期刊论文详细信息
BMC Neuroscience
Gender effect on neurodegeneration and myelin markers in an animal model for multiple sclerosis
Luciana Giardino2  Laura Calzà2  Roberto C Melcangi3  Silvia Giatti3  Luca Lorenzini2  Sandra Sivilia2  Mercedes Fernández1  Giulia D'Intino2  Alessandro Massella2 
[1] Health Sciences and Technology - Interdepartmental Center for Industrial Research (HST-ICIR), University of Bologna, Via Tolara di Sopra 50, 40064 Ozzano Emilia, Italy;Department of Veterinary Medicine, University of Bologna, Via Tolara di Sopra 50, 40064 Ozzano Emilia, Italy;Dept. of Endocrinology, Pathophysiology and Applied Biology - Center of Excellence on Neurodegenerative Diseases, University of Milan, Via Balzaretti 9, 20133 Milano, Italy
关键词: neurotrophins and related receptors;    cerebellum;    spinal cord;    rat;    gender-related;    experimental allergic encephalomyelitis;   
Others  :  1170845
DOI  :  10.1186/1471-2202-13-12
 received in 2011-08-25, accepted in 2012-01-24,  发布年份 2012
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【 摘 要 】

Background

Multiple sclerosis (MS) varies considerably in its incidence and progression in females and males. In spite of clinical evidence, relatively few studies have explored molecular mechanisms possibly involved in gender-related differences. The present study describes possible cellular- and molecular-involved markers which are differentially regulated in male and female rats and result in gender-dependent EAE evolution and progression. Attention was focused on markers of myelination (MBP and PDGFαR) and neuronal distress and/or damage (GABA synthesis enzymes, GAD65 and GAD67, NGF, BDNF and related receptors), in two CNS areas, i.e. spinal cord and cerebellum, which are respectively severely and mildly affected by inflammation and demyelination. Tissues were sampled during acute, relapse/remission and chronic phases and results were analysed by two-way ANOVA.

Results

1. A strong gender-dependent difference in myelin (MBP) and myelin precursor (PDGFαR) marker mRNA expression levels is observed in control animals in the spinal cord, but not in the cerebellum. This is the only gender-dependent difference in the expression level of the indicated markers in healthy animals; 2. both PDGFαR and MBP mRNAs in the spinal cord and MBP in the cerebellum are down-regulated during EAE in gender-dependent manner; 3. in the cerebellum, the expression profile of neuron-associated markers (GAD65, GAD67) is characterized by a substantial down-regulation during the inflammatory phase of the disease, which does not differ between male and female rats (two-way ANOVA); 4. there is an up-regulation of NGF, trkA and p75 mRNA expression in the early phases of the disease (14 and 21 days post-immunization), which is not different between male and female.

Conclusions

It is reported herein that the regulation of markers involved in demyelination and neuroprotection processes occurring during EAE, a well-established MS animal model, is gender- and time-dependent. These findings might contribute to gender- and phase disease-based therapy strategies.

