Timely N-Acetyl-Cysteine and Environmental Enrichment Rescue Oxidative Stress-Induced Parvalbumin Interneuron Impairments via MMP9/RAGE Pathway: A Translational Approach for Early Intervention in Psychosis.
Acetylcysteine
/ pharmacology
Adult
Animals
Combined Modality Therapy
Disease Models, Animal
Exercise Therapy
Female
Glutamate-Cysteine Ligase
/ deficiency
Humans
Interneurons
/ drug effects
Male
Matrix Metalloproteinase 9
/ drug effects
Mice
Mice, Inbred C57BL
Mice, Knockout
Oxidative Stress
/ drug effects
Parvalbumins
/ metabolism
Psychotic Disorders
/ drug therapy
Receptor for Advanced Glycation End Products
/ drug effects
Signal Transduction
/ drug effects
Translational Research, Biomedical
antioxidant
brain development
cognition
early psychosis
mechanism
physical exercice
Journal
Schizophrenia bulletin
ISSN: 1745-1701
Titre abrégé: Schizophr Bull
Pays: United States
ID NLM: 0236760
Informations de publication
Date de publication:
21 10 2021
21 10 2021
Historique:
pubmed:
4
6
2021
medline:
11
2
2022
entrez:
3
6
2021
Statut:
ppublish
Résumé
Research in schizophrenia (SZ) emphasizes the need for new therapeutic approaches based on antioxidant/anti-inflammatory compounds and psycho-social therapy. A hallmark of SZ is a dysfunction of parvalbumin-expressing fast-spiking interneurons (PVI), which are essential for neuronal synchrony during sensory/cognitive processing. Oxidative stress and inflammation during early brain development, as observed in SZ, affect PVI maturation. We compared the efficacy of N-acetyl-cysteine (NAC) and/or environmental enrichment (EE) provided during juvenile and/or adolescent periods in rescuing PVI impairments induced by an additional oxidative insult during childhood in a transgenic mouse model with gluthation deficit (Gclm KO), relevant for SZ. We tested whether this rescue was promoted by the inhibition of MMP9/RAGE mechanism, both in the mouse model and in early psychosis (EP) patients, enrolled in a double-blind, randomized, placebo-controlled clinical trial of NAC supplementation for 6 months. We show that a sequential combination of NAC+EE applied after an early-life oxidative insult recovers integrity and function of PVI network in adult Gclm KO, via the inhibition of MMP9/RAGE. Six-month NAC treatment in EP patients reduces plasma sRAGE in association with increased prefrontal GABA, improvement of cognition and clinical symptoms, suggesting similar neuroprotective mechanisms. The sequential combination of NAC+EE reverses long-lasting effects of an early oxidative insult on PVI/perineuronal net (PNN) through the inhibition of MMP9/RAGE mechanism. In analogy, patients vulnerable to early-life insults could benefit from a combined pharmacological and psycho-social therapy.
Identifiants
pubmed: 34080015
pii: 6291440
doi: 10.1093/schbul/sbab066
pmc: PMC8530393
doi:
Substances chimiques
Parvalbumins
0
Receptor for Advanced Glycation End Products
0
Matrix Metalloproteinase 9
EC 3.4.24.35
GCLM protein, mouse
EC 6.3.2.2
Glutamate-Cysteine Ligase
EC 6.3.2.2
Acetylcysteine
WYQ7N0BPYC
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1782-1794Informations de copyright
© The Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.
