Neutral sphingomyelinase 2 inhibition attenuates extracellular vesicle release and improves neurobehavioral deficits in murine HIV.
Depression
EcoHIV
Extracellular vesicle
HIV
Mice
Neutral sphingomyelinase 2
Sleep
Journal
Neurobiology of disease
ISSN: 1095-953X
Titre abrégé: Neurobiol Dis
Pays: United States
ID NLM: 9500169
Informations de publication
Date de publication:
07 2022
07 2022
Historique:
received:
29
12
2021
revised:
22
03
2022
accepted:
13
04
2022
pubmed:
25
4
2022
medline:
20
5
2022
entrez:
24
4
2022
Statut:
ppublish
Résumé
People living with HIV (PLH) have significantly higher rates of cognitive impairment (CI) and major depressive disorder (MDD) versus the general population. The enzyme neutral sphingomyelinase 2 (nSMase2) is involved in the biogenesis of ceramide and extracellular vesicles (EVs), both of which are dysregulated in PLH, CI, and MDD. Here we evaluated EcoHIV-infected mice for behavioral abnormalities relevant to depression and cognition deficits, and assessed the behavioral and biochemical effects of nSMase2 inhibition. Mice were infected with EcoHIV and daily treatment with either vehicle or the nSMase2 inhibitor (R)-(1-(3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)-carbamate (PDDC) began 3 weeks post-infection. After 2 weeks of treatment, mice were subjected to behavior tests. EcoHIV-infected mice exhibited behavioral abnormalities relevant to MDD and CI that were reversed by PDDC treatment. EcoHIV infection significantly increased cortical brain nSMase2 activity, resulting in trend changes in sphingomyelin and ceramide levels that were normalized by PDDC treatment. EcoHIV-infected mice also exhibited increased levels of brain-derived EVs and altered microRNA cargo, including miR-183-5p, miR-200c-3p, miR-200b-3p, and miR-429-3p, known to be associated with MDD and CI; all were normalized by PDDC. In conclusion, inhibition of nSMase2 represents a possible new therapeutic strategy for the treatment of HIV-associated CI and MDD.
Identifiants
pubmed: 35462006
pii: S0969-9961(22)00126-7
doi: 10.1016/j.nbd.2022.105734
pmc: PMC9202342
mid: NIHMS1812116
pii:
doi:
Substances chimiques
Ceramides
0
MicroRNAs
0
Sphingomyelin Phosphodiesterase
EC 3.1.4.12
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
105734Subventions
Organisme : NIDA NIH HHS
ID : R01 DA040390
Pays : United States
Organisme : NIMH NIH HHS
ID : P30 MH075673
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG063831
Pays : United States
Organisme : NIDA NIH HHS
ID : R01 DA047807
Pays : United States
Organisme : NINDS NIH HHS
ID : R56 NS119438
Pays : United States
Organisme : NCI NIH HHS
ID : UH3 CA241694
Pays : United States
Organisme : NIDA NIH HHS
ID : R01 DA052272
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH104145
Pays : United States
Organisme : NIMH NIH HHS
ID : R33 MH118164
Pays : United States
Organisme : NCCIH NIH HHS
ID : K01 AT010984
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG059799
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH110246
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI144997
Pays : United States
Informations de copyright
Copyright © 2021. Published by Elsevier Inc.
