protectin-d1 and Disease-Models--Animal

Inflammation is generally accepted as a component of the host defence system and a protective response in the context of infectious diseases. However, altered inflammatory responses can contribute to disease in infected individuals. Many endogenous mediators that drive the resolution of inflammation are now known. Overall, mediators of resolution tend to decrease inflammatory responses and provide normal or greater ability of the host to deal with infection. In the lung, it seems that pro-resolution molecules, or strategies that promote their increase, tend to suppress inflammation and lung injury and facilitate control of bacterial or viral burden. Here, we argue that the demonstrated anti-inflammatory, pro-resolving, anti-thrombogenic and anti-microbial effects of such endogenous mediators of resolution may be useful in the treatment of the late stages of the disease in patients with COVID-19.

Topics: Acetates; Angiotensin I; Animals; Annexin A1; Anti-Inflammatory Agents; COVID-19; COVID-19 Drug Treatment; Disease Models, Animal; Docosahexaenoic Acids; Humans; Hydrogen Peroxide; Inflammation; Inflammation Mediators; Mice; Orthomyxoviridae Infections; Oxidants; Peptide Fragments; Peptides; Phosphodiesterase 4 Inhibitors; Pneumonia, Viral; Rolipram; Vasodilator Agents

To report recent data on the potential role of omega-3 fatty acids, in particular docosahexaenoic acid and its derivatives, in the treatment of dry eye syndrome.. Dietary supplementation with polyunsaturated fatty acids yields positive results in the improvement of dry eye signs and symptoms. Although several studies have shown this, evidence is still lacking as to which fatty acid or what combination constitutes the most effective treatment. Studies show that treatment with alpha-linoleic acid reduces dry eye-induced inflammation. Eicosapentaenoic acid and docosahexaenoic acid derivatives, particularly resolvin E1 (RvE1) and neuroprotectin D1, appear to be responsible for docosahexaenoic acid's anti-inflammatory effect. This is supported in a study in which topical RvE1 resulted in decreased inflammation in a mouse dry eye model. Topical administration of pigment epithelium-derived factor in combination with docosahexaenoic acid accelerates the regeneration of corneal nerves after their damage during corneal surgery, promoting the return of sensitivity and reducing the signs of dry eye. This combined treatment also reduces objective signs of dry eye, such as rose bengal staining.. No firm recommendations can be made regarding optimal dietary supplementation of essential fatty acids that benefit dry eye patients. On the basis of animal data and preliminary human studies, docosahexaenoic acid and its derivatives appear to be a safe, effective topical treatment for dry eye patients. This may result from their role in the resolution of inflammation and the regeneration of damaged corneal nerves.

Topics: Animals; CD59 Antigens; Dietary Supplements; Disease Models, Animal; Docosahexaenoic Acids; Dry Eye Syndromes; Fatty Acids, Omega-3; Humans; Mice; Treatment Outcome

A well-integrated host inflammatory response is essential in maintaining health and fighting disease. It is important to achieve a complete understanding of the cellular and molecular events that govern the resolution of acute inflammation. Because novel lipid-derived mediators, called resolvins and protectins in animal models, control the duration and magnitude of inflammation, the mapping of these resolution circuits may provide new ways of understanding the molecular basis of many inflammatory diseases. This article provides an overview of recent studies on resolvin and protectin biosynthesis and of advances in understanding the actions of these novel anti-inflammatory and proresolving lipid mediators. These new families of lipid-derived mediators were originally isolated from experimental murine models of acute inflammation identified during the natural spontaneous resolution phase. They are biosynthesized from omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid) and possess potent anti-inflammatory, proresolving, and antifibrotic actions in vivo. Taken together, these findings suggest that defective resolution mechanisms may underlie the inflammatory phenotypes that are believed to characterize many common human diseases. The new families of endogenous proresolving and anti-inflammatory agonists constitute a new genus of anti-inflammatories.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents; Disease Models, Animal; Docosahexaenoic Acids; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Humans; Inflammation; Inflammation Mediators; Lipoxins

