title: Neurosteroid biosynthetic pathway changes in substantia nigra and caudate nucleus in Parkinson's disease.
abstract: There is emerging evidence from animal studies for a neuroprotective role of sex steroids in neurodegenerative diseases, but studies in human brain are lacking. We have carried out an extensive study of the neurosteroid biosynthetic pathways in substantia nigra (SN), caudate nucleus (CN) and putamen (PU) of 7 Parkinson's disease (PD) patients and 7 matched controls. The mRNA levels of 37 genes including neurosteroid biosynthetic enzymes, hormone receptors and the neurosteroid-modulated gamma-amino-butyric acid -A (GABA-A) receptor subunits were analyzed by quantitative PCR (qPCR). In the SN, we found downregulation of 5alpha-reductase type 1 (5alpha-R1), sulfotransferase 2B1 (SULT2B1) and some GABA-A receptor subunits (alpha4, beta1) while in the CN, upregulation of 3alpha-hydroxysteroid dehydrogenase type 3 (3alpha-HSD3) and alpha4 GABA-A receptor subunit (22-fold) was observed. No significant differences were found in the PU. These data imply an involvement of pregnane steroids and changes in GABAergic neurotransmission in the neurodegenerative process and suggest that neurosteroids may deserve further investigation as potential therapeutic agents in PD.
authors.affiliation: Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands. s.luchetti@nin.knaw.nl
authors.forename: Sabina
authors.initials: S
authors.lastname: Luchetti
authors.forename: Koen
authors.initials: K
authors.lastname: Bossers
authors.forename: Giovanni Vanni
authors.initials: GV
authors.lastname: Frajese
authors.forename: Dick F
authors.initials: DF
authors.lastname: Swaab
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002421:Caudate Nucleus / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D008297:Male; D009434:Neural Pathways / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010300:Parkinson Disease / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D018079:Receptors, GABA / Q000235:genetics / Q000378:metabolism; D013378:Substantia Nigra / Q000378:metabolism*; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D018377:Neurotransmitter Agents; D012333:RNA, Messenger; D018079:Receptors, GABA; D015238:Sulfotransferases; C433248:SULT2B1 protein, human
references.citation: Brain Res. 1997 Aug 1;764(1-2):173-8
references.pmid: 9295207
references.citation: Brain Res. 1987 Feb 24;404(1-2):355-60
references.pmid: 3032339
references.citation: Brain Res. 1996 Nov 25;741(1-2):142-52
references.pmid: 9001716
references.citation: Mov Disord. 2003 Mar;18(3):241-53
references.pmid: 12621627
references.citation: Brain Pathol. 2009 Jan;19(1):91-107
references.pmid: 18462474
references.citation: Eur J Pharmacol. 1999 Jun 30;375(1-3):225-35
references.pmid: 10443579
references.citation: Restor Neurol Neurosci. 2004;22(1):19-31
references.pmid: 15096691
references.citation: Neuroendocrinology. 2006;84(4):275-9
references.pmid: 17124377
references.citation: Neurosci Lett. 2002 Aug 2;328(1):33-6
references.pmid: 12123853
references.citation: Pharmacol Biochem Behav. 2009 Jun;92(4):608-13
references.pmid: 19268499
references.citation: Genome Biol. 2002 Jun 18;3(7):RESEARCH0034
references.pmid: 12184808
references.citation: Ann Neurol. 1986 Jul;20(1):26-31
references.pmid: 2874765
references.citation: Neuroendocrinology. 2003 Apr;77(4):223-31
references.pmid: 12766322
references.citation: Synapse. 2000 Sep 15;37(4):245-51
references.pmid: 10891861
references.citation: Mol Cell Endocrinol. 2008 Aug 13;290(1-2):60-9
references.pmid: 18515001
references.citation: J Neurosci. 2009 Feb 11;29(6):1755-65
references.pmid: 19211882
references.citation: Neurosci Lett. 1988 Nov 22;94(1-2):182-6
references.pmid: 3241667
references.citation: Science. 1986 May 23;232(4753):1004-7
references.pmid: 2422758
