DHA Shortage Causes the Early Degeneration of Photoreceptors and RPE in Mice With Peroxisomal ß-Oxidation Deficiency.

Purpose: Patients deficient in peroxisomal ß-oxidation, which is essential for the synthesis of docosahexaenoic acid (DHA, C22:6n-3) and breakdown of very-long-chain polyunsaturated fatty acids (VLC-PUFAs), both important components of photoreceptor outer segments, develop retinopathy present with retinopathy. The representative mouse model lacking the central enzyme of this pathway, multifunctional protein 2 (Mfp2-/-), also show early-onset retinal decay and cell-autonomous retinal pigment epithelium (RPE) degeneration, accompanied by reduced plasma and retinal DHA levels. In this study, we investigated whether DHA supplementation can rescue the retinal degeneration of Mfp2-/- mice. Methods: Mfp2+/- breeding pairs and their offspring were fed a 0.12% DHA or control diet during gestation and lactation and until sacrifice. Offspring were analyzed for retinal function via electroretinograms and for lipid composition of neural retina and plasma with lipidome analysis and gas chromatography, respectively, and histologically using retinal sections and RPE flatmounts at the ages of 4, 8, and 16 weeks. Results: DHA supplementation to Mfp2-/- mice restored retinal DHA levels and prevented photoreceptor shortening, death, and impaired functioning until 8 weeks. In addition, rescue of retinal DHA levels temporarily improved the ability of the RPE to phagocytose outer segments and delayed the RPE dedifferentiation. However, despite the initial rescue of retinal integrity, DHA supplementation could not prevent retinal degeneration at 16 weeks. Conclusions: We reveal that the shortage of a systemic supply of DHA is pivotal for the early retinal degeneration in Mfp2-/- mice. Furthermore, we report that adequate retinal DHA levels are essential not only for photoreceptors but also for RPE homeostasis.

Rod-specific downregulation of omega-3 very-long-chain polyunsaturated fatty acid pathway in age-related macular degeneration.

Docosahexaenoic acid (DHA; 22:6) plays a key role in vision and is the precursor for very-long-chain polyunsaturated fatty acids (VLC-PUFAs). The release of 32- and 34-carbon VLC-PUFAs and DHA from sn-1 and sn-2 of phosphatidylcholine (PC) leads to the synthesis of cell-survival mediators, the elovanoids (ELVs) and neuroprotectin D1 (NPD1), respectively. Macula and periphery from age-related macular degeneration (AMD) donor retinas were assessed for the availability of DHA-related lipids by LC-MS/MS-based lipidomic analysis and MALDI-molecular imaging. We found reduced retina DHA and VLC-PUFA pathways to synthesize omega-3 ELVs from precursors that likely resulted in altered disks and photoreceptor loss. Additionally, we compared omega-3 (n-3) fatty acid with DHA (22:6) and omega-6 (n-6) fatty acid with arachidonic acid (AA; 20:4) pathways. n-3 PC(22:6/22:6, 44:12) and n-6 PC(20:4/20:4, 40:8) showed differences among male/female, macula/periphery, and normal/AMD retinas. Periphery of AMD retina males increased 44:12 abundance, while normal females increased 40:8 (all macula had an upward 40:8 tendency). We also showed that female AMD switched from n-3 to n-6 fatty acids; most changes in AMD occurred in the periphery of female AMD retinas. DHA and VLC-PUFA release from PCs leads to conversion in pro-survival NPD1 and ELVs. The loss of the neuroprotective precursors of ELVs in the retina periphery from AMD facilitates uncompensated stress and cell loss. In AMD, the female retina loses peripheral rods VLC-PUFAs to about 33% less than in males limiting ELV formation and its protective bioactivity.

Bariatric surgery related proximal myopathy: A partially reversible complication.

Deficiency neuropathies and rhabdomyolysis have previously been reported after bariatric surgery (BS) but never myopathies. We report cases of five patients with morbid obesity who developed within 2 to 4 months of a BS, proximal myopathy following significant and rapid weight loss worsened by postoperative gastrointestinal complications. Muscle weakness concerned lower limbs in particular in quadriceps and less frequently in upper limbs and diaphragm, sometimes mimicked a Guillain-Barré syndrome. Muscle biopsy performed in 1 patient, revealed selective atrophy of type 2 fibers. Weakness slowly decreased with refeeding with vitamins supplementation. We enlarge here the clinical pattern of post-BS complications.

