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The failure to resolve inflammation underpins to several prevalent diseases, like atherosclerosis, and so identifying ways to boost resolution is unmet clinical needs. The resolution of inflammation is governed by several factors such as specialized pro-resolving mediators (SPMs) that counter-regulate pro-inflammatory pathways and promote tissue repair without compromising host defense. A major function of nearly all SPMs is to enhance the clearance of dead cells or efferocytosis. As such, phagocytes, such as macrophages, are essential cellular players in the resolution of inflammation because of their ability to rapidly and efficiently clear dead cells. This review highlights the role of SPMs in the clearance of apoptotic and necroptotic cells and offers insights into how targeting efferocytosis may provide new treatments for non-resolving diseases, like atherosclerosis., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The resolution of inflammation (or inflammation-resolution) is an active and highly coordinated process. Inflammation-resolution is governed by several endogenous factors, and specialized pro-resolving mediators (SPMs) are one such class of molecules that have robust biological function. Non-resolving inflammation is associated with a variety of human diseases, including atherosclerosis. Moreover, non-resolving inflammation is a hallmark of ageing, an inevitable process associated with increased risk for cardiovascular disease. Uncovering mechanisms as to why inflammation-resolution is impaired in ageing and in disease and identifying useful biomarkers for non-resolving inflammation are unmet needs. Recent work has pointed to a critical role for balanced ratios of SPMs and pro-inflammatory lipids (i.e. leucotrienes and/or specific prostaglandins) as a key determinant of timely inflammation resolution. This review will focus on the accumulating findings that support the role of non-resolving inflammation and imbalanced pro-resolving and pro-inflammatory mediators in atherosclerosis. We aim to provide insight as to why these imbalances occur, the importance of ageing in disease progression, and how haematopoietic function impacts inflammation-resolution and atherosclerosis. We highlight open questions regarding therapeutic strategies and mechanisms of disease to provide a framework for future studies that aim to tackle this important human disease., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

The resolution of inflammation is a tissue protective program that is governed by several factors including specialized pro-resolving mediators (SPMs), proteins, gasses and nucleotides. Pro-resolving mediators activate counterregulatory programs to quell inflammation and promote tissue repair in a manner that does not compromise host defense. Phagocytes like neutrophils and macrophages play key roles in the resolution of inflammation because of their ability to remove debris, microbes and dead cells through processes including phagocytosis and efferocytosis. Emerging evidence suggests that failed resolution of inflammation and defective phagocytosis or efferocytosis underpins several prevalent human diseases. Therefore, understanding factors and mechanisms associated with enhancing these processes is a critical need. SPMs enhance phagocytosis and efferocytosis and this review will highlight mechanisms associated with their actions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Decker, Sadhu and Fredman.)

Inflammation-resolution is mediated by the balance between specialized pro-resolving mediators (SPMs) like resolvin D1 (RvD1) and pro-inflammatory factors, like leukotriene B 4 (LTB 4 ). A key cellular process of inflammation-resolution is efferocytosis. Aging is associated with defective inflammation-resolution and the accumulation of pro-inflammatory senescent cells (SCs). Therefore, understanding mechanism(s) that underpin this impairment is a critical gap. Here, using a model of hind limb ischemia-reperfusion (I/R) remote lung injury, we present evidence that aging is associated with heightened inflammation, impaired SPM:LT ratio, defective efferocytosis, and a decrease in MerTK levels in injured lungs. Treatment with RvD1 mitigated I/R lung injury in aging, promoted efferocytosis, and prevented the decrease of MerTK in injured lungs from old mice. Old MerTK cleavage-resistant mice (MerTK CR ) exhibited less neutrophils or polymorpho nuclear cells infiltration and had improved efferocytosis compared with old WT controls. Mechanistically, macrophages that were treated with conditioned media (CM) from senescent cells had increased MerTK cleavage, impaired efferocytosis, and a defective RvD1:LTB 4 ratio. Macrophages from MerTK CR mice were resistant to CM-induced efferocytosis defects and had an improved RvD1:LTB 4 ratio. RvD1-stimulated macrophages prevented CM-induced MerTK cleavage and promoted efferocytosis. Together, these data suggest a new mechanism and a potential therapy to promote inflammation-resolution and efferocytosis in aging., (© 2019 Federation of American Societies for Experimental Biology.)