Lipid mediators are important messengers in many physiological processes. The pro-inflammatory effect of many prostaglandins, derived from the essential arachidonic acid, are well established. However, there are also anti-inflammatory lipid mediators: lipoxins and resolvins, derived from essential omega-6 and omega-3 polyunsaturated fatty acids (n-3 and n-6 PUFA), have been shown to control and resolve inflammation in a variety of experimental models of inflammatory disorders. Recent research implicates n-6 PUFA-derived lipoxins and their stable analogues as potent anti-inflammatory compounds in models of inflammatory bowel disease. Similarly, n-3 PUFA-derived lipid mediators such as resolvin E1 were shown to protect from experimental colitis in animal models. Some of their anti-inflammatory effects are mediated by dendritic cells. In this article we discuss the emerging knowledge on the effects of lipoxins and resolvins on various inflammatory pathways and why they are promising candidates for novel therapies of human inflammatory bowel disease.

Topics: Animals; Anti-Inflammatory Agents; Disease Models, Animal; Docosahexaenoic Acids; Eicosapentaenoic Acid; Humans; Inflammatory Bowel Diseases; Lipoxins; Treatment Outcome

Intrarenal calcium oxalate (CaOx) crystals induce renal tubular epithelial cell (TEC) inflammatory and oxidative injury. This study is aimed at exploring potential therapeutic lipid components in kidney stones because lipids are involved in the development of several diseases and indicate the risk of kidney stones. Serum specimens were collected from 35 kidney stone patients and 35 normal controls. The lipid components in serum were measured, and differences were analyzed. The documented biological importance was comprehensively reviewed to identify lipids that differed significantly between the two groups to find potential agents associated with kidney stones. CaOx nephrocalcinosis mouse model was established to examine the therapeutic effects of specific lipids on CaOx deposition and CaOx-induced oxidative renal injury. Several lipids with significantly different levels were present in the serum of patients with stones and normal controls. Resolvin D1 (RvD1) (4.93-fold change,

Topics: Adult; Aged; Animals; Anti-Inflammatory Agents; Antioxidants; Calcium Oxalate; Case-Control Studies; Disease Models, Animal; Docosahexaenoic Acids; Female; Glyoxylates; Humans; Kidney Calculi; Kidney Tubules; Male; Mice; Mice, Inbred C57BL; Middle Aged; Nephrocalcinosis; Oxidative Stress; Reactive Oxygen Species; Signal Transduction

We examined a neuroinflammatory response associated with glial activation in the cochlea exposed to blast overpressure and evaluated the potential therapeutic efficacy of specialized pro-resolving mediators such as neuroprotectin D1, NPD1; (10R, 17S-dihydroxy-4Z, 7Z, 11E, 13E, 15Z, 19Z-docosahexaenoic acid) in a rodent blast-induced auditory injury model.. Animal Research.. A compressed-air driven shock tube was used to expose anesthetized adult male Long-Evan rats to shock waves simulating an open-field blast exposure. Approximately 30 minutes after blast exposure, rats were treated with NPD1 (100 ng/kg body wt.) or vehicle delivered intravenously via tail vein injection. Rats were then euthanized 48 hours after blast exposure. Unexposed rats were included as controls. Tissue sections containing both middle and inner ear were prepared with hematoxylin-eosin staining to elucidate histopathological changes associated with blast exposure. Cochlear tissues were evaluated for relative expression of ionized calcium-binding adaptor 1 (Iba1), as an indicator of microglial activation by immunohistochemistry and western blot analyses.. Our animal model resulted in an acute injury mechanism manifested by damage to the tympanic membrane, hemorrhage, infiltration of inflammatory cells, and increased expression of Iba1 protein. Moreover, therapeutic intervention with NPD1 significantly reduced Iba1 expression in the cochlea, suggesting a reduction of a neuroinflammatory response caused by blast overpressure.. Blast overpressure resulted in an increased expression of proteins involved in gliosis within the auditory system, which were reduced by NPD1. Treatment of NPD1 suggests an effective strategy to reduce or halt auditory microglial cell activation due to primary blast exposure.. NA Laryngoscope, 131:E2018-E2025, 2021.

