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Neuroprotectin D1: A docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress
Open accessAbstract
Docosahexaenoic acid (DHA) is a lipid peroxidation target in oxidative injury to retinal pigment epithelium (RPE) and retina. Photoreceptor and synaptic membranes share the highest content of DHA of all cell membranes. This fatty acid is required for RPE functional integrity; however, it is not known whether specific mediators generated from DHA contribute to its biological significance. We used human ARPE-19 cells and demonstrated the synthesis of 10,17S-docosatriene [neuroprotectin D1 (NPD1)]. This synthesis was enhanced by the calcium ionophore A-23187, by IL-1beta, or by supplying DHA. Under these conditions, there is a time-dependent release of endogenous free DHA followed by NPD1 formation, suggesting that phospholipase A(2) releases the mediator's precursor. Added NPD1 potently counteracted H(2)O(2)/tumor necrosis factor alpha oxidative-stress-triggered apoptotic RPE DNA damage. NPD1 also up-regulated the antiapoptotic proteins Bcl-2 and Bcl-x(L) and decreased proapoptotic Bax and Bad expression. Moreover, NPD1 (50 nM) inhibited oxidative-stress-induced caspase-3 activation. NPD1 also inhibited IL-1beta-stimulated expression of cyclooxygenase 2 promoter transfected into ARPE-19 cells. Overall, NPD1 protected RPE cells from oxidative-stress-induced apoptosis, and we predict that it will similarly protect neurons. This lipid mediator therefore may indirectly contribute to photoreceptor cell survival as well. Because both RPE and photoreceptor cells die in retinal degenerations, our findings contribute to the understanding of retinal cell survival signaling and potentially to the development of new therapeutic strategies.
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“DHA then ends up amounting to more than 50% of OS phospholipid fatty acyl chains and therefore DHA-containing phospholipids in the retina and other cells are reservoirs for docosanoids (Bazan et al., 1984; Mukherjee et al., 2004).”
From Docosanoids and elovanoids from omega-3 fatty acids are pro-homeostatic modulators of inflammatory responses, cell damage and neuroprotection (2018) · cites this paper as Mukherjee et al., 2004
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“In fact, NPD1 also induces the anti-apoptotic Bcl-2 family of proteins Bcl-2 and Bcl-xl in oxidatively challenged human RPE cells (Mukherjee et al., 2004) and promotes cytoprotection.”
From Docosanoids and elovanoids from omega-3 fatty acids are pro-homeostatic modulators of inflammatory responses, cell damage and neuroprotection (2018) · cites this paper as Mukherjee et al., 2004
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Identification of 14,20-dihydroxy-docosahexaenoic acid as a novel anti-inflammatory metabolite
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“PD1 reduces retinal and corneal injury (12), stroke damage (13), and improves corneal wound healing in mouse models (14).”
Anti-inflammatory and anti-virus potential of poxytrins, especially protectin DX
Lagarde, M., Guichardant, M., & Bernoud‐Hubac, N. (2020) · Biochimie · doi:10.1016/j.biochi.2020.09.008 · Cited by 19
“The geometric and stereoisomer of the poxytrin PDX, PD1, has also been named neuroprotectin D1, because of its neuroprotective activity [11,17].”
Ruiz-Pastor, M. J., Kutsyr, O., Lax, P., & Cuenca, N. (2021) · Experimental Eye Research · doi:10.1016/j.exer.2021.108667 · Cited by 19
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“0 min), showed the ions characteristic of the compound corresponding to 10,17(S)dihydroxydocosahexaenoic acid [18, 19, 20]; a representa-”
Nutrition challenges for the twenty-first century
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“This docosanoid, 10-17S-docosatriene, more recently named neuroprotectin D1 (Mukherjee et al. 2004), has been shown to act potently on cultured neuronal cells to down-regulate proinflammatory gene expression (Marcheselli et al. 2003).”