Defective inflammation resolution is the underlying cause of prevalent chronic inflammatory diseases, such as arthritis, asthma, cancer, and neurodegenerative and cardiovascular diseases. Inflammation resolution is governed by several endogenous factors, including fatty acid-derived specialized proresolving mediators and proteins, such as annexin A1. Specifically, specialized proresolving mediators comprise a family of mediators that include arachidonic acid-derived lipoxins, omega-3 fatty acid eicosapentaenoic acid-derived resolvins, docosahexaenoic acid-derived resolvins, protectins, and maresins. Emerging evidence indicates that imbalances between specialized proresolving mediators and proinflammatory mediators are associated with several prevalent human diseases, including atherosclerosis. Mechanisms that drive this imbalance remain largely unknown and will be discussed in this review. Furthermore, the concept of dysregulated inflammation resolution in atherosclerosis has been known for several decades. Recently, there has been an explosion of new work with regard to the therapeutic application of proresolving ligands in experimental atherosclerosis. Therefore, this review will highlight recent advances in our understanding of how inflammation resolution may become defective in atherosclerosis and the potential for proresolving therapeutics in atherosclerosis. Last, we offer insight for future implications of the field., (Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Nonresolving inflammation is now considered the underpinning of several prevalent human diseases, including atherosclerosis. The resolution of inflammation is a highly coordinated program to counterbalance proinflammatory signals for a swift return to tissue homeostasis. This process is controlled in part by endogenous specialized proresolving lipid mediators (SPMs). Emerging evidence has revealed that the balance of SPMs and proinflammatory mediators during acute inflammation regulates the duration of the inflammatory response and the timing of tissue resolution. Moreover, an imbalance between SPMs and proinflammatory mediators has been linked to several prevalent chronic inflammatory diseases in humans, including atherosclerosis., Recent Findings: Lipid mediator imbalances have recently been linked to atherosclerotic plaque instability. Administration of key SPMs restored this imbalance and led to plaque stability. SPMs have also recently been shown to be protective in other cardiovascular disease models including myocardial infarction, stroke and neointimal hyperplasia., Summary: The current review highlights recent work that supports the concept of dysregulated inflammation-resolution in atherosclerosis with a particular focus on mechanisms and therapeutic opportunities associated with SPM receptors and lipid mediator imbalances. This article is based on experimental studies.

The acute inflammatory response requires a coordinated resolution program to prevent excessive inflammation, repair collateral damage, and restore tissue homeostasis, and failure of this response contributes to the pathology of numerous chronic inflammatory diseases. Resolution is mediated in part by long-chain fatty acid-derived lipid mediators called specialized proresolving mediators (SPMs). However, how SPMs are regulated during the inflammatory response, and how this process goes awry in inflammatory diseases, are poorly understood. We now show that signaling through the Mer proto-oncogene tyrosine kinase (MerTK) receptor in cultured macrophages and in sterile inflammation in vivo promotes SPM biosynthesis by a mechanism involving an increase in the cytoplasmic:nuclear ratio of a key SPM biosynthetic enzyme, 5-lipoxygenase. This action of MerTK is linked to the resolution of sterile peritonitis and, after ischemia-reperfusion (I/R) injury, to increased circulating SPMs and decreased remote organ inflammation. MerTK is susceptible to ADAM metallopeptidase domain 17 (ADAM17)-mediated cell-surface cleavage under inflammatory conditions, but the functional significance is not known. We show here that SPM biosynthesis is increased and inflammation resolution is improved in a new mouse model in which endogenous MerTK was replaced with a genetically engineered variant that is cleavage-resistant (Mertk(CR)). Mertk(CR) mice also have increased circulating levels of SPMs and less lung injury after I/R. Thus, MerTK cleavage during inflammation limits SPM biosynthesis and the resolution response. These findings contribute to our understanding of how SPM synthesis is regulated during the inflammatory response and suggest new therapeutic avenues to boost resolution in settings where defective resolution promotes disease progression.