Topics: Animals; Blast Injuries; Calcium-Binding Proteins; Cochlea; Disease Models, Animal; Docosahexaenoic Acids; Explosions; Male; Microfilament Proteins; Microglia; Rats

Docosahexaenoic acid-derived protectin D1 (PD1) was identified critical in the resolution of inflammation in vivo, where it modulates the innate immune response and stimulates resolution. Acute pancreatitis (AP) is characterized by local pancreatic inflammation with mild forms whereas systemic inflammation with severe forms. Herein we investigate the impact of PD1 in murine models of pancreatitis.. Three independent AP models, which induced in male mice via intraperitoneal injection of caerulein, L-arginine or pancreatic duct ligation, were used to confirm the protective effect of PD1. Infiltrationsof neutrophils and macrophages in pancreas were detected by flow cytometry and immunohistochemistry. In vitro and in vivo neutrophil extracellular traps formation was detected by immunofluorescence staining. Expression of peptidylarginine deiminase 4 (PAD4) in activated neutrophils was evaluated by western blotting.. Systemic treatment with PD1 reduced serum activities of amylase and lipase, blunted the concentrations of tumor necrosis factor-α and interleukin-6 in serum and protected against pancreas histologic damage in three AP models. PD1 also prolonged the survival in the pancreatic duct ligation model. Moreover, pancreatic infiltrationofneutrophils and neutrophil CitH3 expression were reduced after PD1 administration. In vitro studies revealed PD1 decreased supernatant cell-free DNA and CitH3 levels and downregulated PAD4 expression in mouse bone-marrow derived neutrophils. However, in the caerulein mice pretreated with GSK484 hydrochloride, an inhibitor of PAD4, PD1 treatment showed no more protective effect.. PD1 ameliorates AP by decreasing early infiltration of neutrophils into the pancreas and neutrophil extracellular traps formation through PAD4. These results supply the foundation to consider PD1 as a therapy for AP.

Topics: Animals; Disease Models, Animal; Docosahexaenoic Acids; Extracellular Traps; Macrophages; Male; Mice, Inbred ICR; Neutrophils; Pancreas; Pancreatitis; Protein-Arginine Deiminase Type 4

GPR37 was discovered more than two decades ago, but its biological functions remain poorly understood. Here we report a protective role of GPR37 in multiple models of infection and sepsis. Mice lacking Gpr37 exhibited increased death and/or hypothermia following challenge by lipopolysaccharide (LPS), Listeria bacteria, and the mouse malaria parasite Plasmodium berghei. Sepsis induced by LPS and Listeria in wild-type mice is protected by artesunate (ARU) and neuroprotectin D1 (NPD1), but the protective actions of these agents are lost in Gpr37

Topics: Adoptive Transfer; Animals; Artesunate; Disease Models, Animal; Docosahexaenoic Acids; Lipopolysaccharides; Listeria monocytogenes; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Docking Simulation; Pain; Phagocytosis; Plasmodium berghei; Receptors, G-Protein-Coupled; Sepsis

Specialized proresolving mediators are enzymatically oxygenated natural molecules derived from polyunsaturated fatty acids and are considered novel. These novel mediators include lipoxins from arachidonic acid, resolvins and protectins from omega-3 essential fatty acids, and new maresins. These mediators harbor potent dual proresolving and anti-inflammatory properties. Resolvins and protectins are known to be potent when administered to various inflammation-associated animal models of human diseases. Although psoriasis' etiology remains unknown, there is accumulating evidence indicating that cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-23, and IL-17, play pivotal roles in its development. Experimentally, resolvins, maresins, and lipoxins downregulate the cytokine expression of the IL-23/IL-17 axis and inhibition of mitogen-activated protein kinases and nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) cell signaling transduction pathways. Here, we assessed the effects of protectin D1 (PD1) on imiquimod (IMQ)-induced psoriasiform skin inflammation and keratinocytes. PD1 showed clinical improvement in skin thickness, redness, and scaling in psoriasis mouse models. Moreover, PD1 decreased IL-1β, IL-6, IL-17, and CXCL1 mRNA expressions and reduced STAT1 and NF-κB signaling pathway activation in lesions. Serum myeloperoxidase, IgG2a, IL-1β, IL-6, IL-17, and TNF-α and spleen CD4