InfluentialBate, C., Marshall, V., Colombo, L., Diomede, L., Salmona, M., & Williams, A. (2008) · Neuropharmacology · doi:10.1016/j.neuropharm.2008.02.003 · Cited by 19
“Recent studies suggest that DHA is a substrate for lipoxygenases and cyclooxygenases and is metabolised into docosanoids (Mukherjee et al., 2004; Serhan, 2005) and since the effects of such DHA metabolites are not fully understood, the possibility that they may have adverse affects on neuronal survival cannot be exclu…”
Knott, E. J., Gordon, W. C., Jun, B., Do, K., & Bazan, N. G. (2018) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-017-0565-2 · Cited by 18
Lipid mediators in glaucoma: Unraveling their diverse roles and untapped therapeutic potential
Mathew, D., & Sivak, J. M. (2024) · Prostaglandins & Other Lipid Mediators · doi:10.1016/j.prostaglandins.2024.106815 · Cited by 18
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Reid, M. M., Kautzmann, M.-A. I., Andrew, G., Obenaus, A., Mukherjee, P. K., Khoutorova, L., Ji, J. X., Roque, C. R., Oriá, R. B., Habeb, B. F., et al. (2023) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-023-01363-3 · Cited by 20
Shewchuk, B. M. (2014) · Prostaglandins Leukotrienes and Essential Fatty Acids · doi:10.1016/j.plefa.2014.09.005 · Cited by 20
“their ability to protect against damage to neural tissue in the context of ischemic stroke [31–33].”
ResolvinD1 reduces apoptosis and inflammation in primary human alveolar epithelial type 2 cells
Xie, W., Wang, H., Liu, Q., Li, Y., Wang, J., Yao, S., & Wu, Q. (2016) · Laboratory Investigation · doi:10.1038/labinvest.2016.31 · Cited by 18
Ugalde, V., Armenta, R. E., Kermanshahi‐pour, A., Sun, Z., Berryman, K. T., & Brooks, M. S. (2017) · Journal of Applied Phycology · doi:10.1007/s10811-017-1274-4 · Cited by 18
“It is hypothesized that the biosynthesis of EPA and other PUFAs by thraustochytrids is to provide antioxidants to protect cells when subjected to oxidative stress during starvation periods (Mukherjee et al. 2004).”
Synthesis of protectin D1 analogs: novel pro-resolution and radiotracer agents
Tungen, J. E., Aursnes, M., Ramon, S., Colas, R. A., Serhan, C. N., Olberg, D. E., Nuruddin, S., Willoch, F., & Hansen, T. V. (2018) · Organic & Biomolecular Chemistry · doi:10.1039/c8ob01232f · Cited by 19
Cytochrome P450 2C Epoxygenases Mediate Photochemical Stress-induced Death of Photoreceptors
Chang, Q., Berdyshev, E. V., Cao, D., Bogaard, J. D., White, J. J., Chen, S., Shah, R., Mu, W., Grantner, R., Bettis, S., et al. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.507152 · Cited by 18
“In the eye, neuroprotectin D1 (10,17S-docosatriene), a 15-lipoxygenase-1-mediated metabolite of DHA, acts as a potent cytoprotective mediator that prevents oxidative stress-induced apoptosis in retinal pigment epithelial cells (82).”
Calandria, J. M., Sharp, M., & Bazan, N. G. (2015) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-015-0206-6 · Cited by 18
“Also, under oxidative stress conditions, DHA is converted into NPD1 (Calandria et al. 2009) and the latter decreases caspase activation in neurons (Calandria et al. 2012; Mukherjee et al. 2004).”