Bioavailability and spatial distribution of fatty acids in the rat retina after dietary omega-3 supplementation.

Spatial changes of FAs in the retina in response to different dietary n-3 formulations have never been explored, although a diet rich in EPA and DHA is recommended to protect the retina against the effects of aging. In this study, Wistar rats were fed for 8 weeks with balanced diet including either EPA-containing phospholipids (PLs), EPA-containing TGs, DHA-containing PLs, or DHA-containing TGs. Qualitative changes in FA composition of plasma, erythrocytes, and retina were evaluated by gas chromatography-flame ionization detector. Following the different dietary intakes, changes to the quantity and spatial organization of PC and PE species in retina were determined by LC coupled to MS/MS and MALDI coupled to MS imaging. The omega-3 content in the lipids of plasma and erythrocytes suggests that PLs as well as TGs are good omega-3 carriers for retina. However, a significant increase in DHA content in retina was observed, especially molecular species as di-DHA-containing PC and PE, as well as an increase in very long chain PUFAs (more than 28 carbons) following PL-EPA and TG-DHA diets only. All supplemented diets triggered spatial organization changes of DHA in the photoreceptor layer around the optic nerve. Taken together, these findings suggest that dietary omega-3 supplementation can modify the content of FAs in the rat retina.

Docosanoids and elovanoids from omega-3 fatty acids are pro-homeostatic modulators of inflammatory responses, cell damage and neuroprotection.

The functional significance of the selective enrichment of the omega-3 essential fatty acid docosahexaenoic acid (DHA; 22C and 6 double bonds) in cellular membrane phospholipids of the nervous system is being clarified by defining its specific roles on membrane protein function and by the uncovering of the bioactive mediators, docosanoids and elovanoids (ELVs). Here, we describe the preferential uptake and DHA metabolism in photoreceptors and brain as well as the significance of the Adiponectin receptor 1 in DHA retention and photoreceptor cell (PRC) survival. We now know that this integral membrane protein is engaged in DHA retention as a necessary event for the function of PRCs and retinal pigment epithelial (RPE) cells. We present an overview of how a) NPD1 selectively mediates preconditioning rescue of RPE and PR cells; b) NPD1 restores aberrant neuronal networks in experimental epileptogenesis; c) the decreased ability to biosynthesize NPD1 in memory hippocampal areas of early stages of Alzheimer's disease takes place; d) NPD1 protection of dopaminergic circuits in an in vitro model using neurotoxins; and e) bioactivity elicited by DHA and NPD1 activate a neuroprotective gene-expression program that includes the expression of Bcl-2 family members affected by Aß42, DHA, or NPD1. In addition, we highlight ELOVL4 (ELOngation of Very Long chain fatty acids-4), specifically the neurological and ophthalmological consequences of its mutations, and their role in providing precursors for the biosynthesis of ELVs. Then we outline evidence of ELVs ability to protect RPE cells, which sustain PRC integrity. In the last section, we present a summary of the protective bioactivity of docosanoids and ELVs in experimental ischemic stroke. The identification of early mechanisms of neural cell survival mediated by DHA-synthesized ELVs and docosanoids contributes to the understanding of cell function, pro-homeostatic cellular modulation, inflammatory responses, and innate immunity, opening avenues for prevention and therapeutic applications in neurotrauma, stroke and neurodegenerative diseases.

Docosanoids Promote Neurogenesis and Angiogenesis, Blood-Brain Barrier Integrity, Penumbra Protection, and Neurobehavioral Recovery After Experimental Ischemic Stroke.