【 授权许可】

   
2012 Massella et al; licensee BioMed Central Ltd.

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【 参考文献 】
  • [1]Hauser SL, Oksenberg JR: The neurobiology of multiple sclerosis: genes, inflammation, and neurodegeneration. Neuron 2006, 52:61-76.
  • [2]Hawkins SA, McDonnell GV: Benign multiple sclerosis? Clinical course, long term follow up, and assessment of prognostic factors. J Neurol Neurosurg Psychiatry 1999, 67:148-52.
  • [3]Confavreux C, Vukusic S, Adeleine P: Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process. Brain 2003, 126:770-782.
  • [4]Tomassini V, Pozzilli C: Sex hormones: a role in the control of multiple sclerosis? Expert Opin Pharmacother 2006, 7:857-868.
  • [5]Schwendimann RN, Alekseeva N: Gender issues in multiple sclerosis. Int Rev Neurobiol 2007, 79:377-392.
  • [6]Cosgrove KP, Mazure CM, Staley JK: Evolving knowledge of sex differences in brain structure, function, and chemistry. Biol Psychiatry 2007, 62:847-855.
  • [7]Hsu JL, Leemans A, Bai CH, Lee CH, Tsai YF, Chiu HC, Chen WH: Gender differences and age-related white matter changes of the human brain: a diffusion tensor imaging study. NeuroImage 2008, 39:566-577.
  • [8]Highley JR, DeLisi LE, Roberts N, Webb JA, Relja M, Razi K, Crow TJ: Sex-dependent effects of schizophrenia: an MRI study of gyral folding, and cortical and white matter volume. Psychiatry Res 2003, 124:11-23.
  • [9]Bramlett HM, Dietrich WD: Pathophysiology of cerebral ischemia and brain trauma: similarities and differences. J Cereb Blood Flow Metab 2004, 24:133-150.
  • [10]Webber KM, Casadesus G, Marlatt MW, Perry G, Hamlin CR, Atwood CS, Bowen RL, Smith MA: Estrogen bows to a new master: the role of gonadotropins in Alzheimer pathogenesis. Ann N Y Acad Sci 2005, 1052:201-209.
  • [11]Polman CH, Uitdehaag BM: New and emerging treatment options for multiple sclerosis. Lancet Neurol 2003, 2:563-566.
  • [12]Melcangi RC, Garcia-Segura LM: Sex-specific therapeutic strategies based on neuroactive steroids: In search for innovative tools for neuroprotection. Horm Behav 2010, 57:2-11.
  • [13]Calzà L, Giardino L, Pozza M, Micera A, Aloe L: Time-course changes of nerve growth factor, corticotropin-releasing hormone, and nitric oxide synthase isoforms and their possible role in the development of inflammatory response in experimental allergic encephalomyelitis. Proc Natl Acad Sci USA 1997, 94:3368-3373.
  • [14]Calzà L, Giardino L, Pozza M, Bettelli C, Micera A, Aloe L: Proliferation and phenotype regulation in the subventricular zone during experimental allergic encephalomyelitis: in vivo evidence of a role for nerve growth factor. Proc Natl Acad Sci USA 1998, 95:3209-3214.
  • [15]Calza L, Fernández M, Giuliani A, Aloe L, Giardino L: Thyroid hormone activates oligodendrocyte precursors and increases a myelin-forming protein and NGF content in the spinal cord during experimental allergic encephalomyelitis. Proc Natl Acad Sci USA 2002, 99:3258-3263.
  • [16]Fernández M, Giuliani A, Pirondi S, D'intino G, Giardino L, Aloe L, Levi-Montalcini R, Calza' L: Thyroid hormone administration facilitates remyelination in chronic experimental demyelinating-inflammatory disease. Proc Natl Acad Sci USA 2004, 101:16363-16368.
  • [17]Giardino L, Giuliani A, Fernández M, Calzà L: Spinal motoneurone distress during experimental allergic encephalomyelitis. Neuropathol Appl Neurobiol 2004, 30:522-531.
  • [18]D'Intino G, Paradisi M, Fernández M, Giuliani A, Aloe L, Giardino L, Calzà L: Cognitive deficit associated with cholinergic and nerve growth factor down-regulation in experimental allergic encephalomyelitis in rats. Proc Natl Acad Sci USA 2005, 102:3070-3075.
  • [19]Caruso D, Pesaresi M, Maschi O, Giatti S, Garcia-Segura LM, Melcangi RC: Effect of short-and long-term gonadectomy on neuroactive steroid levels in the central and peripheral nervous system of male and female rats. J Neuroendocrinol 2010, 22:1137-1147.
  • [20]Giatti S, D'Intino G, Maschi O, Pesaresi M, Garcia-Segura LM, Calza L, Caruso D, Melcangi RC: Acute experimental autoimmune encephalomyelitis induces sex dimorphic changes in neuroactive steroid levels. Neurochem Int 2010, 56:118-127.