Inflammation contributes to many of the characteristics of plaques implicated in the pathogenesis of acute coronary syndromes. Moreover, inflammatory pathways not only regulate the properties of plaques that precipitate acute coronary syndromes but also modulate the clinical consequences of the thrombotic complications of atherosclerosis. This synthesis will provide an update on the fundamental mechanisms of inflammatory responses that govern acute coronary syndromes and also highlight the ongoing balance between proinflammatory mechanisms and endogenous pathways that can promote the resolution of inflammation. An appreciation of the countervailing mechanisms that modulate inflammation in relation to acute coronary syndromes enriches our fundamental understanding of the pathophysiology of this important manifestation of atherosclerosis. In addition, these insights provide glimpses into potential novel therapeutic interventions to forestall this ultimate complication of the disease., (© 2014 American Heart Association, Inc.)

Resolution of acute inflammation is an active process that involves the biosynthesis of specialized proresolving lipid mediators. Among them, resolvin D1 (RvD1) actions are mediated by two G protein-coupled receptors (GPCRs), ALX/FPR2 and GPR32, that also regulate specific microRNAs (miRNAs) and their target genes in novel resolution circuits. We report the ligand selectivity of RvD1 activation of ALX/FPR2 and GPR32. In addition to RvD1, its aspirin-triggered epimer and RvD1 analogs each dose dependently and effectively activated ALX/FPR2 and GPR32 in GPCR-overexpressing β-arrestin systems using luminescence and electric cell-substrate impedance sensing. To corroborate these findings in vivo, neutrophil infiltration in self-limited peritonitis was reduced in human ALX/FPR2-overexpressing transgenic mice that was further limited to 50% by RvD1 treatment with as little as 10 ng of RvD1 per mouse. Analysis of miRNA expression revealed that RvD1 administration significantly up-regulated miR-208a and miR-219 in exudates isolated from ALX/FPR2 transgenic mice compared with littermates. Overexpression of miR-208a in human macrophages up-regulated IL-10. In comparison, in ALX/FPR2 knockout mice, RvD1 neither significantly reduced leukocyte infiltration in zymosan-induced peritonitis nor regulated miR-208a and IL-10 in these mice. Together, these results demonstrate the selectivity of RvD1 interactions with receptors ALX/FPR2 and GPR32. Moreover, they establish a new molecular circuit that is operative in the resolution of acute inflammation activated by the proresolving mediator RvD1 involving specific GPCRs and miRNAs., (Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Mechanisms underlying delays in resolution programs of inflammation are of interest for many diseases. Here, we addressed delayed resolution of inflammation and identified specific microRNA (miR)-metabolipidomic signatures. Delayed resolution initiated by high-dose challenges decreased miR-219-5p expression along with increased leukotriene B(4) (5-fold) and decreased (~3-fold) specialized pro-resolving mediators, e.g. protectin D1. Resolvin (Rv)E1 and RvD1 (1 nM) reduced miR-219-5p in human macrophages, not shared by RvD2 or PD1. Since mature miR-219-5p is produced from pre-miRs miR-219-1 and miR-219-2, we co-expressed in human macrophages a 5-lipoxygenase (LOX) 3'UTR-luciferase reporter vector together with either miR-219-1 or miR-219-2. Only miR-219-2 reduced luciferase activity. Apoptotic neutrophils administered into inflamed exudates in vivo increased miR-219-2-3p expression and PD1/NPD1 levels as well as decreased leukotriene B(4). These results demonstrate that delayed resolution undermines endogenous resolution programs, altering miR-219-2 expression, increasing pro-inflammatory mediators and compromising SPM production that contribute to failed catabasis and homeostasis.

