Review
Neuroprotective effects of estrogens and androgens in CNS inflammation and neurodegeneration

https://doi.org/10.1016/j.yfrne.2011.12.001Get rights and content

Abstract

Multiple sclerosis (MS) is a disease characterized by inflammation and demyelination. Currently, the cause of MS is unknown. Experimental autoimmune encephalomyelitis (EAE) is the most common mouse model of MS. Treatments with the sex hormones, estrogens and androgens, are capable of offering disease protection during EAE and are currently being used in clinical trials of MS. Beyond endogenous estrogens and androgens, treatments with selective estrogen receptor modulators (SERMs) for estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) are also capable of providing disease protection. This protection includes, but is not limited to, prevention of clinical disease, reduction of CNS inflammation, protection against demyelination, and protection against axonal loss. In EAE, current efforts are focused on using conditional cell specific knockouts of sex hormone receptors to identify the in vivo targets of these estrogens and androgens as well as downstream molecules responsible for disease protection.

Highlights

► Effects of estrogens and androgens in neuroinflammation and neurodegeneration. ► Effects of estrogens on receptors in the immune and central nervous systems. ► Mechanisms of androgens in the immune and central nervous systems.

Section snippets

Multiple sclerosis (MS)

Multiple sclerosis (MS) is an autoimmune disease characterized by inflammation and demyelination in the CNS from unknown causes [77], [143]. Clinical symptoms usually begin to occur in young adults. Nearly 80% of patients develop a relapse-remitting (RR-MS) course of disease, which can eventually become a more chronic secondary progressive (SP-MS) form after many years. About 15% of patients exhibit disease progression from the start called primary progressive MS (PP-MS) [21]. With myelin

Experimental autoimmune encephalomyelitis (EAE)

EAE is the most common mouse model of MS [24], [49]. It is a CD4+ Th1/Th17 mediated autoimmune disease in which perivascular T-cells, followed by macrophages, enter the CNS, leading to lesioned areas of demyelination and axonal loss [54]. This demyelination and axonal loss correlates with motor deficits in standard EAE clinical scores which primarily assess walking ability [152]. EAE has strain specific effects. In the SJL model, the disease is relapse-remitting, similar to that of RR-MS. In

Gender differences in MS and EAE

There are large gender differences in the prevalence of human autoimmune diseases. Most of these gender differences entail a higher incidence in females as compared to males: systemic lupus erythematosis (SLE), rheumatoid arthritis (RA), Graves disease, and multiple sclerosis (MS) [9], [37], [73], [78], [84], [98], [103], [125]. While the reasons for these gender differences are still unknown, possible explanations include differences in sex hormones or sex chromosomes. Specifically,

Pregnancy in MS and EAE

In MS, during the last trimester of pregnancy, circulating levels of estrogens are at their highest levels correlating with a reduction in relapse rates among women with MS. Post-partum levels of estrogens drop precipitously and correlate with a significant increase in relapse rates during the 3–6 months after delivery [22]. While controversial, some reports have demonstrated that pregnancy could offer long term protection to women with MS [121], [146]. MS patients who had one or more

Estrogens and neuroprotection

Estrogens are made up of three endogenous biologically different compounds: estrone, estradiol, and estriol [44], [157]. Furthermore, exogenous selective estrogen receptor modulators (SERMs) are capable of activating either estrogen receptor alpha (ERα) or estrogen receptor beta (ERβ) on select tissues [68]. Testosterone and dihydrotestosterone (DHT) are able to act on the androgen receptor (AR). However, DHT is also able to act indirectly through ERβ [63], [75]. It is always difficult to

Estradiol and EAE

Treatment with a wide dosage range of estradiol is able to ameliorate EAE during both the induction and effector phases of both active and adoptive EAE. This amelioration can occur in both sexes of mice, as well as multiple mouse strains with EAE [7], [35], [56], [79], [95], [135], [148]. The protective effects of estradiol in EAE include a decrease in inflammatory cells in the CNS as well as protection against demyelination [7], [99], [135]. With respect to inflammation, estradiol treatment

Estrogen receptor alpha ligand and EAE

Given that estradiol is able to act both on ERα and ERβ, a host of research has now been focused on which receptor might be responsible for the protective effects of estrogens during EAE. While data have shown that this effect is mediated through ERα [66], [67], [111], other data have shown that ERβ can also offer protection during EAE [23], [33].

