PMID- 33133437
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220418
IS  - 2008-2010 (Print)
IS  - 2008-322X (Electronic)
IS  - 2008-322X (Linking)
VI  - 15
IP  - 4
DP  - 2020 Oct-Dec
TI  - Memantine, Simvastatin, and Epicatechin Inhibit 7-Ketocholesterol-induced 
      Apoptosis in Retinal Pigment Epithelial Cells But Not Neurosensory Retinal Cells 
      In Vitro.
PG  - 470-480
LID - 10.18502/jovr.v15i4.7781 [doi]
AB  - PURPOSE: 7-ketocholesterol (7kCh), a natural byproduct of oxidation in 
      lipoprotein deposits is implicated in the pathogenesis of diabetic retinopathy 
      and age-related macular degeneration (AMD). This study was performed to 
      investigate whether several clinical drugs can inhibit 7kCh-induced caspase 
      activation and mitigate its apoptotic effects on retinal cells in vitro. METHODS: 
      Two populations of retinal cells, human retinal pigment epithelial cells 
      (ARPE-19) and rat neuroretinal cells (R28) were exposed to 7kCh in the presence 
      of the following inhibitors: Z-VAD-FMK (pan-caspase inhibitor), simvastatin, 
      memantine, epicatechin, and Z-IETD-FMK (caspase-8 inhibitor) or Z-ATAD-FMK 
      (caspase-12 inhibitor). Caspase-3/7, -8, and -12 activity levels were measured by 
      fluorochrome caspase assays to quantify cell death. IncuCyte live-cell 
      microscopic images were obtained to quantify cell counts. RESULTS: Exposure to 
      7kCh for 24 hours significantly increased caspase activities for both ARPE-19 and 
      R28 cells (P  <  0.05). In ARPE cells, pretreatment with various drugs had 
      significantly lower caspase-3/7, -8, and -12 activities, reported in % change in 
      mean signal intensity (msi): Z-VAD-FMK (48% decrease, P  <  0.01), memantine 
      (decreased 47.8% at 1 microM, P = 0.0039 and 81.9% at 1 mM, P  <  0.001), simvastatin 
      (decreased 85.3% at 0.01 microM, P  <  0.001 and 84.8% at 0.05 microM, P  <  0.001) or 
      epicatechin (83.6% decrease, P  <  0.05), Z-IETD-FMK (68.1% decrease, P  <  
      0.01), and Z-ATAD-FMK (47.7% decrease, P = 0.0017). In contrast, R28 cells 
      exposed to 7kCh continued to have elevated caspase-3/7, -8, and -12 activities 
      (between 25.7% decrease and 17.5% increase in msi, P  >  0.05) regardless of the 
      pretreatment. CONCLUSION: Several current drugs protect ARPE-19 cells but not R28 
      cells from 7kCh-induced apoptosis, suggesting that a multiple-drug approach is 
      needed to protect both cells types in various retinal diseases.
CI  - Copyright (c) 2020 Neekhra et al.
FAU - Neekhra, Aneesh
AU  - Neekhra A
AD  - Gavin Herbert Eye Institute, University of California, Irvine, California.
FAU - Tran, Julia
AU  - Tran J
AD  - Gavin Herbert Eye Institute, University of California, Irvine, California.
FAU - Esfahani, Parsa R
AU  - Esfahani PR
AD  - Gavin Herbert Eye Institute, University of California, Irvine, California.
FAU - Schneider, Kevin
AU  - Schneider K
AD  - Gavin Herbert Eye Institute, University of California, Irvine, California.
FAU - Pham, Khoa
AU  - Pham K
AD  - Gavin Herbert Eye Institute, University of California, Irvine, California.
FAU - Sharma, Ashish
AU  - Sharma A
AD  - Gavin Herbert Eye Institute, University of California, Irvine, California.
FAU - Chwa, Marilyn
AU  - Chwa M
AD  - Gavin Herbert Eye Institute, University of California, Irvine, California.
FAU - Luthra, Saurabh
AU  - Luthra S
AD  - Gavin Herbert Eye Institute, University of California, Irvine, California.
FAU - Gramajo, Ana L
AU  - Gramajo AL
AD  - Gavin Herbert Eye Institute, University of California, Irvine, California.
FAU - Mansoor, Saffar
AU  - Mansoor S
AD  - Gavin Herbert Eye Institute, University of California, Irvine, California.
FAU - Kuppermann, Baruch D
AU  - Kuppermann BD
AD  - Gavin Herbert Eye Institute, University of California, Irvine, California.
FAU - Kenney, M Cristina
AU  - Kenney MC
AD  - Gavin Herbert Eye Institute, University of California, Irvine, California.
AD  - Department of Pathology and Laboratory Medicine, University of California Irvine, 
      Irvine, CA, USA.
LA  - eng
GR  - R01 EY027363/EY/NEI NIH HHS/United States
PT  - Journal Article
DEP - 20201025
PL  - United Arab Emirates
TA  - J Ophthalmic Vis Res
JT  - Journal of ophthalmic & vision research
JID - 101497643
PMC - PMC7591846
OTO - NOTNLM
OT  - 7-Ketocholesterol
OT  - Memantine
OT  - Epicatechin
COIS- There are no conflicts of interest.
EDAT- 2020/11/03 06:00
MHDA- 2020/11/03 06:01
PMCR- 2020/10/25
CRDT- 2020/11/02 06:17
PHST- 2020/03/20 00:00 [received]
PHST- 2020/06/21 00:00 [accepted]
PHST- 2020/11/02 06:17 [entrez]
PHST- 2020/11/03 06:00 [pubmed]
PHST- 2020/11/03 06:01 [medline]
PHST- 2020/10/25 00:00 [pmc-release]
AID - 10.18502/jovr.v15i4.7781 [doi]
PST - epublish
SO  - J Ophthalmic Vis Res. 2020 Oct 25;15(4):470-480. doi: 10.18502/jovr.v15i4.7781. 
      eCollection 2020 Oct-Dec.