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JHU-083 selectively blocks glutaminase activity in brain CD11b+ cells and prevents depression-associated behaviors induced by chronic social defeat stress

X. Zhu, MT. Nedelcovych, AG. Thomas, Y. Hasegawa, A. Moreno-Megui, W. Coomer, V. Vohra, A. Saito, G. Perez, Y. Wu, J. Alt, E. Prchalova, L. Tenora, P. Majer, R. Rais, C. Rojas, BS. Slusher, A. Kamiya,

. 2019 ; 44 (4) : 683-694. [pub] 20180813

Jazyk angličtina Země Velká Británie

Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc19045291

Grantová podpora
P50 MH094268 NIMH NIH HHS - United States
R01 CA193895 NCI NIH HHS - United States
P50MH094268 U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) - International
P30 MH075673 NIMH NIH HHS - United States
R21AT008547 U.S. Department of Health & Human Services | NIH | National Center for Complementary and Integrative Health (NCCIH) - International
K01 MH086050 NIMH NIH HHS - United States
R21 AT008547 NCCIH NIH HHS - United States
R01 MH110246 NIMH NIH HHS - United States
R01DA041208 U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (NIDA) - International
P30MH075673 U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) - International
R01 CA229451 NCI NIH HHS - United States
R25 MH080661 NIMH NIH HHS - United States
R01CA193895 U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) - International
R01 DA041208 NIDA NIH HHS - United States

E-zdroje Online Plný text

NLK Free Medical Journals od 1994 do Před 1 rokem
PubMed Central od 2010 do Před 1 rokem
Europe PubMed Central od 2010 do Před 1 rokem
ProQuest Central od 2000-01-01 do Před 1 rokem
Open Access Digital Library od 1994-01-01
Health & Medicine (ProQuest) od 2000-01-01 do Před 1 rokem
Psychology Database (ProQuest) od 2000-01-01 do Před 1 rokem

Odkazy

PubMed 30127344
DOI 10.1038/s41386-018-0177-7
Knihovny.cz E-zdroje

There are a number of clinically effective treatments for stress-associated psychiatric diseases, including major depressive disorder (MDD). Nonetheless, many patients exhibit resistance to first-line interventions calling for novel interventions based on pathological mechanisms. Accumulating evidence implicates altered glutamate signaling in MDD pathophysiology, suggesting that modulation of glutamate signaling cascades may offer novel therapeutic potential. Here we report that JHU-083, our recently developed prodrug of the glutaminase inhibitor 6-diazo-5-oxo-L-norleucine (DON) ameliorates social avoidance and anhedonia-like behaviors in mice subjected to chronic social defeat stress (CSDS). JHU-083 normalized CSDS-induced increases in glutaminase activity specifically in microglia-enriched CD11b+ cells isolated from the prefrontal cortex and hippocampus. JHU-083 treatment also reverses the CSDS-induced inflammatory activation of CD11b+ cells. These results support the importance of altered glutamate signaling in the behavioral abnormalities observed in the CSDS model, and identify glutaminase in microglia-enriched CD11b+ cells as a pharmacotherapeutic target implicated in the pathophysiology of stress-associated psychiatric conditions such as MDD.

Citace poskytuje Crossref.org

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