PMID- 24023368
OWN - NLM
STAT- MEDLINE
DCOM- 20131223
LR  - 20211021
IS  - 1521-0103 (Electronic)
IS  - 0022-3565 (Print)
IS  - 0022-3565 (Linking)
VI  - 347
IP  - 2
DP  - 2013 Nov
TI  - Pharmacological inhibition of pleckstrin homology domain leucine-rich repeat 
      protein phosphatase is neuroprotective: differential effects on astrocytes.
PG  - 516-28
LID - 10.1124/jpet.113.206888 [doi]
AB  - Pleckstrin homology domain and leucine-rich repeat protein phosphatase 1 (PHLPP1) 
      inhibits protein kinase B (AKT) survival signaling in neurons. Small molecule 
      pan-PHLPP inhibitors (selective for PHLPP1 and PHLPP2) may offer a translatable 
      method to induce AKT neuroprotection. We tested several recently discovered PHLPP 
      inhibitors (NSC117079 and NSC45586; benzoic acid, 
      5-[2-[4-[2-(2,4-diamino-5-methylphenyl)diazenyl]phenyl]diazenyl]-2-hydroxy-,sodium 
      salt.) in rat cortical neurons and astrocytes and compared the biochemical 
      response of these agents with short hairpin RNA (shRNA)-mediated PHLPP1 knockdown 
      (KD). In neurons, both PHLPP1 KD and experimental PHLPP inhibitors activated AKT 
      and ameliorated staurosporine (STS)-induced cell death. Unexpectedly, in 
      astrocytes, both inhibitors blocked AKT activation, and NSC117079 reduced 
      viability. Only PHLPP2 KD mimicked PHLPP inhibitors on astrocyte biochemistry. 
      This suggests that these inhibitors could have possible detrimental effects on 
      astrocytes by blocking novel PHLPP2-mediated prosurvival signaling mechanisms. 
      Finally, because PHLPP1 levels are reportedly high in the hippocampus (a region 
      prone to ischemic death), we characterized hippocampal changes in PHLPP and 
      several AKT targeting prodeath phosphatases after cardiac arrest (CA)-induced 
      brain injury. PHLPP1 levels increased in rat brains subjected to CA. None of the 
      other AKT inhibitory phosphatases increased after global ischemia (i.e., PHLPP2, 
      PTEN, PP2A, and PP1). Selective PHLPP1 inhibition (such as by shRNA KD) activates 
      AKT survival signaling in neurons and astrocytes. Nonspecific PHLPP inhibition 
      (by NSC117079 and NSC45586) only activates AKT in neurons. Taken together, these 
      results suggest that selective PHLPP1 inhibitors should be developed and may 
      yield optimal strategies to protect injured hippocampal neurons and 
      astrocytes-namely from global brain ischemia.
FAU - Jackson, Travis C
AU  - Jackson TC
AD  - University of Pittsburgh School of Medicine, Department of Critical Care 
      Medicine, Safar Center for Resuscitation Research (T.C.J., P.M.K., H.B., R.S.C, 
      K.J.F., C.D., T.U.) and Department of Pharmacology and Chemical Biology (J.D.V., 
      D.G.G., E.K.J.),University of Pittsburgh School of Medicine, Pittsburgh, 
      Pennsylvania; and Department of Anesthesiology, Presbyterian Hospital (T.D.), 
      Pittsburgh, Pennsylvania.
FAU - Verrier, Jonathan D
AU  - Verrier JD
FAU - Drabek, Tomas
AU  - Drabek T
FAU - Janesko-Feldman, Keri
AU  - Janesko-Feldman K
FAU - Gillespie, Delbert G
AU  - Gillespie DG
FAU - Uray, Thomas
AU  - Uray T
FAU - Dezfulian, Cameron
AU  - Dezfulian C
FAU - Clark, Robert S
AU  - Clark RS
FAU - Bayir, Hulya
AU  - Bayir H
FAU - Jackson, Edwin K
AU  - Jackson EK
FAU - Kochanek, Patrick M
AU  - Kochanek PM
LA  - eng
GR  - K08 NS069817/NS/NINDS NIH HHS/United States
GR  - P30 DK079307/DK/NIDDK NIH HHS/United States
GR  - K08-NS069817/NS/NINDS NIH HHS/United States
GR  - DK079307/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20130910
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (Anthraquinones)
RN  - 0 (Azo Compounds)
RN  - 0 (NSC117079)
RN  - 0 (NSC45586)
RN  - 0 (Neuroprotective Agents)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Phenylenediamines)
RN  - 0 (Sulfonamides)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 3.1.3.16 (PHLPP1 protein, rat)
SB  - IM
MH  - Animals
MH  - Anthraquinones/chemistry/*pharmacology
MH  - Astrocytes/*drug effects/metabolism/pathology
MH  - Azo Compounds/chemistry/*pharmacology
MH  - Brain Ischemia/etiology/metabolism/pathology/prevention & control
MH  - Cell Culture Techniques
MH  - Cell Survival/drug effects
MH  - Dose-Response Relationship, Drug
MH  - HEK293 Cells
MH  - Heart Arrest/complications/metabolism/pathology
MH  - Humans
MH  - Molecular Structure
MH  - Neurons/drug effects/metabolism/pathology
MH  - Neuroprotective Agents/chemistry/*pharmacology
MH  - Nuclear Proteins/*antagonists & inhibitors/genetics
MH  - Phenylenediamines/chemistry/*pharmacology
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Signal Transduction/drug effects
MH  - Sulfonamides/chemistry/*pharmacology
PMC - PMC3807060
EDAT- 2013/09/12 06:00
MHDA- 2013/12/24 06:00
PMCR- 2014/11/01
CRDT- 2013/09/12 06:00
PHST- 2013/09/12 06:00 [entrez]
PHST- 2013/09/12 06:00 [pubmed]
PHST- 2013/12/24 06:00 [medline]
PHST- 2014/11/01 00:00 [pmc-release]
AID - jpet.113.206888 [pii]
AID - JPET_206888 [pii]
AID - 10.1124/jpet.113.206888 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2013 Nov;347(2):516-28. doi: 10.1124/jpet.113.206888. Epub 
      2013 Sep 10.