Topics: Animals; Anti-Inflammatory Agents; Cytokines; Disease Models, Animal; Docosahexaenoic Acids; Female; HaCaT Cells; Humans; Imiquimod; Injections, Subcutaneous; Keratinocytes; Mice; Phosphorylation; Psoriasis; Signal Transduction; Skin; Spleen; STAT1 Transcription Factor; Th1 Cells; Th17 Cells

Specialized proresolving mediators from ω-3 polyunsaturated fatty acid may control resolution of inflammation. We evaluated the influence of two specialized proresolving mediators, resolvin D1 (RvD1) and protectin D1 isomer (PD1 iso) on neointimal hyperplasia after balloon injury.. Sprague Dawley male rats at 12-14 wk of age were injured as a model of balloon angioplasty. Then, 1 μg/rat of RvD1 or PD1 iso was administered intravenously via the tail vein immediately and 2 d after angioplasty. The proliferation of injured artery and the infiltration of leukocytes, monocytes, and macrophages at 3 d after injury were evaluated by immunostaining. The activity of the inflammatory transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) in the injured artery at 3 d after injury was evaluated using an enzyme-linked immuno sorbent assay kit. The proliferation of the neointima was evaluated by calculating the ratio of the neointimal and medial areas using specimens at 14 d after injury.. RvD1 and PD1 iso attenuated proliferation of medial cells (P < 0.05) and infiltration of leukocytes (P < 0.05) and monocytes/macrophages (P < 0.01). Although both RvD1 and PD1 iso mitigated NFκB activity (P < 0.01), RvD1 attenuated this activity more strongly (P < 0.01). RvD1 decreased neointimal hyperplasia by 37.3% (P < 0.01), whereas PD1 iso decreased neointimal hyperplasia by 31.8% (P < 0.05) (RvD1 versus PD1 iso: P = 0.51).. RvD1 and PD1 iso reduced the activity of inflammatory transcription factor NFκB within the injured artery and attenuated inflammatory cell infiltration, leading to a reduction in early inflammation and subsequent neointimal hyperplasia.

Topics: Angioplasty, Balloon; Animals; Carotid Arteries; Carotid Artery Injuries; Disease Models, Animal; Docosahexaenoic Acids; Humans; Hyperplasia; Injections, Intravenous; Male; Neointima; NF-kappa B; Rats; Rats, Sprague-Dawley; Treatment Outcome; Tunica Intima

Low levels of the long chain polyunsaturated fatty acid (LCPUFA) docosahexaenoic acid (DHA) have been implicated in retinopathy of prematurity (ROP). However, oral DHA suffers from poor palatability and is associated with increased bleeding in premature infants. We asked whether oral administration of the neutraceutical arginine-glutamine (Arg-Glu) could increase retinal DHA and improve outcomes in a mouse model of oxygen-induced retinopathy (OIR).. Postnatal day 7 (P7) pups were maintained at 75% oxygen for 5 days and then returned to room air on P12. Pups were gavaged twice daily with Arg-Gln or vehicle from P12 to P17 and eyes were harvested for analysis on P17. Vaso-obliteration and vascular density were assessed on retinal flat mounts and preretinal neovascularization was assessed on retinal cross sections. Retinas were used for measurement of DHA and 10,17S-docosatriene (neuroprotectin D1, NPD1), a key DHA-derived lipid, and for analysis by reverse-phase protein array (RPPA).. With Arg-Gln treatment, retinal DHA and NPD1 levels were increased in OIR pups. Arg-Gln reduced preretinal neovascularization by 39 ± 6% (P < 0.05) relative to vehicle control. This was accompanied by a restoration of vascular density of the retina in the pups treated with Arg-Gln (73.0 ± 3.0%) compared to vehicle (53.1 ± 3.4%; P < 0.05). Arg-Gln dipeptide restored OIR-induced signaling changes toward normoxia and was associated with normalization of insulin-like growth factor receptor 1 signaling and reduction of apoptosis and an increase in anti-apoptosis proteins.. Arg-Gln may serve as a safer and easily tolerated nutraceutical agent for prevention or treatment of ROP.