Background: Local and volatile anesthetics are widely used for surgery. It is not known whether anesthetics impinge on the orchestrated events in spontaneous resolution of acute inflammation. Here we investigated whether a commonly used local anesthetic (lidocaine) and a widely used inhaled anesthetic (isoflurane) impact the active process of resolution of inflammation., Methods and Findings: Using murine peritonitis induced by zymosan and a systems approach, we report that lidocaine delayed and blocked key events in resolution of inflammation. Lidocaine inhibited both PMN apoptosis and macrophage uptake of apoptotic PMN, events that contributed to impaired PMN removal from exudates and thereby delayed the onset of resolution of acute inflammation and return to homeostasis. Lidocaine did not alter the levels of specific lipid mediators, including pro-inflammatory leukotriene B(4), prostaglandin E(2) and anti-inflammatory lipoxin A(4), in the cell-free peritoneal lavages. Addition of a lipoxin A(4) stable analog, partially rescued lidocaine-delayed resolution of inflammation. To identify protein components underlying lidocaine's actions in resolution, systematic proteomics was carried out using nanospray-liquid chromatography-tandem mass spectrometry. Lidocaine selectively up-regulated pro-inflammatory proteins including S100A8/9 and CRAMP/LL-37, and down-regulated anti-inflammatory and some pro-resolution peptides and proteins including IL-4, IL-13, TGF-â and Galectin-1. In contrast, the volatile anesthetic isoflurane promoted resolution in this system, diminishing the amplitude of PMN infiltration and shortening the resolution interval (Ri) approximately 50%. In addition, isoflurane down-regulated a panel of pro-inflammatory chemokines and cytokines, as well as proteins known to be active in cell migration and chemotaxis (i.e., CRAMP and cofilin-1). The distinct impact of lidocaine and isoflurane on selective molecules may underlie their opposite actions in resolution of inflammation, namely lidocaine delayed the onset of resolution (T(max)), while isoflurane shortened resolution interval (Ri)., Conclusions: Taken together, both local and volatile anesthetics impact endogenous resolution program(s), altering specific resolution indices and selective cellular/molecular components in inflammation-resolution. Isoflurane enhances whereas lidocaine impairs timely resolution of acute inflammation.

Inflammation-resolution is an active process that is governed in part by specialized pro-resolving mediators (SPMs) such as lipoxins, resolvins, protectins, and maresins. SPMs, which are endogenously biosynthesized, quell inflammation and repair tissue damage in a manner that does not compromise host defense. Importantly, failed inflammation-resolution is an important driving force in the progression of several prevalent diseases including atherosclerosis. Atherosclerosis is a leading cause of death worldwide and uncovering mechanisms that underpin defective inflammation-resolution and whether SPMs themselves can revert the progression of the disease are of utmost clinical interest. Because atherosclerosis is a disease in which low-grade persistent inflammation results in tissue injury, SPMs have garnered immense interest as a potential treatment strategy. This mini review will highlight recent work that describes mechanisms associated with defective inflammation-resolution in atherosclerosis, as well as the protective actions of SPMs and their potential use as a therapeutic. [ABSTRACT FROM AUTHOR]

