de Boland AR (2008) 17beta-estradiol signaling in skeletal muscle cells and its relationship to apoptosis. Steroids 73:859–863. doi:10.1016/j.steroids.2007.12.027

    Article  CAS  PubMed  Google Scholar 

  61. Ilieva H, Polymenidou M, Cleveland DW (2009) Non-cell autonomous toxicity in neurodegenerative disorders: ALS and beyond. J Cell Biol 187:761–772. doi:10.1083/jcb.200908164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Philips T, Rothstein JD (2014) Glial cells in amyotrophic lateral sclerosis. Exp Neurol 262(Pt B):111–120. doi:10.1016/j.expneurol.2014.05.015

    Article  CAS  PubMed  Google Scholar 

  63. Henkel JS, Beers DR, Zhao W, Appel SH (2009) Microglia in ALS: the good, the bad, and the resting. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 4:389–398. doi:10.1007/s11481-009-9171-5

    Article  Google Scholar 

  64. Gravel M, Beland LC, Soucy G, Abdelhamid E (2016) IL-10 controls early microglial phenotypes and disease onset in ALS caused by misfolded superoxide dismutase 1. J Neurosci 36:1031–1048. doi:10.1523/jneurosci.0854-15.2016

    Article  CAS  PubMed  Google Scholar 

  65. Liao B, Zhao W, Beers DR, Henkel JS, Appel SH (2012) Transformation from a neuroprotective to a neurotoxic microglial phenotype in a mouse model of ALS. Exp Neurol 237:147–152. doi:10.1016/j.expneurol.2012.06.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Ben Haim L, Carrillo-de Sauvage MA, Ceyzeriat K, Escartin C (2015) Elusive roles for reactive astrocytes in neurodegenerative diseases. Front Cell Neurosci 9:278. doi:10.3389/fncel.2015.00278

    Article  PubMed  PubMed Central  Google Scholar 

  67. Arevalo MA, Santos-Galindo M, Bellini MJ, Azcoitia I, Garcia-Segura LM (2010) Actions of estrogens on glial cells: implications for neuroprotection. Biochim Biophys Acta 1800:1106–1112. doi:10.1016/j.bbagen.2009.10.002

    Article  CAS  PubMed  Google Scholar 

  68. Habib P, Slowik A, Zendedel A, Johann S, Dang J, Beyer C (2014) Regulation of hypoxia-induced inflammatory responses and M1-M2 phenotype switch of primary rat microglia by sex steroids. Journal of molecular neuroscience : MN 52:277–285. doi:10.1007/s12031-013-0137-y

    Article  CAS  PubMed  Google Scholar 

  69. Mor G et al (1999) Estrogen and microglia: a regulatory system that affects the brain. J Neurobiol 40:484–496

    Article  CAS  PubMed  Google Scholar 

  70. Apolloni S, Fabbrizio P, Amadio S, Volonte C (2016) Actions of the antihistaminergic clemastine on presymptomatic SOD1-G93A mice ameliorate ALS disease progression. J Neuroinflammation 13:191. doi:10.1186/s12974-016-0658-8

    Article  PubMed  PubMed Central  Google Scholar 

  71. Patel P, Julien JP, Kriz J (2015) Early-stage treatment with Withaferin A reduces levels of misfolded superoxide dismutase 1 and extends lifespan in a mouse model of amyotrophic lateral sclerosis. Neurotherapeutics the journal of the American Society for Experimental NeuroTherapeutics 12:217–233. doi:10.1007/s13311-014-0311-0

    Article  CAS  PubMed  Google Scholar 

  72. Sunyach C et al (2012) Olesoxime delays muscle denervation, astrogliosis, microglial activation and motoneuron death in an ALS mouse model. Neuropharmacology 62:2346–2352. doi:10.1016/j.neuropharm.2012.02.013

    Article  CAS  PubMed  Google Scholar 

  73. Tanaka K et al (2008) A dopamine receptor antagonist L-745,870 suppresses microglia activation in spinal cord and mitigates the progression in ALS model mice. Exp Neurol 211:378–386. doi:10.1016/j.expneurol.2008.02.004

    Article  CAS  PubMed  Google Scholar 

  74. Thornton P, Pinteaux E, Gibson RM, Allan SM, Rothwell NJ (2006) Interleukin-1-induced neurotoxicity is mediated by glia and requires caspase activation and free radical release. J Neurochem 98:258–266. doi:10.1111/j.1471-4159.2006.03872.x

    Article  CAS  PubMed  Google Scholar 

  75. Ye L et al (2013) IL-1beta and TNF-alpha induce neurotoxicity through glutamate production: a potential role for neuronal glutaminase. J Neurochem 125:897–908. doi:10.1111/jnc.12263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. de Rivero Vaccari JP, Dietrich WD, Keane RW (2014) Activation and regulation of cellular inflammasomes: gaps in our knowledge for central nervous system injury. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 34:369–375. doi:10.1038/jcbfm.2013.227

