PMID- 38015174
OWN - NLM
STAT- MEDLINE
DCOM- 20231129
LR  - 20231205
IS  - 1552-5783 (Electronic)
IS  - 0146-0404 (Print)
IS  - 0146-0404 (Linking)
VI  - 64
IP  - 14
DP  - 2023 Nov 1
TI  - GSK840 Alleviates Retinal Neuronal Injury by Inhibiting RIPK3/MLKL-Mediated RGC 
      Necroptosis After Ischemia/Reperfusion.
PG  - 42
LID - 10.1167/iovs.64.14.42 [doi]
LID - 42
AB  - PURPOSE: This study aimed to explore the impact of GSK840 on retinal neuronal 
      injury after retinal ischemia/reperfusion (IR) and its associated mechanism. 
      METHODS: We established an in vivo mouse model of IR and an in vitro model of 
      oxygen and glucose deprivation/reoxygenation (OGDR) in primary mouse retinal 
      ganglion cells (RGCs). GSK840, a small-molecule compound, was used to 
      specifically inhibit RIPK3/MLKL-dependent necroptosis. Retinal structure and 
      function evaluation was performed by using hematoxylin and eosin staining, 
      optical coherence tomography, and electroretinography. Propidium Iodide (PI) 
      staining was used for detection of necroptotic cell death, whereas Western blot 
      analysis and immunofluorescence were used to assess necroptosis-related proteins 
      and inner retinal neurons. RESULTS: RIPK3/MLKL-dependent necroptosis was rapidly 
      activated in RGCs following retinal IR or OGDR. GSK840 helped maintain relatively 
      normal inner retinal structure and thickness by preserving inner retinal neurons, 
      particularly RGCs. Meanwhile, GSK840 ameliorated IR-induced visual dysfunction, 
      as evidenced by the improved amplitudes of photopic negative response, a-wave, 
      b-wave, and oscillatory potentials. And GSK840 treatment significantly reduced 
      the population of PI+ RGCs after injury. Mechanistically, GSK840 ameliorated RGC 
      necroptosis by inhibiting the RIPK3/MLKL pathway. CONCLUSIONS: GSK840 exerts 
      protective effects against retinal neuronal injury after IR by inhibiting 
      RIPK3/MLKL-mediated RGC necroptosis. GSK840 may represent a protective strategy 
      for RGC degeneration in ischemic retinopathy.
FAU - Feng, Yanlin
AU  - Feng Y
AD  - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen 
      University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual 
      Science, Guangzhou, China.
FAU - Hu, Chenyang
AU  - Hu C
AD  - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen 
      University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual 
      Science, Guangzhou, China.
FAU - Cui, Kaixuan
AU  - Cui K
AD  - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen 
      University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual 
      Science, Guangzhou, China.
FAU - Fan, Matthew
AU  - Fan M
AD  - Yale College, Yale University, New Haven, Connecticut, United States.
FAU - Xiang, Wu
AU  - Xiang W
AD  - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen 
      University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual 
      Science, Guangzhou, China.
FAU - Ye, Dan
AU  - Ye D
AD  - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen 
      University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual 
      Science, Guangzhou, China.
FAU - Shi, Yuxun
AU  - Shi Y
AD  - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen 
      University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual 
      Science, Guangzhou, China.
FAU - Ye, Huiwen
AU  - Ye H
AD  - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen 
      University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual 
      Science, Guangzhou, China.
FAU - Bai, Xue
AU  - Bai X
AD  - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen 
      University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual 
      Science, Guangzhou, China.
FAU - Wei, Yantao
AU  - Wei Y
AD  - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen 
      University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual 
      Science, Guangzhou, China.
FAU - Xu, Yue
AU  - Xu Y
AD  - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen 
      University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual 
      Science, Guangzhou, China.
FAU - Huang, Jingjing
AU  - Huang J
AD  - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen 
      University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual 
      Science, Guangzhou, China.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Invest Ophthalmol Vis Sci
JT  - Investigative ophthalmology & visual science
JID - 7703701
RN  - IY9XDZ35W2 (Glucose)
RN  - S88TT14065 (Oxygen)
RN  - EC 2.7.- (MLKL protein, mouse)
RN  - EC 2.7.- (Protein Kinases)
SB  - IM
MH  - Animals
MH  - Mice
MH  - Necroptosis
MH  - *Retinal Diseases/etiology/prevention & control
MH  - Retinal Ganglion Cells
MH  - *Eye Injuries
MH  - Glucose
MH  - Ischemia
MH  - Oxygen
MH  - Protein Kinases
PMC - PMC10691386
COIS- Disclosure: Y. Feng, None; C. Hu, None; K. Cui, None; M. Fan, None; W. Xiang, 
      None; D. Ye, None; Y. Shi, None; H. Ye, None; X. Bai, None; Y. Wei, None; Y. Xu, 
      None; J. Huang, None
EDAT- 2023/11/28 12:41
MHDA- 2023/11/29 06:42
PMCR- 2023/11/28
CRDT- 2023/11/28 10:33
PHST- 2023/11/29 06:42 [medline]
PHST- 2023/11/28 12:41 [pubmed]
PHST- 2023/11/28 10:33 [entrez]
PHST- 2023/11/28 00:00 [pmc-release]
AID - 2793053 [pii]
AID - IOVS-23-37681 [pii]
AID - 10.1167/iovs.64.14.42 [doi]
PST - ppublish
SO  - Invest Ophthalmol Vis Sci. 2023 Nov 1;64(14):42. doi: 10.1167/iovs.64.14.42.