Originally it was shown that EAE was less severe in B10.PL male mice with a global knockout of the ERα gene, termed Esr1 (−/−), as compared to WT,

Estrogen receptor beta ligand and EAE

Data have shown that the global knock out of the ERβ gene does not alter EAE disease severity compared to WT mice, suggesting endogenous estrogens do not act through ERβ to offer disease protection [112], [111]. However, exogenous treatment with an ERβ ligand has been shown to ameliorate EAE in the C57BL/6 strain, but not in the SJL strain [35], [141]. This difference in clinical protection could be due to strain differences or due to differences in the timing of the effect of treatment on

GPR30 and EAE

While ERα and ERβ are classically viewed as nuclear receptors, G protein-coupled receptor 30 (GPR30) is expressed on cellular membranes of both human and mouse cells [76], [91], [115]. Recent evidence suggested that estradiol binding to the GPR30 may contribute to some of the protective effects of estradiol treatment in EAE [10], [151], [154]. While not lost completely, the magnitude of the estradiol mediated protection during disease, specifically inflammation and demyelination, was reduced in

Estriol treatment in EAE

Estriol can bind to both ERα and ERβ, but has a preference for binding ERβ over ERα [63]. Studies have shown that doses of estriol, consistent with physiological murine pregnancy levels, can ameliorate EAE in female mice [7], [59]. Estriol treatment was protective in multiple strains of mice including SJL, C57/B6, and B10.Pl. Furthermore, both female and male of SJL and C57BL/6 mice respond to estriol treatment, demonstrating that estriol treatment was not female specific [7], [51], [56], [59],

Estriol treatment in MS

A pilot clinical trial of estriol was conducted in females with relapsing-remitting MS (RRMS). In the study, patients were observed for 6 months, then treated with pregnancy levels of oral estriol (8 mg per day) for the following 6 months. After 6 months of treatment the patients were taken off estriol for 6 months and then placed back on treatment for another 4 months. During treatment, RRMS patients exhibited a significant decrease in the number of gadolinium enhancing lesions on brain MRI as

Tamoxifen, raloxifene, and genistein in EAE

Given the possibility of estrogen treatment for MS, studies have explored the use of the SERMs, tamoxifen and raloxifene, and the phytoestrogen, genistein, in EAE [8], [28], [35]. At a low dosage, both tamoxifen and raloxifene have been shown to reduce the clinical severity of EAE compared to placebo treatment. However, when both estradiol and tamoxifen were used at an equal dose (2.5 mg), estradiol was able to abrogate disease entirely, while tamoxifen only partially reduced disease severity

Testosterone, 5αDHT, and EAE

SJL mice show a sex bias similar to humans with MS characterized by greater susceptibility in females as compared to males [26]. It appears that this sex bias is due at least in part to a protective effect of androgens. Castrated SJL male mice show a worsening of clinical disease as well as greater demyelination and inflammation in the spinal cord when compared to sham operated males [5], [105]. Interestingly, C57BL/6 mice show neither a sex difference in EAE nor an effect from male castration,

Testosterone and MS

Given that males are less susceptible than females to MS, as well as the animal data demonstrating testosterone’s beneficial effect in EAE, a preliminary study was performed in which men with MS were treated with testosterone. Ten men with RRMS were given a daily treatment of 10 g of a gel containing 100 mg of testosterone for 12 months. This was preceded by a 6-month observation period. Testosterone treatment resulted in a significant slowing of the rate of brain atrophy as measured by monthly

Conclusion

Currently, MS treatments have a primary focus on reducing inflammation. Given that MS is both an inflammatory and neurodegenerative disease, there is a need for neuroprotective treatments if one aims to fully halt the disease [86]. Estrogens and androgens both have the potential to play neuroprotective roles in the treatment of MS. EAE studies with various estrogen and androgen treatments led to clinical disease protection, as well as protection from CNS inflammation, axonal loss, as well as

Acknowledgments

Rhonda R. Voskuhl, is supported by the National Institutes of Health (RO1 NS051591, R21 NS071210, and K24NS052117) and the National Multiple Sclerosis Society (CA 1028, RG 4033, and 4364) as well as funding from the Skirball Foundation, the Conrad Hilton Foundation and the Sherak Family Foundation. Rory Spence is supported by an NIH training grant from the UCLA Laboratory of Neuroendocrinology.

References (157)

  • A.L. Croxford et al.

    Mouse models for multiple sclerosis: historical facts and future implications

    Biochim. Biophys. Acta

    (2011)
  • L. Danel et al.

    Distribution of androgen and estrogen receptors among lymphoid and haemopoietic cell lines

    Leuk. Res.

    (1985)
  • M.L. De Paula et al.

    Genistein down-modulates pro-inflammatory cytokines and reverses clinical signs of experimental autoimmune encephalomyelitis

    Int. Immunopharmacol.

    (2008)
  • K.M. Dhandapani et al.

    Role of astrocytes in estrogen-mediated neuroprotection

    Exp. Gerontol.

    (2007)
  • P.D. Drew et al.

    Female sex steroids: effects upon microglial cell activation

    J. Neuroimmunol.

    (2000)
  • M. El-Etr et al.

    Hormonal influences in multiple sclerosis: new therapeutic benefits for steroids

    Maturitas

    (2011)
  • D. Fairweather et al.

    Sex differences in autoimmune disease from a pathological perspective

    Am. J. Pathol.

    (2008)
  • A. Gabory et al.

    Sexual dimorphism in environmental epigenetic programming

    Mol. Cell. Endocrinol.

    (2009)
  • L.M. Garcia-Segura et al.

    Neuroprotection by estradiol

    Prog. Neurobiol.

    (2001)
  • N.N. Gatson et al.

    Induction of pregnancy during established EAE halts progression of CNS autoimmune injury via pregnancy-specific serum factors

    J. Neuroimmunol.

    (2011)
  • S.M. Gold et al.

