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Modifications of Neuroactive Steroid Levels in an Experimental Model of Nigrostriatal Degeneration: Potential Relevance to the Pathophysiology of Parkinson’s Disease

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Abstract

An important link between neuroactive steroids and neurodegenerative disorders has recently been suggested. Indeed, in several neurodegenerative experimental models the levels of neuroactive steroids are affected and their administration exerts neuroprotective effects. However, scarce information has so far been obtained on the neuroactive steroid levels present in Parkinson’s disease. To this aim, using an experimental model of loss of nigrostriatal dopaminergic neurons obtained by stereotaxic injection of the neurotoxin 6-hydroxydopamine (6-OHDA), we evaluated by liquid chromatography tandem mass spectrometry the levels of several neuroactive steroids in the striatum and cerebral cortex of 6-OHDA-lesioned male rats. Among the neuroactive steroid levels assessed (i.e., pregnenolone, progesterone, dihydroprogesterone, tetrahydroprogesterone, isopregnanolone, testosterone, dihydrotestosterone, 3α-diol, dehydroepiandrosterone, 17α-estradiol, and 17β-estradiol), we observed a significant decrease of pregnenolone in the striatum. A similar effect was also observed on the levels of dihydroprogesterone present in this cerebral area and also in the cerebral cortex. Interestingly, an increase of isopregnanolone also occurred in the striatum and in the cerebral cortex. Altogether, these results suggesting that progesterone metabolism is affected in an experimental model of Parkinson’s disease further highlight the link between neuroactive steroids and the neurodegenerative diseases.

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References

  • Backstrom T, Wahlstrom G, Wahlstrom K, Zhu D, Wang MD (2005) Isoallopregnanolone; an antagonist to the anaesthetic effect of allopregnanolone in male rats. Eur J Pharmacol 512:15–21

    Article  PubMed  Google Scholar 

  • Belelli D, Lambert JJ (2005) Neurosteroids: endogenous regulators of the GABA(A) receptor. Nat Rev Neurosci 6:565–575

    Article  PubMed  CAS  Google Scholar 

  • Benedetti MD, Maraganore DM, Bower JH et al (2001) Hysterectomy, menopause, and estrogen use preceding Parkinson's disease: an exploratory case-control study. Mov Disord 16:830–837

    Article  PubMed  CAS  Google Scholar 

  • Bixo M, Andersson A, Winblad B, Purdy RH, Backstrom T (1997) Progesterone, 5alpha-pregnane-3,20-dione and 3alpha-hydroxy-5alpha-pregnane-20-one in specific regions of the human female brain in different endocrine states. Brain Res 764:173–178

    Article  PubMed  CAS  Google Scholar 

  • Blandini F, Nappi G, Tassorelli C, Martignoni E (2000) Functional changes of the basal ganglia circuitry in Parkinson's disease. Prog Neurobiol 62:63–88

    Article  PubMed  CAS  Google Scholar 

  • Blandini F, Armentero MT, Martignoni E (2008) The 6-hydroxydopamine model: news from the past. Parkinsonism Relat Disord 14(Suppl 2):S124–S129

    Article  PubMed  Google Scholar 

  • Bourque M, Dluzen DE, Di Paolo T (2009) Neuroprotective actions of sex steroids in Parkinson's disease. Front Neuroendocrinol 30:142–157

    Article  PubMed  CAS  Google Scholar 

  • Callier S, Morissette M, Grandbois M, Di Paolo T (2000) Stereospecific prevention by 17beta-estradiol of MPTP-induced dopamine depletion in mice. Synapse 37:245–251

    Article  PubMed  CAS  Google Scholar 

  • Callier S, Morissette M, Grandbois M, Pelaprat D, Di Paolo T (2001) Neuroprotective properties of 17beta-estradiol, progesterone, and raloxifene in MPTP C57Bl/6 mice. Synapse 41:131–138

    Article  PubMed  CAS  Google Scholar 

  • Caruso D, Scurati S, Maschi O et al (2008a) Evaluation of neuroactive steroid levels by liquid chromatography-tandem mass spectrometry in central and peripheral nervous system: effect of diabetes. Neurochem Int 52:560–568

    Article  PubMed  CAS  Google Scholar 

  • Caruso D, Scurati S, Roglio I, Nobbio L, Schenone A, Melcangi RC (2008b) Neuroactive steroid levels in a transgenic rat model of CMT1A neuropathy. J Mol Neurosci 34:249–253

