PMID- 18922884
OWN - NLM
STAT- MEDLINE
DCOM- 20090312
LR  - 20181113
IS  - 1931-857X (Print)
IS  - 1522-1466 (Electronic)
IS  - 1522-1466 (Linking)
VI  - 295
IP  - 6
DP  - 2008 Dec
TI  - Methyl-2-acetamidoacrylate, an ethyl pyruvate analog, decreases sepsis-induced 
      acute kidney injury in mice.
PG  - F1825-35
LID - 10.1152/ajprenal.90442.2008 [doi]
AB  - We tested the anti-inflammatory agent methyl-2-acetamidoacrylate (M2AA), an ethyl 
      pyruvate analog, in a cecal ligation-and-puncture (CLP) model of sepsis in CD-1 
      mice. M2AA administration at the time of CLP improved survival, renal function, 
      kidney histology, liver injury, and splenocyte apoptosis, and lowered cytokine 
      levels (TNF-alpha, IL-6, IFN-gamma, and IL-10). When M2AA treatment was delayed 6 
      h (but not 12 h), M2AA still significantly reduced kidney dysfunction, liver 
      injury, splenocyte apoptosis, and cytokine levels. NF-kappaB, a M2AA target, was 
      transiently activated in spleen, peaking at 6 h; kidney and liver NF-kappaB 
      increased steadily with a plateau at 12-24 h. M2AA reduced NF-kappaB activation 
      in spleen at 6 h and in kidney and liver at 24 h. Splenectomy diminished the 
      ability of M2AA to reduce cytokines, especially IL-6, but M2AA still decreased 
      kidney and liver dysfunction, suggesting that splenic NF-kappaB is not central to 
      M2AA action. In contrast, beneficial effects of chloroquine on cytokines and 
      organ damage were neutralized by splenectomy, demonstrating a spleen-specific 
      chloroquine target. Because M2AA and chloroquine act differently, we tested this 
      combination. Survival at 96 h was highest with combination therapy (57%) vs. 
      chloroquine (38%), M2AA (47.6%), or vehicle (5%). The benefit of combination 
      therapy over chloroquine or M2AA alone did not reach statistical significance, 
      indicating potential mechanistic overlap. We conclude that the transient 
      target(s) for M2AA responsible for the narrow 6-h therapeutic window is not 
      splenic NF-kappaB. Identifying this new target and downstream signaling pathways 
      could lengthen the therapeutic window and improve combination therapy with 
      chloroquine.
FAU - Leelahavanichkul, Asada
AU  - Leelahavanichkul A
AD  - NIH/NIDDK, Bldg. 10, Rm. 3N108, 10 Center Drive, MSC 1268, Bethesda, MD 
      20892-1268, USA.
FAU - Yasuda, Hideo
AU  - Yasuda H
FAU - Doi, Kent
AU  - Doi K
FAU - Hu, Xuzhen
AU  - Hu X
FAU - Zhou, Hua
AU  - Zhou H
FAU - Yuen, Peter S T
AU  - Yuen PS
FAU - Star, Robert A
AU  - Star RA
LA  - eng
GR  - Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
DEP - 20081015
PL  - United States
TA  - Am J Physiol Renal Physiol
JT  - American journal of physiology. Renal physiology
JID - 100901990
RN  - 0 (Acrylates)
RN  - 0 (NF-kappa B)
RN  - 35356-70-8 (N-acetyldehydroalanine methyl ester)
RN  - 886U3H6UFF (Chloroquine)
SB  - IM
MH  - Acrylates/*therapeutic use
MH  - Animals
MH  - Cecum/injuries
MH  - Chloroquine/therapeutic use
MH  - Inflammation/physiopathology
MH  - Kidney/drug effects/*injuries/physiopathology
MH  - Kidney Function Tests
MH  - Kinetics
MH  - Ligation
MH  - Mice
MH  - NF-kappa B/physiology
MH  - Punctures
MH  - Sepsis/etiology/*prevention & control
MH  - Splenectomy
PMC - PMC2604833
EDAT- 2008/10/17 09:00
MHDA- 2009/03/13 09:00
PMCR- 2009/12/01
CRDT- 2008/10/17 09:00
PHST- 2008/10/17 09:00 [pubmed]
PHST- 2009/03/13 09:00 [medline]
PHST- 2008/10/17 09:00 [entrez]
PHST- 2009/12/01 00:00 [pmc-release]
AID - 90442.2008 [pii]
AID - F-90442-2008 [pii]
AID - 10.1152/ajprenal.90442.2008 [doi]
PST - ppublish
SO  - Am J Physiol Renal Physiol. 2008 Dec;295(6):F1825-35. doi: 
      10.1152/ajprenal.90442.2008. Epub 2008 Oct 15.