Activation of the liver X receptor increases neuroactive steroid levels and protects from diabetes-induced peripheral neuropathy.
Neuroactive steroids act in the peripheral nervous system as physiological regulators and as protective agents for acquired or inherited peripheral neuropathy. In recent years, modulation of neuroactive steroids levels has been studied as a potential therapeutic approach to protect peripheral nerves from damage induced by diabetes. Nuclear receptors of the liver X receptor (LXR) family regulate adrenal steroidogenesis via their ability to control cholesterol homeostasis. Here we show that rat sciatic nerve expresses both LRXα and β isoforms and that these receptors are functional. Activation of liver X receptors using a synthetic ligand results in increased levels of neurosteroids and protection of the sciatic nerve from neuropathy induced by diabetes. LXR ligand treatment of streptozotocin-treated rats increases expression in the sciatic nerve of steroidogenic acute regulatory protein (a molecule involved in the transfer of cholesterol into mitochondria), of the enzyme P450scc (responsible for conversion of cholesterol into pregnenolone), of 5α-reductase (an enzyme involved in the generation of neuroactive steroids) and of classical LXR targets involved in cholesterol efflux, such as ABCA1 and ABCG1. These effects were associated with increased levels of neuroactive steroids (e.g., pregnenolone, progesterone, dihydroprogesterone and 3α-diol) in the sciatic nerve, and with neuroprotective effects on thermal nociceptive activity, nerve conduction velocity, and Na(+), K(+)-ATPase activity. These results suggest that LXR activation may represent a new pharmacological avenue to increase local neuroactive steroid levels that exert neuroprotective effects in diabetic neuropathy.
Cermenati
Gaia
G
Department of Pharmacological Sciences, Giovanni Armenise-Harvard Foundation Laboratory, Università degli Studi di Milano, Milano, Italy.
Giatti
Silvia
S
Cavaletti
Guido
G
Bianchi
Roberto
R
Maschi
Omar
O
Pesaresi
Marzia
M
Abbiati
Federico
F
Volonterio
Alessandro
A
Saez
Enrique
E
Caruso
Donatella
D
Melcangi
Roberto Cosimo
RC
Mitro
Nico
N
D000704:Analysis of Variance; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D002853:Chromatography, Liquid / Q000379:methods; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D003929:Diabetic Neuropathies / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006930:Hyperalgesia / Q000209:etiology; D008024:Ligands; D000071518:Liver X Receptors; D008297:Male; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism; D009431:Neural Conduction / Q000502:physiology; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D017288:Pain Threshold; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000378:metabolism / Q000382:microbiology / Q000473:pathology / Q000503:physiopathology; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013256:Steroids / Q000378:metabolism* / Q000627:therapeutic use*; D053719:Tandem Mass Spectrometry / Q000379:methods
D001565:Benzoates; D001596:Benzylamines; C473027:GW 3965; D008024:Ligands; D000071518:Liver X Receptors; D009185:Myelin Proteins; D057093:Orphan Nuclear Receptors; D013256:Steroids; D000254:Sodium-Potassium-Exchanging ATPase
Neuroscience. 2010 Apr 14;166(4):1101-9
20096333
Diabetologia. 2000 Aug;43(8):957-73
10990072
FEBS Lett. 2008 Oct 15;582(23-24):3396-400
18789330
Diabetes Care. 2007 Jul;30(7):1912-9
17496237
Pharmacol Ther. 2007 Oct;116(1):77-106
17659348
J Clin Invest. 2006 Jul;116(7):1902-12
16823488
Biochim Biophys Acta. 2009 Jul;1791(7):646-58
19286473
Proc Natl Acad Sci U S A. 2004 Jan 20;101(3):823-8
14718663
J Neurosci. 2007 Dec 26;27(52):14470-80
18160655
J Neurol Sci. 1998;156(1):18-29
9559982
Circulation. 2008 Sep 30;118(14):1450-9
18794391
Cell Mol Life Sci. 2007 May;64(9):1158-68
17417742
Neuroscience. 2009 Dec 1;164(2):520-9
19665520
Horm Behav. 2010 Jan;57(1):46-55
19422828
Neuroscience. 2008 Aug 26;155(3):673-85
18625290
Brain Res Rev. 2008 Mar;57(2):460-9
17543391
Bioorg Med Chem Lett. 2009 Oct 1;19(19):5617-21
19717304
Diabetes Care. 2007 Jan;30 Suppl 1:S4-S41
17192377
Glia. 2006 Nov 1;54(6):485-98
16906540
Proc Natl Acad Sci U S A. 2007 Jun 19;104(25):10601-6
17563384
Diabetes Metab Res Rev. 2000 Nov-Dec;16(6):408-33
11114101
Cell Mol Life Sci. 2008 Mar;65(5):777-97
18038216
Biochem Soc Trans. 2006 Dec;34(Pt 6):1110-3
17073762
Expert Rev Neurother. 2006 Aug;6(8):1121-5
16893339
Neurochem Int. 2008 Mar-Apr;52(4-5):503-5
17977620
Psychoneuroendocrinology. 2009 Dec;34 Suppl 1:S1-8
19954893
Neuroscience. 2007 Feb 23;144(4):1293-304
17187935
Eur J Pain. 2010 Apr;14(4):343-50
19695912
Genes Dev. 2000 Nov 15;14(22):2831-8
11090131
Annu Rev Med. 2006;57:313-29
16409152
J Steroid Biochem Mol Biol. 2007 Apr;104(1-2):61-7
17197174
J Med Chem. 2002 May 9;45(10):1963-6
11985463
J Lipid Res. 2004 Dec;45(12):2161-73
15489539
Neurochem Int. 2008 Mar-Apr;52(4-5):560-8
17686551