    Article  PubMed  CAS  Google Scholar 

  • Caruso D, D'Intino G, Giatti S et al (2010) Sex-dimorphic changes in neuroactive steroid levels after chronic experimental autoimmune encephalomyelitis. J Neurochem 114:921–932

    Article  PubMed  CAS  Google Scholar 

  • Ciriza I, Azcoitia I, Garcia-Segura LM (2004) Reduced progesterone metabolites protect rat hippocampal neurones from kainic acid excitotoxicity in vivo. J Neuroendocrinol 16:58–63

    Article  PubMed  CAS  Google Scholar 

  • D'Astous M, Morissette M, Tanguay B, Callier S, Di Paolo T (2003) Dehydroepiandrosterone (DHEA) such as 17beta-estradiol prevents MPTP-induced dopamine depletion in mice. Synapse 47:10–14

    Article  PubMed  Google Scholar 

  • di Michele F, Longone P, Romeo E et al (2003) Decreased plasma and cerebrospinal fluid content of neuroactive steroids in Parkinson's disease. Neurol Sci 24:172–173

    Article  PubMed  Google Scholar 

  • Gee KW, Bolger MB, Brinton RE, Coirini H, McEwen BS (1988) Steroid modulation of the chloride ionophore in rat brain: structure-activity requirements, regional dependence and mechanism of action. J Pharmacol Exp Ther 246:803–812

    PubMed  CAS  Google Scholar 

  • Giatti S, D'Intino G, Maschi O et al (2010) Acute experimental autoimmune encephalomyelitis induces sex dimorphic changes in neuroactive steroid levels. Neurochem Int 56:118–127

    Article  PubMed  CAS  Google Scholar 

  • Gillies GE, Murray HE, Dexter D, McArthur S (2004) Sex dimorphisms in the neuroprotective effects of estrogen in an animal model of Parkinson's disease. Pharmacol Biochem Behav 78:513–522

    Article  PubMed  CAS  Google Scholar 

  • Grandbois M, Morissette M, Callier S, Di Paolo T (2000) Ovarian steroids and raloxifene prevent MPTP-induced dopamine depletion in mice. Neuroreport 11:343–346

    Article  PubMed  CAS  Google Scholar 

  • Huang XF, Luu-The V (2000) Molecular characterization of a first human 3(alpha→beta)-hydroxysteroid epimerase. J Biol Chem 275:29452–29457

    Article  PubMed  CAS  Google Scholar 

  • Luchetti S, di Michele F, Romeo E et al (2006) Comparative non-radioactive RT-PCR assay: an approach to study the neurosteroids biosynthetic pathway in humans. J Neurosci Methods 153:290–298

    Article  PubMed  CAS  Google Scholar 

  • Luchetti S, Bossers K, Frajese GV, Swaab DF (2010) Neurosteroid biosynthetic pathway changes in substantia nigra and caudate nucleus in Parkinson's disease. Brain Pathol 20:945–951

    PubMed  Google Scholar 

  • Lundgren P, Stromberg J, Backstrom T, Wang M (2003) Allopregnanolone-stimulated GABA-mediated chloride ion flux is inhibited by 3beta-hydroxy-5alpha-pregnan-20-one (isoallopregnanolone). Brain Res 982:45–53

    Article  PubMed  CAS  Google Scholar 

  • Marsden CD, Olanow CW (1998) The causes of Parkinson's disease are being unraveled and rational neuroprotective therapy is close to reality. Ann Neurol 44:S189–S196

    PubMed  CAS  Google Scholar 

  • Melcangi RC, Garcia-Segura LM (2010) Sex-specific therapeutic strategies based on neuroactive steroids: In search for innovative tools for neuroprotection. Horm Behav 57:2–11

    Article  Google Scholar 

  • Melcangi RC, Garcia-Segura LM, Mensah-Nyagan AG (2008) Neuroactive steroids: state of the art and new perspectives. Cell Mol Life Sci 65:777–797

    Article  PubMed  CAS  Google Scholar 

  • Morissette M, Al SS, Callier S, Di Paolo T (2008) Estrogen and SERM neuroprotection in animal models of Parkinson's disease. Mol Cell Endocrinol 290:60–69

    Article  PubMed  CAS  Google Scholar 

  • Nuwayhid SJ, Werling LL (2003) Steroids modulate N-methyl-d-aspartate-stimulated [3H] dopamine release from rat striatum via sigma receptors. J Pharmacol Exp Ther 306:934–940

    Article  PubMed  CAS  Google Scholar 

  • Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates, 4th edn. Academic, San Diego