Docosahexaenoic acid (DHA) and neuroprotectin D1 (NPD1) are neuroprotective after experimental ischemic stroke. To explore underlying mechanisms, SD rats underwent 2 h of middle cerebral artery occlusion (MCAo) and treated with DHA (5 mg/kg, IV) or NPD1 (5 µg/per rat, ICV) and vehicles 1 h after. Neuro-behavioral assessments was conducted on days 1, 2, and 3, and on week 1, 2, 3, or 4. BrdU was injected on days 4, 5, and 6, immunohistochemistry was performed on week 2 or 4, MRI on day 7, and lipidomic analysis at 4 and 5 h after onset of stroke. DHA improved short- and long-term behavioral functions and reduced cortical, subcortical, and total infarct volumes (by 42, 47, and 31%, respectively) after 2 weeks and reduced tissue loss by 50% after 4 weeks. DHA increased the number of BrdU+/Ki-67+, BrdU+/DCX+, and BrdU+/NeuN+ cells in the cortex, subventricular zone, and dentate gyrus and potentiated NPD1 synthesis in the penumbra at 5 h after MCAo. NPD1 improved behavior, reduced lesion volumes, protected ischemic penumbra, increased NeuN, GFAP, SMI-71-positive cells and vessels, axonal regeneration in the penumbra, and attenuated blood-brain barrier (BBB) after MCAo. We conclude that docosanoid administration increases neurogenesis and angiogenesis, activates NPD1 synthesis in the penumbra, and diminishes BBB permeability, which correlates to long-term neurobehavioral recovery after experimental ischemic stroke.

Are "Legal Highs" users satisfied? Evidence from online customer comments.

This article describes the results of a clustering analysis of more than 2,100 comments posted by online purchasers of "Legal Highs" on five websites in 2012. The aim is to investigate the reasons for satisfaction/dissatisfaction on the part of legal highs users. Our results show that the reasons for satisfaction depend on the price/quality ratio and the real effects of the product (compared to illicit drugs). Dissatisfaction seems to stem from the disparity between the advertising of the product and its real quality. We conclude that online purchasers are certainly illicit drug users who consider legal highs as substitution products.

Neuroprotectin D1 restores corneal nerve integrity and function after damage from experimental surgery.

PURPOSE: To investigate if topical treatment of neuroprotectin D1 (NPD1) increases regeneration of functional nerves after lamellar keratectomy. METHODS: An 8-mm stromal dissection was performed in the left eye of each rabbit. The rabbits were treated with NPD1, pigment epithelial-derived factor (PEDF) in combination with docosahexaenoic acid (DHA) or vehicle for 6 weeks, and corneas were obtained at 8 weeks. After fixation, corneal wholemounts were stained with mouse monoclonal anti-ßIII-tubulin antibody and double stained with chicken anti-calcitonin gene-related peptide (CGRP) antibody. Corneal sensitivity and tear secretion were measured using the Cochet-Bonnet esthesiometer and the Schirmer's test, respectively. Additional rabbits were treated with NPD1, PEDF+DHA, or vehicle, and corneal sections were stained with a rat monoclonal anti-neutrophil antibody. Cultures of trigeminal ganglia from 5-day-old mice were treated with NPD1, PEDF+DHA, lipoxin A4 (LXA4), 12- or 15-hydroxyeicosatetraenoic acid (12[S] or 15[S]-HETE), and nerve growth factor (NGF) as positive control. RESULTS: NPD1 increased subepithelial corneal nerve area three times compared with vehicle-treated rabbits. The effect was similar to PEDF+DHA-treated animals. There was recovery of CGRP-positive neurons and an increase in corneal sensitivity and tear secretion in NPD1-treated animals. NPD1 decreased neutrophil infiltration after 2 and 4 days of treatment. In the in vitro cultures, NPD1 and PEDF+DHA induced a 3-fold increase in neurite outgrowth compared with cultures without supplementation. Treatments with LXA4, 12(S)-, and 15(S)- HETE did not stimulate neurite outgrowth. CONCLUSIONS: NPD1 has anti-inflammatory and nerve regenerative properties. This study demonstrates that NPD1 may offer an effective treatment for neurotrophic corneas.

N-3 fatty acid rich triglyceride emulsions are neuroprotective after cerebral hypoxic-ischemic injury in neonatal mice.