Topics: Administration, Oral; Animals; Animals, Newborn; Chromatography, High Pressure Liquid; Dipeptides; Disease Models, Animal; Docosahexaenoic Acids; Female; Male; Mice; Mice, Inbred C57BL; Oxygen; Pregnancy; Retina; Retinal Neovascularization; Retinal Vessels; Retinopathy of Prematurity

Epilepsy therapy is based on drugs that treat the symptoms rather than the underlying mechanisms of the disease (epileptogenesis). There are no treatments for preventing seizures or improving disease prognosis, including neurological comorbidities. The search of pathogenic mechanisms of epileptogenesis highlighted that neuroinflammatory cytokines [i.e. interleukin-1β (IL-1β), tumour necrosis factor-α (Tnf-α)] are induced in human and experimental epilepsies, and contribute to seizure generation in animal models. A major role in controlling the inflammatory response is played by specialized pro-resolving lipid mediators acting on specific G-protein coupled receptors. Of note, the role that these pathways have in epileptogenic tissue remains largely unexplored. Using a murine model of epilepsy, we show that specialized pro-resolving mechanisms are activated by status epilepticus before the onset of spontaneous seizures, but with a marked delay as compared to the neuroinflammatory response. This was assessed by measuring the time course of mRNA levels of 5-lipoxygenase (Alox5) and 15-lipoxygenase (Alox15), the key biosynthetic enzymes of pro-resolving lipid mediators, versus Il1b and Tnfa transcripts and proteins. In the same hippocampal tissue, we found a similar delayed expression of two main pro-resolving receptors, the lipoxin A4 receptor/formyl peptide receptor 2 and the chemerin receptor. These receptors were also induced in the human hippocampus after status epilepticus and in patients with temporal lobe epilepsy. This evidence supports the hypothesis that the neuroinflammatory response is sustained by a failure to engage pro-resolving mechanisms during epileptogenesis. Lipidomic LC-MS/MS analysis showed that lipid mediator levels apt to resolve the neuroinflammatory response were also significantly altered in the hippocampus during epileptogenesis with a shift in the biosynthesis of several pro-resolving mediator families including the n-3 docosapentaenoic acid (DPA)-derived protectin D1. Of note, intracerebroventricular injection of this mediator during epileptogenesis in mice dose-dependently reduced the hippocampal expression of both Il1b and Tnfa mRNAs. This effect was associated with marked improvement in mouse weight recovery and rescue of cognitive deficit in the novel object recognition test. Notably, the frequency of spontaneous seizures was drastically reduced by 2-fold on average and the average seizure duration was shortened by 40% after

Topics: Animals; Anticonvulsants; Arachidonate 15-Lipoxygenase; Arachidonate 5-Lipoxygenase; CD11b Antigen; Cytokines; Dinoprostone; Disease Models, Animal; Docosahexaenoic Acids; Encephalitis; Epilepsy; Gene Expression Regulation; Hippocampus; Kainic Acid; Leukotriene B4; Lipid Metabolism; Lipoxins; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic

Neuroprotectin D1 (NPD1) is an anti-inflammatory and proresolving lipid mediator biosynthesized from the omega-3-polyunsaturated fatty acid docosahexaenoic acid (DHA). The purpose of this study is to test the therapeutic potential of NPD1 for the treatment of herpes simplex virus (HSV)-induced stromal keratitis (SK) using a mouse model.. C57BL/6 mice were infected ocularly with HSV-1 strain RE. Infected animals were treated topically with methyl ester prodrug NPD1 (300 ng/eye, 5-μL drop). Development of SK lesions, infiltration of inflammatory cells into the cornea, and production of proinflammatory cytokines, chemokines, and angiogenic factors were compared to untreated animals using slit-lamp biomicroscopy, flow cytometry, ELISA, and quantitative PCR (qPCR).. Topical administration of NPD1 resulted in a significant reduction in the severity and incidence of SK, as well as the extent of corneal neovascularization in the NPD1-treated animals compared to their untreated counterparts. Infiltration of fewer neutrophils and pathogenic CD4⁺ T cells into the cornea, along with a lower number of cells that could be induced ex vivo to produce IFN-γ and IL-17, occurred with NPD1 treatment. Additionally, treatment with NPD1 diminished the production of proinflammatory cytokines, chemokines, and angiogenic factors, such as IL-6, CXCL1, CXCL-10, CCL-20, VEGF-A, MMP-2, and MMP-9 in the corneas of infected animals. Importantly, treatment with NPD1 increased the production of the anti-inflammatory cytokine, IL-10.. Our novel findings demonstrate that NPD1 treatment could represent a valuable therapeutic approach to control SK lesions.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents; Biomarkers; CD4-Positive T-Lymphocytes; Chemokines; Corneal Neovascularization; Cytokines; Disease Models, Animal; Docosahexaenoic Acids; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Immunohistochemistry; Keratitis, Herpetic; Mice; Mice, Inbred C57BL; Neutrophils