    Google Scholar 

  • Pesaresi M, Maschi O, Giatti S, Garcia-Segura LM, Caruso D, Melcangi RC (2010) Sex differences in neuroactive steroid levels in the nervous system of diabetic and non-diabetic rats. Horm Behav 57:46–55

    Article  PubMed  CAS  Google Scholar 

  • Quinn NP, Marsden CD (1986) Menstrual-related fluctuations in Parkinson's disease. Mov Disord 1:85–87

    Article  PubMed  CAS  Google Scholar 

  • Ramirez AD, Liu X, Menniti FS (2003) Repeated estradiol treatment prevents MPTP-induced dopamine depletion in male mice. Neuroendocrinology 77:223–231

    Article  PubMed  CAS  Google Scholar 

  • Sadri-Vakili G, Janis GC, Pierce RC, Gibbs TT, Farb DH (2008) Nanomolar concentrations of pregnenolone sulfate enhance striatal dopamine overflow in vivo. J Pharmacol Exp Ther 327:840–845

    Article  PubMed  CAS  Google Scholar 

  • Saunders-Pullman R, Gordon-Elliott J, Parides M, Fahn S, Saunders HR, Bressman S (1999) The effect of estrogen replacement on early Parkinson's disease. Neurology 52:1417–1421

    PubMed  CAS  Google Scholar 

  • Schumacher M, Guennoun R, Ghoumari A et al (2007) Novel perspectives for progesterone in hormone replacement therapy, with special reference to the nervous system. Endocr Rev 28:387–439

    Article  PubMed  CAS  Google Scholar 

  • Schumacher M, Sitruk-Ware R, De Nicola AF (2008) Progesterone and progestins: neuroprotection and myelin repair. Curr Opin Pharmacol 8:740–746

    Article  PubMed  CAS  Google Scholar 

  • Strijks E, Kremer JA, Horstink MW (1999) Effects of female sex steroids on Parkinson's disease in postmenopausal women. Clin Neuropharmacol 22:93–97

    Article  PubMed  CAS  Google Scholar 

  • Tsang KL, Ho SL, Lo SK (2000) Estrogen improves motor disability in parkinsonian postmenopausal women with motor fluctuations. Neurology 54:2292–2298

    PubMed  CAS  Google Scholar 

  • Vegeto E, Benedusi V, Maggi A (2008) Estrogen anti-inflammatory activity in brain: a therapeutic opportunity for menopause and neurodegenerative diseases. Front Neuroendocrinol 29:507–519

    Article  PubMed  CAS  Google Scholar 

  • Wang M, He Y, Eisenman LN et al (2002) 3beta -hydroxypregnane steroids are pregnenolone sulfate-like GABA(A) receptor antagonists. J Neurosci 22:3366–3375

    PubMed  CAS  Google Scholar 

  • Whittaker MT, Gibbs TT, Farb DH (2008) Pregnenolone sulfate induces NMDA receptor dependent release of dopamine from synaptic terminals in the striatum. J Neurochem 107:510–521

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was conducted in the frame of a cooperation agreement between the CEND and the IRCCS Mondino Foundation, supported by a grant of the Italian Ministry of Health (Ricerca Corrente 2009).

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Authors and Affiliations

  1. Department of Endocrinology, Pathophysiology and Applied Biology-Center of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy

    Roberto Cosimo Melcangi

  2. Department of Pharmacological Sciences, Università degli Studi di Milano, Milan, Italy

    Donatella Caruso & Federico Abbiati

  3. Laboratory of Functional Neurochemistry, Interdepartmental Research Center for Parkinson’s Disease, IRCCS National Institute of Neurology C. Mondino, Pavia, Italy

    Giovanna Levandis, Marie-Therese Armentero & Fabio Blandini

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  1. Roberto Cosimo Melcangi
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  2. Donatella Caruso
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  3. Giovanna Levandis
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  4. Federico Abbiati
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  5. Marie-Therese Armentero
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  6. Fabio Blandini
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Correspondence to Roberto Cosimo Melcangi.

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Melcangi, R.C., Caruso, D., Levandis, G. et al. Modifications of Neuroactive Steroid Levels in an Experimental Model of Nigrostriatal Degeneration: Potential Relevance to the Pathophysiology of Parkinson’s Disease. J Mol Neurosci 46, 177–183 (2012). https://doi.org/10.1007/s12031-011-9570-y

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  • DOI: https://doi.org/10.1007/s12031-011-9570-y

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