  • [21]MacKenzie-Graham A, Tinsley MR, Shah KP, Aguilar C, Strickland LV, Boline J, Martin M, Morales L, Shattuck DW, Jacobs RE, Voskuhl RR, Toga AW: Cerebellar cortical atrophy in experimental autoimmune encephalomyelitis. NeuroImage 2006, 32:1016-1023.
  • [22]Baracskay KL, Kidd GJ, Miller RH, Trapp BD: NG2-positive cells generate A2B5-positive oligodendrocyte precursor cells. Glia 2007, 55:1001-1010.
  • [23]Tzakos AG, Troganis A, Theodorou V, Tselios T, Svarnas C, Matsoukas J, Apostolopoulos V, Gerothanassis IP: Structure and function of the myelin proteins: current status and perspectives in relation to multiple sclerosis. Curr Med Chem 2005, 12:1569-1587.
  • [24]Greer JM, McCombe PA: Role of gender in multiple sclerosis: Clinical effects and potential molecular mechanisms. J Neuroimmunol 2011, 234:7-18.
  • [25]Kuhlmann T, Goldschmidt T, Antel J, Wegner C, Konig F, Metz I, Bruck W: Gender differences in the histopathology of MS? J Neurol Sci 2009, 286:86-91.
  • [26]Gold R, Linington C, Lassmann H: Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain 2006, 129:1953-1971.
  • [27]Fuller AC, Kang B, Kang HK, Yahikozowa H, Dal Canto MC, Kim BS: Gender bias in Theiler's virus-induced demyelinating dosease correlates with the level of antiviral immune responses. J Immunol 2005, 175:3955-3963.
  • [28]Reddy J, Waldner H, Zhang X, Illes Z, Wucherpfennig KW, Sobel RA, Kuchroo VK: Cutting edge: CD4+CD25+ regulatory T cells contribute to gender differences in susceptibility to experimental autoimmune encephalomyelitis. J Immunol 2005, 175:5591-5595.
  • [29]Staykova MA, Cowden W, Willenborg DO: Macrophages and nitric oxide as the possible cellular and molecular basis for strain and gender differences in susceptibility to autoimmune central nervous system inflammation. Immunol Cell Biol 2002, 80:188-97.
  • [30]De Maio A, Torres MB, Reeves RH: Genetic determinants influencing the response to injury, inflammation, and sepsis. Shock 2005, 23:11-17.
  • [31]Sinha S, Kaler LJ, Proctor TM, Teuscher C, Vandenbark AA, Offner H: IL-13-mediated gender difference in susceptibility to autoimmune encephalomyelitis. J Immunol 2008, 180:2679-2685.
  • [32]Gry M, Rimini R, Strömberg S, Asplund A, Pontén F, Uhlén M, Nilsson P: Correlations between RNA and protein expression profiles in 23 human cell lines. BMC Genomics 2009, 10:365-379. BioMed Central Full Text
  • [33]Greenbaum D, Colangelo C, Williams K, Gerstein M: Comparing protein abundance and mRNA expression levels on a genomic scale. Genome Biol 2003, 4:117-225. BioMed Central Full Text
  • [34]Zhao C, Dahlman-Wright , Gustafsson J-A: Estrogen receptor β: an overview and update. Nuclear Receptor Signaling 2008, 6:1-10.
  • [35]Cerghet M, Skoff RP, Bessert D, Zhang Z, Mullins C, Ghandour MS: Proliferation and death of oligodendrocytes and myelin proteins are differentially regulated in male and female rodents. J Neurosci 2006, 26:1439-1447.
  • [36]Cerghet M, Skoff RP, Swamydas M, Bessert D: Sexual dimorphism in the white matter of rodents. J Neurol Sci 2009, 286:76-80.
  • [37]Slavin DA, Bucher AE, Degano AL, Soria NW, Roth GA: Time course of biochemical and immunohistological alterations during experimental allergic encephalomyelitis. Neurochem Int 1996, 29:597-605.
  • [38]Li WW, Penderis J, Zhao C, Schumacher M, Franklin RJ: Females remyelinate more efficiently than males following demyelination in the aged but not young adult CNS. Exp Neurol 2006, 202:250-254.
  • [39]Taylor LC, Gilmore W, Matsushima G: SJL Mice Exposed to Cuprizone Intoxication Reveal Strain and Gender Pattern Differences in Demyelination. Brain Pathol 2009, 19:467-479.
  • [40]MacKenzie-Graham A, Tiwari-Woodruff SK, Sharma G, Aguilar C, Vo KT, Strickland LV, Morales L, Fubara B, Martin M, Jacobs RE, Johnson GA, Toga AW, Voskuhl RR: Purkinje cell loss in experimental autoimmune encephalomyelitis. NeuroImage 2009, 48:637-651.
  • [41]Sastry BR, Morishita W, Yip S, Shew T: GABA-ergic transmission in deep cerebellar nuclei. Prog Neurobiol 1997, 53:259-71.