Références
Brain Res. 2019 May 15;1711:115-119
pubmed: 30677409
Am J Psychiatry. 2008 Feb;165(2):203-13
pubmed: 18172019
J Neurochem. 1998 Nov;71(5):2071-8
pubmed: 9798932
Magn Reson Med. 2006 Nov;56(5):965-70
pubmed: 16991116
Neurobiol Dis. 2018 Jan;109(Pt A):64-75
pubmed: 29024713
Proc Natl Acad Sci U S A. 2018 Dec 4;115(49):12495-12500
pubmed: 30455310
Am J Psychiatry. 2008 Feb;165(2):214-20
pubmed: 18172018
Neuropsychopharmacology. 2015 Jul;40(8):1947-56
pubmed: 25666312
Early Interv Psychiatry. 2013 Aug;7(3):322-8
pubmed: 23445318
Schizophr Bull. 2012 May;38(3):373-6
pubmed: 22461483
Neuroimage. 2011 Oct 15;58(4):1081-9
pubmed: 21801840
Cell. 2016 Jan 14;164(1-2):208-218
pubmed: 26771492
Science. 2014 Aug 1;345(6196):1255263
pubmed: 25082707
J Neurosci. 2016 Nov 9;36(45):11459-11468
pubmed: 27911749
Behav Brain Res. 2020 Jun 18;388:112658
pubmed: 32339550
Mol Psychiatry. 2012 Dec;17(12):1194-205
pubmed: 22290124
Acta Psychiatr Scand. 2013 Jun;127(6):464-73
pubmed: 23106093
BMC Psychiatry. 2015 Aug 25;15:205
pubmed: 26302744
Curr Opin Neurobiol. 2009 Apr;19(2):220-30
pubmed: 19481443
Psychol Med. 2015 May;45(7):1343-61
pubmed: 25650668
Acta Psychiatr Scand. 2018 May;137(5):391-400
pubmed: 29457216
Proc Natl Acad Sci U S A. 2013 May 28;110(22):9130-5
pubmed: 23671099
Neurosci Biobehav Rev. 2016 Nov;70:260-270
pubmed: 27235082
Neuron. 2014 Sep 3;83(5):991-3
pubmed: 25189204
Epidemiol Psychiatr Sci. 2019 Dec 16;29:e78
pubmed: 31839014
Dev Psychobiol. 2016 May;58(4):482-91
pubmed: 26688108
Antioxid Redox Signal. 2013 Apr 20;18(12):1475-90
pubmed: 22746161
Diseases. 2019 Jan 22;7(1):
pubmed: 30678202
Neuron. 2012 Sep 20;75(6):963-80
pubmed: 22998866
Schizophr Res. 2016 Oct;176(2-3):291-303
pubmed: 27256518
BMC Genomics. 2017 Jan 5;18(1):29
pubmed: 28056786
Nat Rev Neurosci. 2016 Feb;17(2):125-34
pubmed: 26763624
Behav Brain Res. 2016 Oct 1;312:84-92
pubmed: 27297027
Am J Psychiatry. 2003 Sep;160(9):1627-35
pubmed: 12944338
Arch Gen Psychiatry. 2010 Feb;67(2):155-66
pubmed: 20124115
Schizophr Res. 2019 Nov;213:96-106
pubmed: 30857872
Behav Brain Res. 2012 Jan 15;226(2):563-70
pubmed: 22033334
Int J Dev Neurosci. 2017 Apr;57:56-61
pubmed: 28099880
Proc Natl Acad Sci U S A. 2020 Sep 22;117(38):23242-23251
pubmed: 32503914
Schizophr Bull. 2018 Feb 15;44(2):317-327
pubmed: 29462456
Neuron. 2014 Sep 3;83(5):1073-1084
pubmed: 25132466
Biol Psychiatry. 2020 Aug 15;88(4):326-336
pubmed: 32560962
J Biol Chem. 2002 Dec 20;277(51):49446-52
pubmed: 12384496
Psychiatry Res. 2015 Aug 30;228(3):501-9
pubmed: 26163731
Magn Reson Med. 2009 Jun;61(6):1279-85
pubmed: 19319893
Eur Neuropsychopharmacol. 2019 May;29(5):590-600
pubmed: 30926324
Neurotoxicol Teratol. 2012 Jul;34(4):450-7
pubmed: 22580179
J Nerv Ment Dis. 2016 Sep;204(9):644-50
pubmed: 27218221
Transl Psychiatry. 2018 Oct 12;8(1):220
pubmed: 30315150
Schizophr Bull. 2015 Jul;41(4):847-58
pubmed: 25782770
Front Psychiatry. 2013 Oct 14;4:136
pubmed: 24133464
Aust N Z J Psychiatry. 2020 May;54(5):453-466
pubmed: 31826654