    Article  CAS  Google Scholar 

  77. Wei Q et al (2015) Estrogen suppresses hepatocellular carcinoma cells through ERbeta-mediated upregulation of the NLRP3 inflammasome. Laboratory investigation; a journal of technical methods and pathology 95:804–816. doi:10.1038/labinvest.2015.63

    Article  CAS  PubMed  Google Scholar 

  78. Xu Y, Sheng H, Bao Q, Wang Y, Lu J, Ni X (2016) NLRP3 inflammasome activation mediates estrogen deficiency-induced depression- and anxiety-like behavior and hippocampal inflammation in mice. Brain Behav Immun 56:175–186. doi:10.1016/j.bbi.2016.02.022

    Article  CAS  PubMed  Google Scholar 

  79. Astiz M, Acaz-Fonseca E, Garcia-Segura LM (2014) Sex differences and effects of estrogenic compounds on the expression of inflammatory molecules by astrocytes exposed to the insecticide dimethoate. Neurotox Res 25:271–285. doi:10.1007/s12640-013-9417-0

    Article  CAS  PubMed  Google Scholar 

  80. Loram LC et al (2012) Sex and estradiol influence glial pro-inflammatory responses to lipopolysaccharide in rats. Psychoneuroendocrinology 37:1688–1699. doi:10.1016/j.psyneuen.2012.02.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Sperlagh B, Illes P (2014) P2X7 receptor: an emerging target in central nervous system diseases. Trends Pharmacol Sci 35:537–547. doi:10.1016/j.tips.2014.08.002

    Article  CAS  PubMed  Google Scholar 

  82. Dubyak GR (2012) P2X7 receptor regulation of non-classical secretion from immune effector cells. Cell Microbiol 14:1697–1706. doi:10.1111/cmi.12001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Feng L et al (2015) P2X7R blockade prevents NLRP3 inflammasome activation and brain injury in a rat model of intracerebral hemorrhage: involvement of peroxynitrite. J Neuroinflammation 12:190. doi:10.1186/s12974-015-0409-2

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Zhao J et al (2013) P2X7 blockade attenuates murine lupus nephritis by inhibiting activation of the NLRP3/ASC/caspase 1 pathway. Arthritis Rheum 65:3176–3185. doi:10.1002/art.38174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Cario-Toumaniantz C, Loirand G, Ferrier L, Pacaud P (1998) Non-genomic inhibition of human P2X7 purinoceptor by 17beta-oestradiol. J Physiol 508(Pt 3):659–666

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Cervetto C, Frattaroli D, Maura G, Marcoli M (2013) Motor neuron dysfunction in a mouse model of ALS: gender-dependent effect of P2X7 antagonism. Toxicology 311:69–77. doi:10.1016/j.tox.2013.04.004

    Article  CAS  PubMed  Google Scholar 

  87. Annand RR et al (1999) Caspase-1 (interleukin-1beta-converting enzyme) is inhibited by the human serpin analogue proteinase inhibitor 9. The Biochemical journal 342(Pt 3):655–665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Boileau C et al (2002) The in situ up-regulation of chondrocyte interleukin-1-converting enzyme and interleukin-18 levels in experimental osteoarthritis is mediated by nitric oxide. Arthritis Rheum 46:2637–2647. doi:10.1002/art.10518

    Article  CAS  PubMed  Google Scholar 

  89. van der Burgh R et al (2016) Reduced serpinB9-mediated caspase-1 inhibition can contribute to autoinflammatory disease. Oncotarget 7:19265–19271. doi:10.18632/oncotarget.8086

    Article  PubMed  PubMed Central  Google Scholar 

  90. Young JL, Sukhova GK, Foster D, Kisiel W, Libby P, Schonbeck U (2000) The serpin proteinase inhibitor 9 is an endogenous inhibitor of interleukin 1beta-converting enzyme (caspase-1) activity in human vascular smooth muscle cells. J Exp Med 191:1535–1544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Kanamori H et al (2000) Proteinase inhibitor 9, an inhibitor of granzyme B-mediated apoptosis, is a primary estrogen-inducible gene in human liver cells. J Biol Chem 275:5867–5873

    Article  CAS  PubMed  Google Scholar 

  92. Krieg SA, Krieg AJ, Shapiro DJ (2001) A unique downstream estrogen responsive unit mediates estrogen induction of proteinase inhibitor-9, a cellular inhibitor of IL-1beta- converting enzyme (caspase 1). Molecular endocrinology (Baltimore, Md) 15:1971–1982. doi:10.1210/mend.15.11.0719