We questioned if acute administration of n-3 fatty acids (FA) carried in n-3 rich triglyceride (TG) emulsions provides neuroprotection in neonatal mice subjected to hypoxic-ischemic (H/I) brain injury. We examined specificity of FA, optimal doses, and therapeutic windows for neuroprotection after H/I. H/I insult was induced in C57BL/6J 10-day-old mice by right carotid artery ligation followed by exposure to 8% O(2) for 15 minutes at 37°C. Intraperitoneal injection with n-3-rich TG emulsions, n-6 rich TG emulsions or saline for control was administered at different time points before and/or after H/I. In separate experiments, dose responses were determined with TG containing only docosahexaenoic acid (Tri-DHA) or eicosapentaenoic acid (Tri-EPA) with a range of 0.1-0.375 g n-3 TG/kg, administered immediately after H/I insult. Infarct volume and cerebral blood flow (CBF) were measured. Treatment with n-3 TG emulsions both before- and after- H/I significantly reduced total infarct volume by a mean of 43% when administered 90 min prior to H/I and by 47% when administered immediately after H/I. In post-H/I experiments Tri-DHA, but not Tri-EPA exhibited neuroprotective effects with both low and high doses (p<0.05). Moreover, delayed post-H/I treatment with Tri-DHA significantly decreased total infarct volume by a mean of 51% when administered at 0 hr, by 46% at 1 hr, and by 51% at 2 hr after H/I insult. No protective effect occurred with Tri-DHA injection at 4 hr after H/I. There were no n-3 TG related differences in CBF. A significant reduction in brain tissue death was maintained after Tri-DHA injection at 8 wk after the initial brain injury. Thus, n-3 TG, specifically containing DHA, is protective against H/I induced brain infarction when administered up to 2 hr after H/I injury. Acute administration of TG-rich DHA may prove effective for treatment of stroke in humans.

High activity and Levy searches: jellyfish can search the water column like fish.

Over-fishing may lead to a decrease in fish abundance and a proliferation of jellyfish. Active movements and prey search might be thought to provide a competitive advantage for fish, but here we use data-loggers to show that the frequently occurring coastal jellyfish (Rhizostoma octopus) does not simply passively drift to encounter prey. Jellyfish (327 days of data from 25 jellyfish with depth collected every 1 min) showed very dynamic vertical movements, with their integrated vertical movement averaging 619.2 m d(-1), more than 60 times the water depth where they were tagged. The majority of movement patterns were best approximated by exponential models describing normal random walks. However, jellyfish also showed switching behaviour from exponential patterns to patterns best fitted by a truncated Lévy distribution with exponents (mean µ=1.96, range 1.2-2.9) close to the theoretical optimum for searching for sparse prey (µopt≈2.0). Complex movements in these 'simple' animals may help jellyfish to compete effectively with fish for plankton prey, which may enhance their ability to increase in dominance in perturbed ocean systems.

Endogenous signaling by omega-3 docosahexaenoic acid-derived mediators sustains homeostatic synaptic and circuitry integrity.

The harmony and function of the complex brain circuits and synapses are sustained mainly by excitatory and inhibitory neurotransmission, neurotrophins, gene regulation, and factors, many of which are incompletely understood. A common feature of brain circuit components, such as dendrites, synaptic membranes, and other membranes of the nervous system, is that they are richly endowed in docosahexaenoic acid (DHA), the main member of the omega-3 essential fatty acid family. DHA is avidly retained and concentrated in the nervous system and known to play a role in neuroprotection, memory, and vision. Only recently has it become apparent why the surprisingly rapid increases in free (unesterified) DHA pool size take place at the onset of seizures or brain injury. This phenomenon began to be clarified by the discovery of neuroprotectin D1 (NPD1), the first-uncovered bioactive docosanoid formed from free DHA through 15-lipoxygenase-1 (15-LOX-1). NPD1 synthesis includes, as agonists, oxidative stress and neurotrophins. The evolving concept is that DHA-derived docosanoids set in motion endogenous signaling to sustain homeostatic synaptic and circuit integrity. NPD1 is anti-inflammatory, displays inflammatory resolving activities, and induces cell survival, which is in contrast to the pro-inflammatory actions of the many of omega-6 fatty acid family members. We highlight here studies relevant to the ability of DHA to sustain neuronal function and protect synapses and circuits in the context of DHA signalolipidomics. DHA signalolipidomics comprises the integration of the cellular/tissue mechanism of DHA uptake, its distribution among cellular compartments, the organization and function of membrane domains containing DHA phospholipids, and the precise cellular and molecular events revealed by the uncovering of signaling pathways regulated by docosanoids endowed with prohomeostatic and cell survival bioactivity. Therefore, this approach offers emerging targets for prevention, pharmaceutical intervention, and clinical translation involving DHA-mediated signaling.