Docosahexaenoic acid, a major omega-3 essential fatty acid family member, improves behavioral deficit and reduces infarct volume and edema after experimental focal cerebral ischemia. We hypothesize that DHA elicits neuroprotection by inducing AKT/p70S6K phosphorylation, which in turn leads to cell survival and protects against ischemic stroke in young and aged rats.. Rats underwent 2 h of middle cerebral artery occlusion (MCAo). DHA, neuroprotectin D1 (NPD1) or vehicle (saline) was administered 3 h after onset of stroke. Neurological function was evaluated on days 1, 2, 3, and 7. DHA treatment improved functional recovery and reduced cortical, subcortical and total infarct volumes 7 days after stroke. DHA also reduced microglia infiltration and increased the number of astrocytes and neurons when compared to vehicle on days 1 and 7. Increases in p473 AKT and p308 AKT phosphorylation/activation were observed in animals treated with DHA 4 h after MCAo. Activation of other members of the AKT signaling pathway were also observed in DHA treated animals including increases in pS6 at 4 h and pGSK at 24 h. DHA or NPD1 remarkably reduced total and cortical infarct in aged rats. Moreover, we show that in young and aged rats DHA treatment after MCAo potentiates NPD1 biosynthesis. The phosphorylation of p308 AKT or pGSK was not different between groups in aged rats. However, pS6 expression was increased with DHA or NPD1 treatment when compared to vehicle.. We suggest that DHA induces cell survival, modulates the neuroinflammatory response and triggers long term restoration of synaptic circuits. Both DHA and NPD1 elicited remarkable protection in aged animals. Accordingly, activation of DHA signaling might provide benefits in the management of ischemic stroke both acutely as well as long term to limit ensuing disabilities.

Topics: Animals; Behavior; Brain Ischemia; Cell Survival; Disease Models, Animal; Docosahexaenoic Acids; Gene Expression Regulation; Humans; Infarction, Middle Cerebral Artery; Male; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Recovery of Function; Signal Transduction; Stroke

Neuroprotectin D1 (NPD1) is a stereoselective mediator derived from the omega-3 essential fatty acid docosahexaenoic acid (DHA) with potent inflammatory resolving and neuroprotective bioactivity. NPD1 reduces Aβ42 peptide release from aging human brain cells and is severely depleted in Alzheimer's disease (AD) brain. Here we further characterize the mechanism of NPD1's neurogenic actions using 3xTg-AD mouse models and human neuronal-glial (HNG) cells in primary culture, either challenged with Aβ42 oligomeric peptide, or transfected with beta amyloid precursor protein (βAPP)(sw) (Swedish double mutation APP695(sw), K595N-M596L). We also show that NPD1 downregulates Aβ42-triggered expression of the pro-inflammatory enzyme cyclooxygenase-2 (COX-2) and of B-94 (a TNF-α-inducible pro-inflammatory element) and apoptosis in HNG cells. Moreover, NPD1 suppresses Aβ42 peptide shedding by down-regulating β-secretase-1 (BACE1) while activating the α-secretase ADAM10 and up-regulating sAPPα, thus shifting the cleavage of βAPP holoenzyme from an amyloidogenic into the non-amyloidogenic pathway. Use of the thiazolidinedione peroxisome proliferator-activated receptor gamma (PPARγ) agonist rosiglitazone, the irreversible PPARγ antagonist GW9662, and overexpressing PPARγ suggests that the NPD1-mediated down-regulation of BACE1 and Aβ42 peptide release is PPARγ-dependent. In conclusion, NPD1 bioactivity potently down regulates inflammatory signaling, amyloidogenic APP cleavage and apoptosis, underscoring the potential of this lipid mediator to rescue human brain cells in early stages of neurodegenerations.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Cell Survival; Cells, Cultured; Disease Models, Animal; Docosahexaenoic Acids; Gene Expression Regulation; Humans; Mice; Neurodegenerative Diseases; Neurons; Neuroprotective Agents; Peptide Fragments; PPAR gamma