references.citation: J Neuroendocrinol. 2004 Jan;16(1):58-63
references.pmid: 14962077
references.citation: Int Rev Neurobiol. 2001;46:1-32
references.pmid: 11599297
references.citation: Eur J Neurosci. 2002 Aug;16(3):445-53
references.pmid: 12193187
references.citation: Mol Pharmacol. 2000 Jun;57(6):1262-70
references.pmid: 10825399
references.citation: Pharmacol Ther. 2007 Oct;116(1):77-106
references.pmid: 17659348
references.citation: Nature. 1998 Apr 30;392(6679):926-30
references.pmid: 9582073
references.citation: Neurol Sci. 2003 Oct;24(3):172-3
references.pmid: 14598072
references.citation: Front Neuroendocrinol. 2000 Jan;21(1):1-56
references.pmid: 10662535
references.citation: Neurobiol Aging. 1995 May-Jun;16(3):271-8; discussion 278-84
references.pmid: 7566337
references.citation: Pharmacol Biochem Behav. 2006 Aug;84(4):545-54
references.pmid: 16914187
references.citation: Neurobiol Aging. 2003 Mar-Apr;24(2):197-211
references.pmid: 12498954
references.citation: J Neurosci Methods. 2006 Jun 15;153(2):290-8
references.pmid: 16378642
references.citation: J Mol Neurosci. 2008 Mar;34(3):193-200
references.pmid: 18219447
references.citation: Brain Res. 1990 Oct 8;529(1-2):57-78
references.pmid: 1704287
references.citation: Int Rev Neurobiol. 2001;46:207-41
references.pmid: 11599301
references.citation: J Neurochem. 1983 Apr;40(4):1120-3
references.pmid: 6131932
references.citation: Mol Pharmacol. 1991 Sep;40(3):333-6
references.pmid: 1654510
references.citation: Eur J Neurosci. 2005 May;21(9):2329-35
references.pmid: 15932592
references.citation: Front Neuroendocrinol. 2009 Aug;30(3):259-301
references.pmid: 19505496
references.citation: Front Neuroendocrinol. 2009 Jul;30(2):142-57
references.pmid: 19410597
references.citation: Neurotherapeutics. 2007 Jan;4(1):102-5
references.pmid: 17199022
references.citation: Nucleic Acids Res. 2001 May 1;29(9):e45
references.pmid: 11328886
references.citation: Neuroscience. 2004;123(2):349-59
references.pmid: 14698743
references.citation: Mol Aspects Med. 2006 Apr-Jun;27(2-3):126-39
references.pmid: 16469371
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):3202-7
references.pmid: 14973190
references.citation: J Neurotrauma. 2005 Jan;22(1):106-18
references.pmid: 15665606
references.citation: J Neurosci. 2005 May 11;25(19):4706-18
references.pmid: 15888646
references.citation: Synapse. 2001 Aug;41(2):131-8
references.pmid: 11400179
references.citation: Cell Mol Life Sci. 2008 Mar;65(5):777-97
references.pmid: 18038216
references.citation: J Neurosci. 2004 Nov 17;24(46):10318-25
references.pmid: 15548645
references.citation: Neuroscience. 2005;131(2):397-405
references.pmid: 15708482
references.citation: Biol Psychiatry. 2004 Feb 15;55(4):346-52
references.pmid: 14960286
references.citation: Proc Natl Acad Sci U S A. 1998 Feb 17;95(4):1852-7
references.pmid: 9465106
references.citation: J Pharmacol Exp Ther. 1997 Mar;280(3):1284-95
references.pmid: 9067315
references.citation: J Neurochem. 2003 Aug;86(4):848-59
references.pmid: 12887683
references.citation: Synapse. 2003 Jan;47(1):10-4
references.pmid: 12422368
references.citation: Eur J Endocrinol. 2001 Dec;145(6):669-79
references.pmid: 11720889
references.citation: Brain Res Rev. 2008 Mar;57(2):410-20
references.pmid: 17629950
references.citation: Epilepsia. 2007 Oct;48(10):1870-4
references.pmid: 17634060
references.citation: Neuroreport. 2000 Feb 7;11(2):343-6
references.pmid: 10674483
references.citation: Horm Behav. 2010 Jan;57(1):23-34
references.pmid: 19538962
references.citation: Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):13284-9
references.pmid: 9789080
references.citation: Brain Res. 2001 Aug 10;910(1-2):55-66
references.pmid: 11489254
references.citation: Nat Rev Neurosci. 2005 Mar;6(3):215-29
references.pmid: 15738957
references.citation: Curr Alzheimer Res. 2007 Dec;4(5):510-7
references.pmid: 18220513