Retinal safety and toxicity study of artesunate in vitro and in vivo
- AOPR Vol. 3, Issue 2, Pages: 47-54(2023)
- 作者机构：
1. ,Hong Kong,China
2. ,Hong Kong,China
3. ,Hong Kong,China
4. ,Guangdong,Guangzhou,China
- 作者简介：
- 基金信息：
DOI：10.1016/j.aopr.2022.11.003
CLC：
扫 描 看 全 文
Bing-Wen Lu, Yu-Xiang Liang, Jin-Feng Liu, et al. Retinal safety and toxicity study of artesunate in vitro and in vivo. [J]. AOPR 3(2):47-54(2023)
Bing-Wen Lu, Yu-Xiang Liang, Jin-Feng Liu, et al. Retinal safety and toxicity study of artesunate in vitro and in vivo. [J]. AOPR 3(2):47-54(2023) DOI： 10.1016/j.aopr.2022.11.003.
摘要
Background,Artesunate (ART), a member of the artemisinin family, possesses multi-properties, including anti-inflammation, anti-oxidation, and anti-tumor. ART was recently reported to show anti-neovascularization effect on the cornea, iris, and retina. Compared to the expensive anti-VEGF treatment, this versatile, economical treatment option is attractive in the ophthalmic field. The safety and toxicity profile of ART intravitreal application are in utmost need.,Methods,In this study, immortalized microglial (IMG) cells were treated with ART to determine the safe concentrations without inducing overt inflammatory reactions. Reverse transcription-polymerase chain reaction analysis was used to detect the cytokine expressions in IMG cells in response to ART stimulation. Various doses of ART were intravitreally injected into the right eyes of C57BL/6 mice. Retinal function was tested by electroretinogram, and retinal ganglion cell (RGC) survival was evaluated by counting Brn3a stained cells in flat-mounted retinas at 7 days after ART injection.,Results,ART below 5μM was safe for IMG cells ,in vitro,. Both 2.5 and 5 μM ART treatment increased IL-10 gene expression in IMG cells while not changing IL-1β, IL-6, TNF-α, and Arg-1. In the ,in vivo, study, intravitreal injection of ART below 100 μM did not cause deterioration in the retinal function and RGC survival of the mouse eyes, while 1 mM ART treatment significantly attenuated both the scotopic and photopic b-wave amplitudes and impaired RGC survival. In addition, treatment with ART of 25, 50, and 100 μM significantly decreased TNF-α gene expression while ART of 100 μM significantly increased IL-10 in the mouse retina.,Conclusions,Intravitreal injection of 100 μM ART could downregulate TNF-α while upregulate IL-10 in the mouse retina without causing retinal functional deterioration and RGC loss. ART might be used as anti-inflammatory agent for retinal disorders.
Abstract
Background,Artesunate (ART), a member of the artemisinin family, possesses multi-properties, including anti-inflammation, anti-oxidation, and anti-tumor. ART was recently reported to show anti-neovascularization effect on the cornea, iris, and retina. Compared to the expensive anti-VEGF treatment, this versatile, economical treatment option is attractive in the ophthalmic field. The safety and toxicity profile of ART intravitreal application are in utmost need.,Methods,In this study, immortalized microglial (IMG) cells were treated with ART to determine the safe concentrations without inducing overt inflammatory reactions. Reverse transcription-polymerase chain reaction analysis was used to detect the cytokine expressions in IMG cells in response to ART stimulation. Various doses of ART were intravitreally injected into the right eyes of C57BL/6 mice. Retinal function was tested by electroretinogram, and retinal ganglion cell (RGC) survival was evaluated by counting Brn3a stained cells in flat-mounted retinas at 7 days after ART injection.,Results,ART below 5μM was safe for IMG cells ,in vitro,. Both 2.5 and 5 μM ART treatment increased IL-10 gene expression in IMG cells while not changing IL-1β, IL-6, TNF-α, and Arg-1. In the ,in vivo, study, intravitreal injection of ART below 100 μM did not cause deterioration in the retinal function and RGC survival of the mouse eyes, while 1 mM ART treatment significantly attenuated both the scotopic and photopic b-wave amplitudes and impaired RGC survival. In addition, treatment with ART of 25, 50, and 100 μM significantly decreased TNF-α gene expression while ART of 100 μM significantly increased IL-10 in the mouse retina.,Conclusions,Intravitreal injection of 100 μM ART could downregulate TNF-α while upregulate IL-10 in the mouse retina without causing retinal functional deterioration and RGC loss. ART might be used as anti-inflammatory agent for retinal disorders.
