PMID- 32749462
OWN - NLM
STAT- MEDLINE
DCOM- 20210101
LR  - 20240329
IS  - 1552-5783 (Electronic)
IS  - 0146-0404 (Print)
IS  - 0146-0404 (Linking)
VI  - 61
IP  - 10
DP  - 2020 Aug 3
TI  - A Clinical Metabolite of Azidothymidine Inhibits Experimental Choroidal 
      Neovascularization and Retinal Pigmented Epithelium Degeneration.
PG  - 4
LID - 10.1167/iovs.61.10.4 [doi]
LID - 4
AB  - PURPOSE: Azidothymidine (AZT), a nucleoside reverse transcriptase inhibitor, 
      possesses anti-inflammatory and anti-angiogenic activity independent of its 
      ability to inhibit reverse transcriptase. The aim of this study was to evaluate 
      the efficacy of 5'-glucuronyl azidothymidine (GAZT), an antiretrovirally inert 
      hepatic clinical metabolite of AZT, in mouse models of retinal pigment epithelium 
      (RPE) degeneration and choroidal neovascularization (CNV), hallmark features of 
      dry and wet age-related macular degeneration (AMD), respectively. METHODS: RPE 
      degeneration was induced in wild-type (WT) C57BL/6J mice by subretinal injection 
      of Alu RNA. RPE degeneration was assessed by fundus photography and confocal 
      microscopy of zonula occludens-1-stained RPE flat mounts. Choroidal 
      neovascularization was induced by laser injury in WT mice, and CNV volume was 
      measured by confocal microscopy. AZT and GAZT were delivered by intravitreous 
      injections. Inflammasome activation was monitored by western blotting for 
      caspase-1 and by ELISA for IL-1beta in Alu RNA-treated bone marrow-derived 
      macrophages (BMDMs). RESULTS: GAZT inhibited Alu RNA-induced RPE degeneration and 
      laser-induced CNV. GAZT also reduced Alu RNA-induced caspase-1 activation and 
      IL-1beta release in BMDMs. CONCLUSIONS: GAZT possesses dual anti-inflammatory and 
      anti-angiogenic properties and could be a viable treatment option for both forms 
      of AMD.
FAU - Narendran, Siddharth
AU  - Narendran S
AD  - ,.
AD  - ,.
AD  - ,.
FAU - Pereira, Felipe
AU  - Pereira F
AD  - ,.
AD  - ,.
FAU - Yerramothu, Praveen
AU  - Yerramothu P
AD  - ,.
AD  - ,.
FAU - Apicella, Ivana
AU  - Apicella I
AD  - ,.
AD  - ,.
FAU - Wang, Shao-Bin
AU  - Wang SB
AD  - ,.
AD  - ,.
FAU - Varshney, Akhil
AU  - Varshney A
AD  - ,.
AD  - ,.
FAU - Baker, Kirstie L
AU  - Baker KL
AD  - ,.
FAU - Marion, Kenneth M
AU  - Marion KM
AD  - ,.
FAU - Ambati, Meenakshi
AU  - Ambati M
AD  - ,.
AD  - ,.
AD  - ,.
FAU - Ambati, Vidya L
AU  - Ambati VL
AD  - ,.
FAU - Ambati, Kameshwari
AU  - Ambati K
AD  - ,.
AD  - ,.
FAU - Sadda, Srinivas R
AU  - Sadda SR
AD  - ,.
AD  - ,.
FAU - Gelfand, Bradley D
AU  - Gelfand BD
AD  - ,.
AD  - ,.
AD  - ,.
FAU - Ambati, Jayakrishna
AU  - Ambati J
AD  - ,.
AD  - ,.
AD  - ,.
AD  - ,.
AD  - ,.
LA  - eng
GR  - R01 EY028027/EY/NEI NIH HHS/United States
GR  - R01 EY029799/EY/NEI NIH HHS/United States
GR  - R01 EY031039/EY/NEI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Invest Ophthalmol Vis Sci
JT  - Investigative ophthalmology & visual science
JID - 7703701
RN  - 0 (Interleukin-1beta)
RN  - 0 (Reverse Transcriptase Inhibitors)
RN  - 0 (Tjp1 protein, mouse)
RN  - 0 (Zonula Occludens-1 Protein)
RN  - 4B9XT59T7S (Zidovudine)
RN  - CD09F5JM6T (3'-azido-3'-deoxy-5'-O-beta-glucopyranuronosylthymidine)
RN  - EC 3.4.22.36 (Casp1 protein, mouse)
RN  - EC 3.4.22.36 (Caspase 1)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - Caspase 1/metabolism
MH  - Choroidal Neovascularization/*drug therapy/metabolism
MH  - *Disease Models, Animal
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Female
MH  - Geographic Atrophy/*drug therapy/metabolism
MH  - Interleukin-1beta/metabolism
MH  - Intravitreal Injections
MH  - Macrophages/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Microscopy, Confocal
MH  - Retinal Pigment Epithelium/*drug effects
MH  - Reverse Transcriptase Inhibitors/administration & dosage/*therapeutic use
MH  - Zidovudine/administration & dosage/*analogs & derivatives/therapeutic use
MH  - Zonula Occludens-1 Protein/metabolism
PMC - PMC7441363
COIS- Disclosure: S. Narendran, University of Virginia (P); F. Pereira, University of 
      Virginia (P); P. Yerramothu, None; I. Apicella, University of Virginia (P); S.-B. 
      Wang, University of Virginia (P); A. Varshney, None; K.L. Baker, None; K.M. 
      Marion, None; M. Ambati, University of Virginia (P); V.L. Ambati, None; K. 
      Ambati, University of Virginia (P), University of Kentucky (P); S.R. Sadda, 4DMT 
      (C), Allergan (C), Amgen (C), Carl Zeiss Meditec (F), Centervue (C), Heidelberg 
      Engineering (C), Roche/Genentech (C), Novartis (C), Optos (C), Regeneron (C), 
      Oxurion (C), Merck (C), Topcon (F), Nidek (F); B.D. Gelfand, University of 
      Virginia (P); J. Ambati, iVeena Holdings (S), iVeena Delivery Systems (S), 
      Inflammasome Therapeutics (P, S), Allergan (C, R), Immunovant (C), Olix 
      Pharmaceuticals (C), Saksin LifeSciences (C, R), University of Virginia (P), 
      University of Kentucky (P)
EDAT- 2020/08/05 06:00
MHDA- 2021/01/02 06:00
PMCR- 2020/08/04
CRDT- 2020/08/05 06:00
PHST- 2020/08/05 06:00 [entrez]
PHST- 2020/08/05 06:00 [pubmed]
PHST- 2021/01/02 06:00 [medline]
PHST- 2020/08/04 00:00 [pmc-release]
AID - 2770569 [pii]
AID - IOVS-20-30387 [pii]
AID - 10.1167/iovs.61.10.4 [doi]
PST - ppublish
SO  - Invest Ophthalmol Vis Sci. 2020 Aug 3;61(10):4. doi: 10.1167/iovs.61.10.4.