  • [42]Aloe L, Calza L (Eds): NGF and related molecules in health and disease In Progress In Brain Research. Elsevier 2003., 146
  • [43]Takei Y, Laskey R: Interpreting crosstalk between TNF-alpha and NGF: potential implications for disease. Trends Mol Med 2008, 14:381-388.
  • [44]Schulte-Herbrüggen O, Braun A, Rochlitzer S, Jockers-Scherübl MC, Hellweg R: Neurotrophic factors--a tool for therapeutic strategies in neurological, neuropsychiatric and neuroimmunological diseases? Curr Med Chem 2007, 14:2318-2329.
  • [45]Bonini S, Rasi G, Bracci-Laudiero ML, Procoli A, Aloe L: Nerve growth factor: neurotrophin or cytokine? Int Arch Allergy Immunol 2003, 131:80-84.
  • [46]Villoslada P, Hauser SL, Bartke I, Unger J, Heald N, Rosenberg D, Cheung SW, Mobley WC, Fisher S, Genain CP: Human nerve growth factor protects common marmosets against autoimmune encephalomyelitis by switching the balance of T helper cell type 1 and 2 cytokines within the central nervous system. J Exp Med 2000, 191:1799-1806.
  • [47]Parvaneh Tafreshi A: Nerve growth factor prevents demyelination, cell death and progression of the disease in experimental allergic encephalomyelitis. Iran J Allergy Asthma Immunol 2006, 5:177-1781.
  • [48]Damarjian TG, Craner MJ, Black JA, Waxman SG: Upregulation and colocalization of p75 and Nav1.8 in Purkinje neurons in experimental autoimmune encephalomyelitis. Neurosci Lett 2004, 369:186-190.
  • [49]Florez-McClure ML, Linseman DA, Chu CT, Barker PA, Bouchard RJ, Le SS, Laessig TA, Heidenreich KA: The p75 neurotrophin receptor can induce autophagy and death of cerebellar Purkinje neurons. J Neurosci 2004, 24:4498-4509.
  • [50]Levi-Montalcini R, Angeletti PU: Hormonal control of the NGF content in the submaxillary glands of mice. Int Ser Monogr Oral Biol 1964, 3:129-141.
  • [51]Lipps BV: Age and sex-related difference in levels of nerve growth factor in organs of Balb/c mice. J Nat Toxins 2002, 11:387-391.
  • [52]Serrano T, Lorigados LC, Armenteros S: Nerve growth factor levels in normal human sera. Neuroreport 1996, 8:179-181.
  • [53]Lang UE, Gallinat J, Danker-Hopfe H, Bajbouj M, Hellweg R: Nerve growth factor serum concentrations in healthy human volunteers: physiological variance and stability. Neurosci Lett 2003, 344:13-16.
  • [54]Tsutsui K: Neurosteroids in the Purkinje cell: biosynthesis, mode of action and functional significance. Mol Neurobiol 2008, 37:116-125.
  • [55]Bimonte-Nelson HA, Granholm AC, Nelson ME, Moore AB: Patterns of neurotrophin protein levels in male and female Fischer 344 rats from adulthood to senescence: how young is "young" and how old is "old"? Exp Aging Res 2008, 34:13-26.
  • [56]Sajdel-Sulkowska EM, Xu M, Koibuchi N: Cerebellar brain-derived neurotrophic factor, nerve growth factor, and neurotrophin-3 expression in male and female rats is differentially affected by hypergravity exposure during discrete developmental periods. Cerebellum 2009, 8:454-462.
  • [57]Acs P, Kipp M, Norkute A, Johann S, Clarner T, Braun A, Berente Z, Komoly S, Beyer C: 17beta-estradiol and progesterone prevent cuprizone provoked demyelination of corpus callosum in male mice. Glia 2009, 57:807-814.
  • [58]Garay L, Gonzalez Deniselle MC, Gierman L, Meyer M, Lima A, Roig P, De Nicola AF: Steroid protection in the experimental autoimmune encephalomyelitis model of multiple sclerosis. Neuroimmunomodulation 2008, 15:76-83.
  • [59]Hickey WF, Cohen JA, Burns JB: A quantitative immunohistochemical comparison of actively versus adoptively induced experimental allergic encephalomyelitis in the Lewis rat. Cell Immunol 1987, 109:272-281.
  • [60]Zang Y, Hong J, Robinson R, Li S, Rivera VM, Zhang JZ: Immune regulatory properties and interactions of copolymer-I and beta-interferon 1a in multiple sclerosis. J Neuroimmunol 2003, 137:144-153.
  • [61]Cabrelle A, Dell'Aica I, Melchiori L, Carraro S, Brunetta E, Niero R, Scquizzato E, D'Intino G, Calzà L, Garbisa S, Agostini C: Hyperforin down-regulates effector function of activated T lymphocytes and shows efficacy against Th1-triggered CNS inflammatory-demyelinating disease. J Leukoc Biol 2008, 83:212-219.
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