miR-21 is one of the most highly expressed members of the small non-coding microRNA family in many mammalian cell types. Its expression is further enhanced in many diseased states including solid tumors, cardiac injury, and inflamed tissue. While the induction of miR-21 by inflammatory stimuli cells has been well documented in both hematopoietic cells of the immune system (particularly monocytes/macrophages but also dendritic and T-cells) and non-hematopoietic tumorigenic cells, the exact functional outcome of this elevated miR-21 is less obvious. Recent studies have confirmed a key role for miR-21 in the resolution of inflammation and in negatively regulating the pro-inflammatory response induced by many of the same stimuli that trigger miR-21 induction itself. In particular, miR- 21 has emerged as a key mediator of the anti-inflammatory response in macrophages. This suggests that miR-21 inhibition in leukocytes will promote inflammation and may enhance current therapies for defective immune responses such as cancer, mycobacterial vaccines, or Th2-associated allergic inflammation. At the same time, miR-21 has been shown to promote inflammatory mediators in non-hematopoietic cells resulting in neoplastic transformation. This reviewwill focus on functional studies of miR-21 during inflammation, which is complicated by the numerous molecular targets and processes that have emerged as miR-21 sensitive. It may be that the exact functional outcome of miR-21 is determined by multiple features including the cell type affected, the inducing signal, the transcriptomic profile of the cell, which ultimately affect the availability and ability to engage different target mRNAs and bring about its unique responses. Reviewing this data may illustrate that RNA-based oligonucleotide therapies for different diseases based upon miR-21 may have to target the unique and operative miRNA:mRNA interactions' functionally active in disease. [ABSTRACT FROM AUTHOR]

Resolution of inflammation is an active temporally orchestrated process demonstrated by the biosynthesis of novel proresolving mediators. Dysregulation of resolution pathways may underlie prevalent human inflammatory diseases such as cardiovascular diseases and periodontitis. Localized Aggressive Periodontitis (LAP) is an early onset, rapidly progressing form of inflammatory periodontal disease. Here, we report increased surface P-selectin on circulating LAP platelets, and elevated integrin (CD18) surface expression on neutrophils and monocytes compared to healthy, asymptomatic controls. Significantly more platelet-neutrophil and platelet-monocyte aggregates were identified in circulating whole blood of LAP patients compared with asymptomatic controls. LAP whole blood generates increased pro-inflammatory LTB4 with addition of divalent cation ionophore A23187 (5 µM) and significantly less, 15-HETE, 12-HETE, 14-HDHA, and lipoxin A4. Macrophages from LAP subjects exhibit reduced phagocytosis. The pro-resolving lipid mediator, Resolvin E1 (0.1-100 nM), rescues the impaired phagocytic activity in LAP macrophages. These abnormalities suggest compromised resolution pathways, which may contribute to persistent inflammation resulting in establishment of a chronic inflammatory lesion and periodontal disease progression. [ABSTRACT FROM AUTHOR]

Summary: Endogenous mechanisms in the resolution of acute inflammation are of interest because excessive inflammation underlies many pathologic abnormalities. We report an aspirin-triggered DHA metabolome that biosynthesizes a potent product in inflammatory exudates and human leukocytes, namely aspirin-triggered Neuroprotectin D1/Protectin D1 [AT-(NPD1/PD1)]. The complete stereochemistry of AT-(NPD1/PD1) proved to be 10R,17R-dihydroxydocosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid. The chirality of hydroxyl groups and geometry of the conjugated triene system essential for bioactivity were established by matching biological materials with stereochemically pure isomers prepared by organic synthesis. AT-(NPD1/PD1) reduced neutrophil (PMN) recruitment in murine peritonitis in a dose-dependent fashion whereby neither a Δ15-trans-isomer nor DHA was effective. With human cells, AT-(NPD1/PD1) decreased transendothelial PMN migration as well as enhanced efferocytosis of apoptotic human PMN by macrophages. These results indicate that AT-(NPD1/PD1) is a potent anti-inflammatory proresolving molecule. [ABSTRACT FROM AUTHOR]