Références
Nat Methods. 2017 Feb 28;14(3):228-232
pubmed: 28245209
J Proteome Res. 2013 Feb 1;12(2):594-604
pubmed: 23270375
Transl Psychiatry. 2015 Nov 17;5:e682
pubmed: 26575223
Free Radic Biol Med. 1999 Dec;27(11-12):1292-301
pubmed: 10641723
Neuropsychopharmacology. 2019 Mar;44(4):683-694
pubmed: 30127344
J Extracell Vesicles. 2019 Apr 23;8(1):1603048
pubmed: 31069026
World J AIDS. 2011 Dec 1;1(4):139-145
pubmed: 23061029
Handb Clin Neurol. 2018;152:187-200
pubmed: 29604976
Int J Neuropsychopharmacol. 2016 Dec 3;19(12):
pubmed: 27450446
Nat Rev Neurol. 2016 Apr;12(4):234-48
pubmed: 26965674
J Neurovirol. 2018 Oct;24(5):549-556
pubmed: 29777462
Mol Psychiatry. 2014 Aug;19(8):895-901
pubmed: 24217256
J Clin Exp Neuropsychol. 2014;36(8):806-17
pubmed: 25111120
Lancet. 2018 Aug 25;392(10148):685-697
pubmed: 30049419
J Clin Cell Immunol. 2016 Jun;7(3):
pubmed: 27478681
Can J Biochem Physiol. 1959 Aug;37(8):911-7
pubmed: 13671378
Proc Natl Acad Sci U S A. 2017 Jul 11;114(28):E5549-E5558
pubmed: 28652336
Front Biosci. 2004 Sep 01;9:2680-5
pubmed: 15358591
J Assoc Nurses AIDS Care. 2013 Jan-Feb;24(1 Suppl):S72-85
pubmed: 23290379
Transl Psychiatry. 2019 Mar 28;9(1):122
pubmed: 30923321
Proc Natl Acad Sci U S A. 2010 Sep 7;107(36):15780-5
pubmed: 20798032
Front Biosci. 2008 May 01;13:5120-30
pubmed: 18508574
J Biol Chem. 2000 Jun 9;275(23):17221-4
pubmed: 10770957
Viruses. 2020 May 22;12(5):
pubmed: 32456011
Am J Psychiatry. 2001 May;158(5):725-30
pubmed: 11329393
J Biol Chem. 2012 Feb 3;287(6):3842-9
pubmed: 22057275
AIDS. 2019 May 1;33(6):973-984
pubmed: 30946151
Chem Biol Interact. 2019 Jul 1;307:223-233
pubmed: 31018114
Science. 2008 Feb 29;319(5867):1244-7
pubmed: 18309083
Sci Rep. 2018 Dec 7;8(1):17715
pubmed: 30531925
PLoS Pathog. 2018 Jun 7;14(6):e1007061
pubmed: 29879225
Genome Biol. 2014;15(12):550
pubmed: 25516281
Neurology. 2001 Aug 28;57(4):671-5
pubmed: 11524477
J Biol Chem. 2018 Jan 5;293(1):296-311
pubmed: 29158267
J Neurovirol. 2018 Aug;24(4):398-410
pubmed: 29594983
J Neurosci. 2011 Nov 23;31(47):17074-90
pubmed: 22114277
AIDS Behav. 2020 Aug;24(8):2282-2289
pubmed: 31965430
Proc Natl Acad Sci U S A. 2005 Mar 8;102(10):3760-5
pubmed: 15728729
J Clin Med. 2019 Jun 13;8(6):
pubmed: 31200571
Nat Commun. 2019 May 1;10(1):2009
pubmed: 31043599
Eur Neuropsychopharmacol. 2013 Jul;23(7):602-11
pubmed: 22925464
AIDS Behav. 2012 Nov;16(8):2309-18
pubmed: 22246512
Acta Neuropathol. 2004 Feb;107(2):97-110
pubmed: 14605830
Cell Rep. 2018 Dec 11;25(11):3194-3203.e4
pubmed: 30540950
Mol Neurobiol. 2018 Jul;55(7):5741-5756
pubmed: 29043558
Drug Discov Today. 2021 Jul;26(7):1656-1668
pubmed: 33798648
Biochem J. 2000 Jul 15;349(Pt 2):385-402
pubmed: 10880336
J Extracell Vesicles. 2020 Feb 11;9(1):1722433
pubmed: 32128073
mBio. 2019 Jul 2;10(4):
pubmed: 31266862
J Extracell Vesicles. 2021 Apr;10(6):e12079
pubmed: 33850608
J Neurosci Res. 1998 Nov 15;54(4):475-85
pubmed: 9822158
Sci Rep. 2021 Jan 21;11(1):2009
pubmed: 33479350
J Neurosci Res. 2010 Oct;88(13):2940-51
pubmed: 20629193
J Neurovirol. 2019 Oct 28;:1-51