关键词
Keywords
ArtesunateSafetyRetinaMicroglia
references
1 BW Lu, L Baum, KF So, et al.More than anti-malarial agents: therapeutic potential of artemisinins in neurodegeneration Neural Regen Res, 14 (2019), pp. 1494-1498, 10.4103/1673-5374.255960
2 N Ruwizhi, RB Maseko, BA AderibigbeRecent advances in the therapeutic efficacy of artesunate Pharmaceutics, 14 (2022), 10.3390/pharmaceutics14030504
3 R Cheng, C Li, C Li, et al.The artemisinin derivative artesunate inhibits corneal neovascularization by inducing ROS-dependent apoptosis in vascular endothelial cells Invest Ophthalmol Vis Sci, 54 (2013), pp. 3400-3409, 10.1167/iovs.12-11068
4 Y Zong, Y Yuan, X Qian, et al.Small molecular-sized artesunate attenuates ocular neovascularization via VEGFR2, PKCα, and PDGFR targets Sci Rep, 6 (2016), Article 30843, 10.1038/srep30843
5 C Li, X Feng, X Wen, et al.A pilot clinical study of intravitreal injection of artesunate for ocular neovascularization J Ocul Pharmacol Therapeut, 35 (2019), pp. 283-290, 10.1089/jop.2018.0097
6 YR Qin, CQ Ma, JH Jiang, et al.Artesunate restores mitochondrial fusion-fission dynamics and alleviates neuronal injury in Alzheimer’s disease models J Neurochem (2022), 10.1111/jnc.15620
7 RC McCarthy, DY Lu, A Alkhateeb, et al.Characterization of a novel adult murine immortalized microglial cell line and its activation by amyloid-beta J Neuroinflammation, 13 (2016), p. 21, 10.1186/s12974-016-0484-z
8 D Cao, J Pokorny, MA GrassiIsolated mesopic rod and cone electroretinograms realized with a four-primary method Doc Ophthalmol, 123 (2011), pp. 29-41, 10.1007/s10633-011-9279-9
9 Y Yang, N Wu, Y Wu, et al.Artesunate induces mitochondria-mediated apoptosis of human retinoblastoma cells by upregulating Kruppel-like factor 6 Cell Death Dis, 10 (2019), p. 862, 10.1038/s41419-019-2084-1
10 HM Kim, SJ WooOcular drug delivery to the retina: current innovations and future perspectives Pharmaceutics, 13 (2021), 10.3390/pharmaceutics13010108
11 EM Del Amo, AK Rimpelä, E Heikkinen, et al.Pharmacokinetic aspects of retinal drug delivery Prog Retin Eye Res, 57 (2017), pp. 134-185, 10.1016/j.preteyeres.2016.12.001
12 MR Khakzad, A Ganji, V Ariabod, et al.Artemisinin therapeutic efficacy in the experimental model of multiple sclerosis Immunopharmacol Immunotoxicol, 39 (2017), pp. 348-353, 10.1080/08923973.2017.1379087
13 D Wang, M Wu, S Li, et al.Artemisinin mimics calorie restriction to extend yeast lifespan via a dual-phase mode: a conclusion drawn from global transcriptome profiling Sci China Life Sci, 58 (2015), pp. 451-465, 10.1007/s11427-014-4736-9
14 G Rathnasamy, WS Foulds, EA Ling, et al.Retinal microglia - a key player in healthy and diseased retina Prog Neurobiol, 173 (2019), pp. 18-40, 10.1016/j.pneurobio.2018.05.006
15 C Cheng, WE Ho, FY Goh, et al.Anti-malarial drug artesunate attenuates experimental allergic asthma via inhibition of the phosphoinositide 3-kinase/Akt pathway PLoS One, 6 (2011), Article e20932, 10.1371/journal.pone.0020932
16 IS Lee, DK Ryu, J Lim, et al.Artesunate activates Nrf2 pathway-driven anti-inflammatory potential through ERK signaling in microglial BV2 cells Neurosci Lett, 509 (2012), pp. 17-21, 10.1016/j.neulet.2011.12.034
17 Y Li, S Wang, Y Wang, et al.Inhibitory effect of the antimalarial agent artesunate on collagen-induced arthritis in rats through nuclear factor kappa B and mitogen-activated protein kinase signaling pathway Transl Res, 161 (2013), pp. 89-98, 10.1016/j.trsl.2012.06.001
18 Z Yang, J Ding, C Yang, et al.Immunomodulatory and anti-inflammatory properties of artesunate in experimental colitis Curr Med Chem, 19 (2012), pp. 4541-4551, 10.2174/092986712803251575
19 S Yin, H Yang, Y Tao, et al.Artesunate ameliorates DSS-induced ulcerative colitis by protecting intestinal barrier and inhibiting inflammatory response Inflammation, 43 (2020), pp. 765-776, 10.1007/s10753-019-01164-1
20 AS Miranda, F Brant, NP Rocha, et al.Further evidence for an anti-inflammatory role of artesunate in experimental cerebral malaria Malar J, 12 (2013), p. 388, 10.1186/1475-2875-12-388
21 J Zhang, Y Zheng, Y Luo, et al.Curcumin inhibits LPS-induced neuroinflammation by promoting microglial M2 polarization via TREM2/TLR4/NF-κB pathways in BV2 cells Mol Immunol, 116 (2019), pp. 29-37, 10.1016/j.molimm.2019.09.020
22 F Mesquida-Veny, JA Del Río, A HerveraMacrophagic and microglial complexity after neuronal injury Prog Neurobiol, 200 (2021), Article 101970, 10.1016/j.pneurobio.2020.101970
23 Okorji Up, OA OlajideA semi-synthetic derivative of artemisinin, artesunate inhibits prostaglandin E2 production in LPS/IFNγ-activated BV2 microglia Bioorg Med Chem, 22 (2014), pp. 4726-4734, 10.1016/j.bmc.2014.07.007
24 E Gugliandolo, R D’Amico, M Cordaro, et al.Neuroprotective effect of artesunate in experimental model of traumatic brain injury Front Neurol, 9 (2018), p. 590, 10.3389/fneur.2018.00590
0
Views
0
下载量
0
CSCD
- Meta-XMLDownload
- BibTeXDownload
- EndnoteDownload
- RefMan Download
- NoteExpressDownload
- NoteFirstDownload
Publicity Resources
Related Articles
Related Author
Related Institution
- Technical support is provided by Beijing Founder electronics co., LTD 京ICP备09064830号-19
京公网安备11010802024621 - It is recommended to read the content of this site in Chrome&IE9+. Please switch to extreme mode in browser 360.
- Cookies We use cookies to help provide and enhance our service and tailor content. By continuing, you agree to the use of cookies.