Inflammation when uncontrolled is associated with prevalent disorders such as arthritis and periodontal disease, diabetes and cardiovascular diseases. Hence mechanisms to dampen the inflammatory response and promote resolution are of immense interest. Recent evidence has prompted a paradigm shift whereby the resolution of acute inflammation is now considered a biochemically active process regulated in part by endogenous PUFA (polyunsaturated fatty acid)-derived autacoids. Among these are specialized pro-resolving mediators ( SPMs) that comprise lipoxins, resolvins, protectins and maresins. SPMs are endogenous stereoselective, potent mediators that temper both the magnitude and duration of inflammatory responses. Moreover, an appreciation of these endogenous mediators and pathways that control timely resolution opens a new terrain for therapeutic approaches targeted at stimulating resolution of local inflammation. The focus of this review is to depict recent advances on the biosynthesis and actions of these novel pro-resolving and protective lipid mediators. Collectively, these findings indicate that defective mechanisms and pathways in resolution may underlie the unchecked inflammatory phenotype(s) that characterize some prevalent human diseases. [ABSTRACT FROM AUTHOR]

Dysregulated inflammation‐resolution programs are associated with atherosclerosis progression. Resolvins, in part, mediate inflammation‐resolution programs. Indeed, Resolvin D2 (RvD2) activates GPR18, a G‐protein‐coupled receptor, and limits plaque progression, though the cellular targets of RvD2 remain unknown. Here, we developed a humanized GPR18 floxed ("fl/fl") and a myeloid (Lysozyme M Cre) GPR18 knockout (mKO) mouse. We functionally validated this model by assessing efferocytosis in bone marrow‐derived macrophages (BMDMs) and found that RvD2 enhanced efferocytosis in the fl/fl, but not in the mKO BMDMs. To understand the functions of RvD2‐GPR18 in atherosclerosis, we performed a bone marrow transfer of fl/fl or mKO bone marrow into Ldlr−/− recipients. For these experiments, we treated each genotype with either Vehicle/PBS or RvD2 (25 ng/mouse, 3 times/week for 3 weeks). Myeloid loss of GPR18 resulted in significantly more necrosis, increased cleaved caspase‐3+ cells and decreased percentage of Arginase‐1+‐Mac2+ cells without a change in overall Mac2+ plaque macrophages, compared with fl/fl➔Ldlr−/− transplanted mice. RvD2 treatment decreased plaque necrosis, the percent of cleaved caspase‐3+ cells and increased the percent of Arginase‐1+‐Mac2+ cells in fl/fl➔Ldlr−/− mice, but not in the mKO➔Ldlr−/− transplanted mice. These results suggest that GPR18 plays a causal role in limiting atherosclerosis progression and that RvD2's ability to limit plaque necrosis is in part dependent on myeloid GRP18. [ABSTRACT FROM AUTHOR]

The polyunsaturated ω-3 fatty acid eicosapentaenoic acid-derived resolvin EI (RvEl) enhances resolution of inflammation, prevents bone loss, and induces bone regeneration. Although the inflammation-resolving actions of RvEl are characterized, the molecular mechanism of its bone-protective actions are of interest. To test the hypothesis that receptor-mediated events impact bone changes, we prepared transgenic mice overexpressing the RvEl receptor chemokine-like receptor 1 (chemR23) on leukocytes. In zymosan-initiated peritonitis, neutrophil polymorphonuclear leukocyte infiltration in response to RvEl was limited requiring log order lower doses in chemR23tg mice. Ligature-induced alveolar bone loss was diminished in chemR23tg mice. Local RvEl treatment of uniform craniotomy in the parietal bone significantly accelerated regeneration of the bone defect. In in vitro bone cultures, RvEl significantly enhanced expression of osteoprotegerin (OPG) without inducing change in receptor activator of NF-KB ligand levels, whereas the osteogenic markers alkaline phosphatase, bone sialoprotein, and Runt-related transcription factor 2 remained unchanged. These results indicate that RvEl modulates osteoclast differentiation and bone remodeling by direct actions on bone, rescuing OPG production and restoring a favorable receptor activator of NF-KB ligand/OPG ratio, in addition to known anti-inflammatory and proresolving actions. [ABSTRACT FROM AUTHOR]

Abstract: 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, 48h, 72h, and 7days. At 3h post-stroke onset, an intravenous administration of 333μg/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 11.7T 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, 48h, 72h and 7days. 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. [Copyright &y& Elsevier]