Temporal lobe epilepsy, one of the most common epilepsy syndromes, is characterized by hippocampal hyperexcitability and progressive seizure susceptibility. Omega-3 fatty acids are involved in neuronal excitability and have anticonvulsant properties. We studied the effect of docosahexaenoic acid (DHA) or its derived lipid mediator, neuroprotectin D1 (NPD1, 10R,17S-dihydroxy-docosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid), in evoked seizures using a rapid kindling model of temporal lobe epilepsy.. DHA or NPD1 was administered in rodents with or without kindling acquisition. Locomotor seizures and evoked epileptiform hippocampal activity immediately after hippocampal stimulations were analyzed.. DHA or NPD1 limits hippocampal electrically induced hyperexcitability. Seizures induced by kindling triggered NPD1 synthesis in the hippocampus. Supplying its precursor, DHA, or direct injection of NPD1 into the third ventricle resulted in attenuation of kindling progression and hippocampal hyperexcitability.. The significance of NPD1 in temporal lobe epilepsy could open new pathways for understanding the initiation and propagation of seizures and the role this lipid mediator plays in the neuronal network.

Topics: Animals; Biophysics; Disease Models, Animal; Docosahexaenoic Acids; Drug Administration Routes; Electric Stimulation; Electroencephalography; Epilepsy, Temporal Lobe; Hippocampus; Kindling, Neurologic; Male; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Rats; Rats, Wistar

Mechanisms of inflammatory pain are not fully understood. We investigated the role of TRPV1 (transient receptor potential subtype V1) and TNF-α, two critical mediators for inflammatory pain, in regulating spinal cord synaptic transmission. We found in mice lacking Trpv1 the frequency but not the amplitude of spontaneous EPSCs (sEPSCs) in lamina II neurons of spinal cord slices is reduced. Further, C-fiber-induced spinal long-term potentiation (LTP) in vivo is abolished in Trpv1 knock-out mice. TNF-α also increases sEPSC frequency but not amplitude in spinal outer lamina II (lamina IIo) neurons, and this increase is abolished in Trpv1 knock-out mice. Single-cell PCR analysis revealed that TNF-α-responding neurons in lamina IIo are exclusively excitatory (vGluT2(+)) neurons. Notably, neuroprotectin-1 (NPD1), an anti-inflammatory lipid mediator derived from ω-3 polyunsaturated fatty acid (docosahexaenoic acid), blocks TNF-α- and capsaicin-evoked sEPSC frequency increases but has no effect on basal synaptic transmission. Strikingly, NPD1 potently inhibits capsaicin-induced TRPV1 current (IC(50) = 0.4 nm) in dissociated dorsal root ganglion neurons, and this IC(50) is ≈ 500 times lower than that of AMG9810, a commonly used TRPV1 antagonist. NPD1 inhibition of TRPV1 is mediated by GPCRs, since the effects were blocked by pertussis toxin. In contrast, NPD1 had no effect on mustard oil-induced TRPA1 currents. Spinal injection of NPD1, at very low doses (0.1-10 ng), blocks spinal LTP and reduces TRPV1-dependent inflammatory pain, without affecting baseline pain. NPD1 also reduces TRPV1-independent but TNF-α-dependent pain hypersensitivity. Our findings demonstrate a novel role of NPD1 in regulating TRPV1/TNF-α-mediated spinal synaptic plasticity and identify NPD1 as a novel analgesic for treating inflammatory pain.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Acrylamides; Analysis of Variance; Animals; Bridged Bicyclo Compounds, Heterocyclic; Cells, Cultured; Disease Models, Animal; Docosahexaenoic Acids; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Freund's Adjuvant; Ganglia, Spinal; In Vitro Techniques; Inflammation; Long-Term Potentiation; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons; Pain; Pain Measurement; Patch-Clamp Techniques; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Spinal Cord; TRPV Cation Channels; Tumor Necrosis Factor-alpha