pubmed: 31659716
Nature. 2011 Aug 03;476(7361):458-61
pubmed: 21814201
Metabolism. 2019 Jun;95:65-76
pubmed: 30954559
J Neuroimmune Pharmacol. 2020 Dec;15(4):729-742
pubmed: 32506353
AIDS. 2011 Nov 13;25(17):2057-67
pubmed: 21857495
J Med Chem. 2020 Jun 11;63(11):6028-6056
pubmed: 32298582
PLoS Pathog. 2019 Jul 25;15(7):e1007907
pubmed: 31344124
Cell Physiol Biochem. 2016;39(2):790-801
pubmed: 27475812
Neurology. 2007 May 1;68(18):1481-7
pubmed: 17470750
J Neuroimmune Pharmacol. 2019 Sep;14(3):391-400
pubmed: 31209775
J Med Chem. 2017 Aug 24;60(16):7186-7198
pubmed: 28759224
Curr HIV Res. 2014;12(2):97-110
pubmed: 24862332
Nat Cell Biol. 2007 Jun;9(6):654-9
pubmed: 17486113
Neuropsychology. 2015 Nov;29(6):919-925
pubmed: 25730729
J Neuroinflammation. 2019 Dec 5;16(1):254
pubmed: 31805958
Science. 1996 Dec 13;274(5294):1855-9
pubmed: 8943189
Pathogens. 2020 Dec 17;9(12):
pubmed: 33348699
Transl Psychiatry. 2012 Mar 13;2:e87
pubmed: 22832852
Neuron. 2020 May 6;106(3):404-420.e8
pubmed: 32135084
Prog Neuropsychopharmacol Biol Psychiatry. 2018 Aug 30;86:150-165
pubmed: 29864451
J Neurosci. 2010 May 19;30(20):6838-51
pubmed: 20484626
J Neuropathol Exp Neurol. 2014 Jan;73(1):59-71
pubmed: 24335529
PLoS One. 2019 Apr 15;14(4):e0215554
pubmed: 30986274
Brain Behav Immun. 2019 Nov;82:230-238
pubmed: 31479730
Indian J Psychol Med. 2017 Nov-Dec;39(6):789-793
pubmed: 29284813
J Extracell Vesicles. 2018 Nov 23;7(1):1535750
pubmed: 30637094
PLoS One. 2015 Oct 22;10(10):e0140943
pubmed: 26492488
AIDS Res Hum Retroviruses. 2003 Aug;19(8):643-52
pubmed: 13678465
Neuropsychopharmacology. 2020 May;45(6):1050-1058
pubmed: 31986519
Neuron. 2010 Feb 25;65(4):480-9
pubmed: 20188653
Ann Neurol. 2004 Feb;55(2):257-67
pubmed: 14755730
J Affect Disord. 2017 Apr 15;213:35-43
pubmed: 28189963
J Neurovirol. 2010 Nov;16(6):445-56
pubmed: 21087113
J Neuroimmune Pharmacol. 2012 Jun;7(2):380-7
pubmed: 21987348
Biochim Biophys Acta. 2007 Mar;1768(3):553-61
pubmed: 17292325
BMC Bioinformatics. 2015 Apr 03;16:112
pubmed: 25880836
PLoS One. 2016 Mar 17;11(3):e0151702
pubmed: 26986758
Am J Psychiatry. 2004 Nov;161(11):1957-66
pubmed: 15514393
Front Mol Neurosci. 2017 Dec 12;10:410
pubmed: 29311803
J Neurosci. 2016 Nov 2;36(44):11362-11373
pubmed: 27807176
AIDS. 2007 May 11;21(8):905-9
pubmed: 17457083
Nat Methods. 2013 Jan;10(1):71-3
pubmed: 23160280
Biochem Soc Trans. 2013 Aug;41(4):815-20
pubmed: 23863137
EMBO J. 2003 Aug 15;22(16):4121-31
pubmed: 12912911
Sci Rep. 2017 Aug 10;7(1):7748
pubmed: 28798382
Curr HIV/AIDS Rep. 2014 Sep;11(3):291-307
pubmed: 25038748
J Neurovirol. 2019 Oct;25(5):702-709
pubmed: 30610738
J Extracell Vesicles. 2020 Jun 30;9(1):1785746
pubmed: 32944174
J Mol Neurosci. 2010 Jan;40(1-2):47-55
pubmed: 19711202
J Neurochem. 2021 May;157(3):429-449
pubmed: 33421125
Curr Psychiatry Rep. 2015 Jan;17(1):530
pubmed: 25413636
Ann Neurol. 1997 Dec;42(6):963-72
pubmed: 9403489
Nat Med. 2013 Jul;19(7):934-8
pubmed: 23770692
Br J Pharmacol. 2019 Oct;176(19):3857-3870
pubmed: 31273753
Mol Neurobiol. 2018 Feb;55(2):917-935
pubmed: 28083819