Trends Pharmacol Sci. 2011 Sep;32(9):507-13
pubmed: 21700346
Mol Psychiatry. 2020 Nov;25(11):2889-2904
pubmed: 30911107
Psychol Med. 2015 Nov;45(15):3147-57
pubmed: 26062741
Front Behav Neurosci. 2017 Jun 06;11:106
pubmed: 28634445
Mol Psychiatry. 2015 Jul;20(7):827-38
pubmed: 25155877
Psychol Med. 2012 Sep;42(9):1893-901
pubmed: 22260948
Biol Psychiatry. 2013 Sep 15;74(6):427-35
pubmed: 23790226
Schizophr Bull. 2013 Sep;39(5):1056-66
pubmed: 23002182
Biol Psychiatry. 2013 Mar 15;73(6):574-82
pubmed: 23140664
Psychiatr Danub. 2015 Mar;27(1):2-13
pubmed: 25751427
Schizophr Bull. 2016 Sep;42(5):1185-96
pubmed: 27069063
Cell Rep. 2018 Nov 27;25(9):2299-2307.e4
pubmed: 30485800
Transl Psychiatry. 2019 Oct 21;9(1):264
pubmed: 31636253
Neuroscience. 2004;123(4):821-34
pubmed: 14751276
Mol Neurobiol. 2018 Jan;55(1):26-41
pubmed: 28822057
Curr Cardiovasc Risk Rep. 2015;9(7):34
pubmed: 26005511
Curr Opin Psychiatry. 2017 May;30(3):171-175
pubmed: 28230631
Am J Psychiatry. 2018 Mar 1;175(3):209-214
pubmed: 29490501
Biol Psychiatry. 2008 Sep 1;64(5):361-8
pubmed: 18436195
J Neurosci. 2010 Feb 17;30(7):2547-58
pubmed: 20164340
Ment Health Clin. 2019 May 10;9(3):116-123
pubmed: 31123658
Brain Struct Funct. 2014 Jan;219(1):395-406
pubmed: 23400698
Eur Neuropsychopharmacol. 2018 Jan;28(1):97-108
pubmed: 29174863
Mol Psychiatry. 2017 Jul;22(7):936-943
pubmed: 28322275
Trends Neurosci. 2016 Jul;39(7):441-448
pubmed: 27233681
J Nerv Ment Dis. 2020 Jan;208(1):70-76
pubmed: 31834192
Front Cell Neurosci. 2014 Aug 20;8:244
pubmed: 25191228
Psychoneuroendocrinology. 2020 May;115:104649
pubmed: 32197198
Psychiatry Res. 2015 Oct 30;229(3):828-39
pubmed: 26254795
Early Interv Psychiatry. 2020 Dec;14(6):755-761
pubmed: 32043308
Psychoneuroendocrinology. 2020 May;115:104645
pubmed: 32171901
BMC Neurosci. 2013 Jan 25;14:13
pubmed: 23347699
Neurosci Biobehav Rev. 2016 Nov;70:4-12
pubmed: 27235076
Clin Neuropharmacol. 2013 Nov-Dec;36(6):185-92
pubmed: 24201233
Mol Neurobiol. 2017 Jul;54(5):3759-3770
pubmed: 27251428
Neuropsychopharmacology. 2008 Aug;33(9):2187-99
pubmed: 18004285
Prog Neuropsychopharmacol Biol Psychiatry. 2015 Mar 3;57:69-75
pubmed: 25315856
Schizophr Res. 2016 Sep;176(1):41-51
pubmed: 25000913
J Neurosci. 2013 Aug 14;33(33):13375-87
pubmed: 23946395
Am J Psychiatry. 2011 May;168(5):472-85
pubmed: 21406461
Int J Neuropsychopharmacol. 2015 Oct 03;19(3):pyv110
pubmed: 26433393
Biol Psychiatry. 2012 Jun 1;71(11):1006-14
pubmed: 21945305
Am J Psychiatry. 2007 Dec;164(12):1791-802
pubmed: 18056233
Neurochem Int. 1998 Feb;32(2):117-31
pubmed: 9542724
Br J Psychiatry. 2001 Nov;179:403-8
pubmed: 11689395
Trends Neurosci. 2012 Jan;35(1):57-67
pubmed: 22154068
Elife. 2018 Sep 27;7:
pubmed: 30260771
Nat Commun. 2020 Feb 21;11(1):1003
pubmed: 32081848
PLoS One. 2016 Dec 15;11(12):e0168256
pubmed: 27977779
Front Cell Neurosci. 2014 Apr 03;8:97
pubmed: 24772064
Mol Neurobiol. 2016 Dec;53(10):7341-7350
pubmed: 26698582
Mol Psychiatry. 2020 Dec;25(12):3278-3291
pubmed: 31488866