    CAS  Google Scholar 

  93. Arevalo MA, Diz-Chaves Y, Santos-Galindo M, Bellini MJ, Garcia-Segura LM (2012) Selective oestrogen receptor modulators decrease the inflammatory response of glial cells. J Neuroendocrinol 24:183–190. doi:10.1111/j.1365-2826.2011.02156.x

    Article  CAS  PubMed  Google Scholar 

  94. Ascenzi P, Bocedi A, Marino M (2006) Structure-function relationship of estrogen receptor alpha and beta: impact on human health. Mol Asp Med 27:299–402. doi:10.1016/j.mam.2006.07.001

    Article  CAS  Google Scholar 

  95. Chakrabarti M, Haque A, Banik NL, Nagarkatti P, Nagarkatti M, Ray SK (2014) Estrogen receptor agonists for attenuation of neuroinflammation and neurodegeneration. Brain Res Bull 109:22–31. doi:10.1016/j.brainresbull.2014.09.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Kipp M, Hochstrasser T, Schmitz C, Beyer C (2016) Female sex steroids and glia cells: impact on multiple sclerosis lesion formation and fine tuning of the local neurodegenerative cellular network. Neurosci Biobehav Rev 67:125–136. doi:10.1016/j.neubiorev.2015.11.016

    Article  CAS  PubMed  Google Scholar 

  97. Matthews J, Gustafsson JA (2003) Estrogen signaling: a subtle balance between ER alpha and ER beta. Mol Interv 3:281–292. doi:10.1124/mi.3.5.281

    Article  CAS  PubMed  Google Scholar 

  98. McDowell ML, Das A, Smith JA, Varma AK, Ray SK, Banik NL (2011) Neuroprotective effects of genistein in VSC4.1 motoneurons exposed to activated microglial cytokines. Neurochem Int 59:175–184. doi:10.1016/j.neuint.2011.04.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Platania P, Seminara G, Aronica E, Troost D, Vincenza Catania M, Angela Sortino M (2005) 17beta-Estradiol rescues spinal motoneurons from AMPA-induced toxicity: a role for glial cells. Neurobiol Dis 20:461–470. doi:10.1016/j.nbd.2005.03.025

    Article  CAS  PubMed  Google Scholar 

  100. Popat RA et al (2006) Effect of reproductive factors and postmenopausal hormone use on the risk of amyotrophic lateral sclerosis. Neuroepidemiology 27:117–121. doi:10.1159/000095550

    Article  PubMed  Google Scholar 

  101. Gargiulo-Monachelli GM, Sivori M, Meyer M, Sica RE, De Nicola AF, Gonzalez-Deniselle MC (2014) Circulating gonadal and adrenal steroids in amyotrophic lateral sclerosis: possible markers of susceptibility and outcome. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 46:433–439. doi:10.1055/s-0034-1371891

    Article  CAS  PubMed  Google Scholar 

  102. Charlier TD, Cornil CA, Balthazart J (2013) Rapid modulation of aromatase activity in the vertebrate brain. Journal of experimental neuroscience 7:31–37. doi:10.4137/jen.s11268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to thank U. Zahn (Institute of Neuroanatomy) for the technical support. This work was supported by a research grant from the Medical Faculty of the RWTH Aachen University (START, SJ).

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Authors and Affiliations

  1. Institute of Neuroanatomy, Faculty of Medicine, RWTH Aachen University, Wendlingweg 2, 52074, Aachen, Germany

    Marius Heitzer, Sarah Kaiser, Mithila Kanagaratnam, Adib Zendedel, Philipp Hartmann, Cordian Beyer & Sonja Johann

  2. Department of Anatomical Sciences, Faculty of Medicine, Guilan University of Medical Sciences, Rasht, Iran

    Adib Zendedel

  3. JARA-BRAIN, 52074, Aachen, Germany

    Cordian Beyer

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  1. Marius Heitzer
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  2. Sarah Kaiser
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  3. Mithila Kanagaratnam
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  5. Philipp Hartmann
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  6. Cordian Beyer
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  7. Sonja Johann
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Correspondence to Sonja Johann.

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The authors declare that they have no conflict of interest.

Ethical Statement

The animals used in this study were housed under pathogen-free conditions with access to standard rodent diet and tap water ad libitum. All experiments were conducted in conformance with the NIH Guidelines for the Care and Use of Laboratory Animals.

Additional information

The original version of this article was revised: In Figure 4 and 5, the unconverted unit “mm” at scale bars were changed to “µm”.

An erratum to this article is available at https://doi.org/10.1007/s12035-017-0391-z.

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Heitzer, M., Kaiser, S., Kanagaratnam, M. et al. Administration of 17β-Estradiol Improves Motoneuron Survival and Down-regulates Inflammasome Activation in Male SOD1(G93A) ALS Mice. Mol Neurobiol 54, 8429–8443 (2017). https://doi.org/10.1007/s12035-016-0322-4

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