Chiang, N., & Serhan, C. N. (2006) · Comprehensive Therapy · doi:10.1007/s12019-006-0005-6 · Cited by 17
Self-citationKolawole, O. R., & Kashfi, K. (2025) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2025.177924 · Cited by 19
Immunomodulation of periodontitis with SPMs
Sahni, V., & Dyke, T. E. V. (2023) · Frontiers in Oral Health · doi:10.3389/froh.2023.1288722 · Cited by 20
The role of 15-LOX-1 in colitis and colitis-associated colorectal cancer
Mao, F., Wang, M., Wang, J., & Xu, W. (2015) · Inflammation Research · doi:10.1007/s00011-015-0852-7 · Cited by 17
“Although COX-2 is thought to contribute to the formation of colitis, COX-2 and 15-LOX-1 play a key role in homeostasis to reverse acute and chronic inflammation.”
InfluentialTotal synthesis of the potent anti-inflammatory lipid mediator Protectin D1
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“DHA by itself or through its metabolites, docosanoids are important in supporting the function of neurons (Bazan, 2009; Mukherjee et al. 2004).”
Zhao, G., Gao, J., Liang, S., Wang, X., Sun, C., Xia, W. T., Hao, Y., Li, X., Cao, Y., & Wu, L. (2015) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2015.04.350 · Cited by 19
“In addition, NPD1 inhibits oxidative stress-induced caspase-3 activation and apoptosis (Mukherjee et al., 2004; Lukiw et al., 2005).”
Tanito, M., & Anderson, R. E. (2009) · Clinical Lipidology · doi:10.2217/clp.09.65 · Cited by 17
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“This DHA derivative also protects the retina against RPE oxidative stress [169].”
Fukuishi, N., Takahama, K., Kurosaki, H., Ono, S., & Asai, H. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26041491 · Cited by 18
“PD was first identified as a defensive mediator released from APRE-19 cells, which is a human retinal pigment epithelial cell line, in response to stimulation with A-23187 or IL-1 β [110].”
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“Moreover, these results and those obtained together with Bazan and colleagues in neural tissues demonstrate that PD1 displays potent immunoregulatory (12, 13, 16) and neuroprotective actions (10, 14, 15) as well as promoting wound healing capacity (25).”
InfluentialIsopropyl‐phloroglucinol‐DHA protects outer retinal cells against lethal dose of all‐ trans ‐retinal
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Metadata
- Authors
- Mukherjee, P. K., Marcheselli, V. L., Serhan, C. N., & Bazan, N. G.
- Affiliations
- Louisiana State University (US)
- Corresponding author
- Bazan, Nicolas G.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2004-05-19
- Volume
- 101
- Issue
- 22
- Pages
- 8491-8496
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC420421
- OpenAlex
- W1739691545
- Cited by
- 753
- References
- 50
- Citations by year
- 2026: 22 · 2025: 14 · 2024: 13 · 2023: 14 · 2022: 24 · 2021: 20 · 2020: 34 · 2019: 23 · 2018: 25 · 2017: 34 · 2016: 24 · 2015: 35 · 2014: 42 · 2013: 52 · 2012: 42
- FWCI
- 44.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Huntsman Cancer Institute
- University of Leicester
- National Institutes of Health (4r37gm038765-19, GM 38765)
- National Eye Institute (EY05121, R01EY005121)
- National Institute of General Medical Sciences (GM 38765, R01GM038765, R37-GM038765)
- National Center for Research Resources (P20RR-16816, P20RR016816)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Health Sciences › Medicine › Biochemistry (medical) › Antioxidant Activity and Oxidative Stress
- Keywords
- neuroprotectin D1, docosahexaenoic acid, retinal pigment epithelium, oxidative stress, apoptosis, phospholipase A2, cyclooxygenase-2, Bcl-2 family proteins, caspase-3, IL-1β, photoreceptor survival, retinal degeneration, lipid mediators
- MeSH terms
- Cell Line, Docosahexaenoic Acids, Epithelial Cells, Humans, Interleukin-1, Isoenzymes, Membrane Proteins, Pigment Epithelium of Eye, Prostaglandin-Endoperoxide Synthases, Lipid Peroxidation, Molecular Structure, Apoptosis, Oxidative Stress, Proto-Oncogene Proteins c-bcl-2, Caspases, Cyclooxygenase 2, Caspase 3, DNA Fragmentation
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