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Novel aspirin-triggered neuroprotectin D1 attenuates cerebral ischemic injury after experimental stroke
Open accessAbstract
Acute ischemic stroke triggers complex neurovascular, neuroinflammatory and synaptic alterations. Aspirin and docosahexaenoic acid (DHA), an omega-3 essential fatty acid family member, have beneficial effects on cerebrovascular diseases. DHA is the precursor of neuroprotectin D1 (NPD1), which downregulates apoptosis and, in turn, promotes cell survival. Here we have tested the effect of aspirin plus DHA administration and discovered the synthesis of aspirin-triggered NPD1 (AT-NPD1) in the brain. Then we performed the total chemical synthesis of this molecule and tested in the setting of 2h middle cerebral artery occlusion (MCAo) in Sprague-Dawley rats. Neurological status was evaluated at 24h, 48 h, 72 h, and 7 days. At 3h post-stroke onset, an intravenous administration of 333 μg/kg of AT-NPD1 sodium salt (AT-NPD1-SS) or methyl-ester (AT-NPD1-ME) or vehicle (saline) as treatment was given. On day 7, ex vivo magnetic resonance imaging (MRI) of the brains was conducted on 11.7 T MRI. T2WI, 3D volumes, and apparent diffusion coefficient (ADC) maps were generated. In addition, infarct volumes and number of GFAP (reactive astrocytes), ED-1 (activated microglia/macrophages) and SMI-71-positive vessels were counted in the cortex and striatum at the level of the central lesion. All animals showed similar values for rectal and cranial temperatures, arterial blood gases, and plasma glucose during and after MCAo. Treatment with both AT-NPD1-SS and AT-NPD1-ME significantly improved neurological scores compared to saline treatment at 24h, 48 h, 72 h and 7 days. Total lesion volumes computed from T2WI images were significantly reduced by both AT-NPD1-SS and AT-NPD1-ME treatment in the cortex (by 44% and 81%), striatum (by 61% and 77%) and total infarct (by 48% and 78%, respectively). Brain edema, computed from T2WI in the cortex (penumbra) and striatum (core), was elevated in the saline group. In contrast, both AT-NPD1 decreased water content in the striatum on day 7. 3D volumes, computed from T2WI, were dramatically reduced with both AT-NPD1 and the lesion was mostly localized in the subcortical areas. Treatment with both AT-NPD1-SS and AT-NPD1-ME significantly reduced cortical (by 76% and 96%), subcortical (by 61% and 70%) and total (69% and 84%, respectively) infarct volumes as defined by histopathology. In conclusion, a novel biosynthetic pathway that leads to the formation of AT-NPD1 mediator in the brain was discovered. In addition, administration of synthetic AT-NPD1, in either its sodium salt or as the methyl ester, was able to attenuate cerebral ischemic injury which leads to a novel approach for pharmaceutical intervention and clinical translation.
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“NPD1 is highlighted here as a neuroprotective mediator in ischemic stroke, as defined by cellular and molecular targets, and demonstrated that the pathway that leads to its formation was enhanced in its neuroprotective bioactivity by the presence of aspirin (Marcheselli et al., 2003) by aspirin-triggered NPD1 (Bazan et al., 2012; Serhan et al., 2015; Serhan and Petasis, 2011).”
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 Bazan et al., 2012
In the citing paper
“NPD1 is highlighted here as a neuroprotective mediator in ischemic stroke, as defined by cellular and molecular targets, and demonstrated that the pathway that leads to its formation was enhanced in its neuroprotective bioactivity by the presence of aspirin (Marcheselli et al., 2003) by aspirin-triggered NPD1 (Bazan et al., 2012; Serhan et al., 2015; Serhan and Petasis, 2011).”
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 Bazan et al., 2012
In the citing paper
“DHA and NPD1 display potent neuroprotective bioactivity when given 1 hour after 2 hours of MCAo in rats (Bazan et al., 2012; Belayev et al., 2018, 2017, 2011; Calandria et al., 2015; Eady et al., 2012; Hong et al., 2015, 2014; Serhan et al., 2011).”
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 Bazan et al., 2012
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“Given its potent protective actions in the retina and brain, we initially termed this DHA-derived mediator neuroprotectin D1 (NPD1) (Bazan et al., 2010; Mukherjee et al., 2004; Stark and Bazan, 2011a).”
Clària, J., & Serhan, C. N. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.21.9475 · Cited by 703
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Metadata
- Authors
- Bazan, N. G., Eady, T. N., Khoutorova, L., Atkins, K. D., Hong, S., Lu, Y., Zhang, C., Jun, B., Obenaus, A., Fredman, G., Zhu, M., Winkler, J. W., Petasis, N. A., Serhan, C. N., & Belayev, L.
- Affiliations
- Louisiana State University Health Sciences Center New Orleans (US)
- Brigham and Women's Hospital (US)
- University of Southern California (US)
- Corresponding author
- Bazan, Nicolas G.
- ORCID
- Venue
- Experimental Neurology
- Publisher
- Elsevier BV
- Published
- 2012-07
- Volume
- 236
- Issue
- 1
- Pages
- 122-130
- ISSN
- 0014-4886 (ISSN-L)
- PMC
- PMC3409566
- OpenAlex
- W2039267832
- Cited by
- 121
- References
- 34
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 3 · 2023: 8 · 2022: 10 · 2021: 8 · 2020: 8 · 2019: 9 · 2018: 9 · 2017: 10 · 2016: 7 · 2015: 8 · 2014: 13 · 2013: 13 · 2012: 4
- FWCI
- 6.11
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Center for Complementary and Alternative Medicine
- National Institute of Neurological Disorders and Stroke (R01NS046741)
- National Center for Complementary and Integrative Health (RC2AT005909)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroprotection in Cerebral Ischemia
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Health Sciences › Medicine › Clinical Neurology › Acute Ischemic Stroke Management
- Keywords
- neuroprotectin D1, aspirin, docosahexaenoic acid, acute ischemic stroke, cerebral ischemia, middle cerebral artery occlusion, neuroprotection, infarct size, cerebral edema, neuroinflammation, microglia/macrophages, astrocytes, omega-3 fatty acids, chemical synthesis
- MeSH terms
- Animals, Anti-Inflammatory Agents, Non-Steroidal, Aspirin, Brain Ischemia, Docosahexaenoic Acids, Male, Rats, Sprague-Dawley, Infarction, Middle Cerebral Artery, Rats
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