    Estrogen and testosterone therapies in multiple sclerosis

    Prog. Brain Res.

    (2009)
  • J. Herz et al.

    Neurodegeneration in autoimmune CNS inflammation

    Exp. Neurol.

    (2010)
  • L. Jansson et al.

    Estrogen induces a potent suppression of experimental autoimmune encephalomyelitis and collagen-induced arthritis in mice

    J. Neuroimmunol.

    (1994)
  • G.G. Kuiper et al.

    The novel estrogen receptor-beta subtype: potential role in the cell- and promoter-specific actions of estrogens and anti-estrogens

    FEBS Lett.

    (1997)
  • H. Lassmann et al.

    Immunopathology of multiple sclerosis: report on an international meeting held at the Institute of Neurology of the University of Vienna

    J. Neuroimmunol.

    (1998)
  • J.S. Lewis et al.

    Selective estrogen receptor modulators (SERMs): mechanisms of anticarcinogenesis and drug resistance

    Mutat. Res.

    (2005)
  • M.D. Lockshin

    Sex differences in autoimmune disease

    Orthop. Clin. North Am.

    (2006)
  • E. Mix et al.

    Animal models of multiple sclerosis – potentials and limitations

    Prog. Neurobiol.

    (2010)
  • T.C. Ngun et al.

    The genetics of sex differences in brain and behavior

    Front. Neuroendocrinol.

    (2011)
  • J. Nilsen

    Estradiol and neurodegenerative oxidative stress

    Front. Neuroendocrinol.

    (2008)
  • B. Almolda et al.

    Antigen presentation in EAE: role of microglia, macrophages and dendritic cells

    Front. Biosci.

    (2011)
  • B.F. Bebo et al.

    Androgens alter the cytokine profile and reduce encephalitogenicity of myelin-reactive T cells

    J. Immunol.

    (1999)
  • B.F. Bebo et al.

    Low-dose estrogen therapy ameliorates experimental autoimmune encephalomyelitis in two different inbred mouse strains

    J. Immunol.

    (2001)
  • B.F. Bebo et al.

    Treatment with selective estrogen receptor modulators regulates myelin specific T-cells and suppresses experimental autoimmune encephalomyelitis

    Glia

    (2009)
  • S. Bodhankar et al.

    Estrogen-induced protection against experimental autoimmune encephalomyelitis is abrogated in the absence of B cells

    Eur. J. Immunol.

    (2011)
  • T.A. Bogush et al.

    Estrogen receptor expression in tumors different from breast cancer

    Antibiot. Khimioter.

    (2009)
  • R. Brambilla et al.

    Inhibition of astroglial nuclear factor kappaB reduces inflammation and improves functional recovery after spinal cord injury

    J. Exp. Med.

    (2005)
  • T. Brenner et al.

    Effect of experimental autoimmune encephalomyelitis on pregnancy: studies in rabbits and rats

    Isr. J. Med. Sci.

    (1991)
  • C. Camprubí et al.

    Does genomic imprinting play a role in autoimmunity?

    Adv. Exp. Med. Biol.

    (2011)
  • D. Caruso et al.

    Sex-dimorphic changes in neuroactive steroid levels after chronic experimental autoimmune encephalomyelitis

    J. Neurochem.

    (2010)
  • J.J. Cho et al.

    The role of the estrogen in neuroprotection: implications for neurodegenerative diseases

    Neuro Endocrinol. Lett.

    (2003)
  • C. Confavreux et al.

    Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group

    N. Engl. J. Med.

    (1998)
  • D.K. Crawford et al.

    Oestrogen receptor beta ligand: a novel treatment to enhance endogenous functional remyelination

    Brain

    (2010)
  • L.J. Currie et al.

    Postmenopausal estrogen use affects risk for Parkinson disease

    Arch. Neurol.

    (2004)
  • M. Dalal et al.

    Testosterone therapy ameliorates experimental autoimmune encephalomyelitis and induces a T helper 2 bias in the autoantigen-specific T lymphocyte response

    J. Immunol.

    (1997)
  • K.M. Dhandapani et al.

    Astrocyte-derived transforming growth factor-{beta} mediates the neuroprotective effects of 17{beta}-estradiol: involvement of nonclassical genomic signaling pathways

    Endocrinology

    (2005)
  • S. Du et al.

    Additive effects of combination treatment with anti-inflammatory and neuroprotective agents in experimental autoimmune encephalomyelitis

    J. Neuroimmunol.

    (2009)
  • S. Du et al.

    Estrogen receptor-β ligand treatment modulates dendritic cells in the target organ during autoimmune demyelinating disease

    Eur. J. Immunol.

    (2011)
  • M.M. Elloso et al.

    Suppression of experimental autoimmune encephalomyelitis using estrogen receptor-selective ligands

    J. Endocrinol.

    (2005)
  • S. Evron et al.

    Suppressive effect of pregnancy on the development of experimental allergic encephalomyelitis in rabbits

    Am. J. Reprod. Immunol.

    (1984)
  • Cited by (0)

    View full text