The omega-3 fatty acid-derived neuroprotectin D1 limits hippocampal hyperexcitability and seizure susceptibility in kindling epileptogenesis.

PURPOSE: 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. METHODS: 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. KEY FINDINGS: 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. SIGNIFICANCE: 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.

Omega-3 essential fatty acids modulate initiation and progression of neurodegenerative disease.

The significance of the selective enrichment in omega-3 essential fatty acids in photoreceptors and synaptic membranes of the nervous system has remained, until recently, incompletely understood. While studying mechanisms of cell survival in neural degeneration, we discovered a docosanoid synthesized from unesterified docosahexaenoic acid (DHA) by a 15-lipoxygenase (15-LOX), which we called neuroprotectin D1 (NPD1; 10R,17S-dihydroxy-docosa-4Z,7Z,11E,13E,15E,19Z hexaenoic acid). This lipid mediator is a docosanoid because it is derived from the 22 carbon (22C) precursor DHA, unlike eicosanoids, which are derived from the 20 carbon (20C) arachidonic acid (AA) family member of essential fatty acids. We discovered that NPD1 is promptly made in response to oxidative stress, as a response to brain ischemia-reperfusion, and in the presence of neurotrophins. NPD1 is neuroprotective in experimental brain damage, in oxidative-stressed retinal pigment epithelial (RPE) cells, and in human brain cells exposed to amyloid-beta (Abeta) peptides. We thus envision NPD1 as a protective sentinel, one of the very first defenses activated when cell homeostasis is threatened by imbalances in normal neural function. We provide here, in three sections, recent experimental examples that highlight the specificity and potency of NPD1 spanning beneficial bioactivity during initiation and early progression of neurodegeneration: (1) during retinal signal phototransduction, (2) during brain ischemia-reperfusion, and (3) in Alzheimer's disease (AD) and stressed human brain cell models of AD. From this experimental evidence, we conclude that DHA-derived NPD1 regulation targets upstream events of brain cell apoptosis, as well as neuro-inflammatory signaling, promoting and maintaining cellular homeostasis, and restoring neural and retinal cell integrity.

[Research in amyotrophic lateral sclerosis: what is new in 2009?]. / La recherche sur la SLA en 2009 : compte rendu du groupe bibliographique de la coordination des centres SLA.

This paper, written by French amyotrophic lateral sclerosis (ALS) center experts, presents an update of recent advances in fundamental, epidemiological and clinical research in ALS based on a review of the literature between September 2008 and November 2009. Among other pathophysiological mechanisms, the role of stress of the endoplasmic reticulum and the importance of energetic metabolic disturbances have been underscored. In the field of genetics, research has been advanced through the identification of mutations of the gene FUsed in Sarcoma/Translated in LipoSarcoma (FUS/TLS) in individuals with familial and sporadic ALS. This gene is involved in the regulation of transcription, splicing and RNA transport, and has functional homology to another ALS gene, TARDBP, which suggests that a common mechanism may underlie motor neuron degeneration. A report showed that mice expressing a mutant form of human TDP-43 develop a progressive and fatal neurodegenerative disease reminiscent of both ALS and frontotemporal lobar degeneration with ubiquitin aggregates (FTLD-U), providing a new animal model that may help to better understand the pathophysiology and test new therapeutics. Beside genetic studies, several epidemiologic studies have investigated the role of environmental factors. A recent study suggests that smoking is a risk factor for developing ALS and it is hypothesized that this could occur through lipid peroxidation via formaldehyde exposure. From a neuroprotective perspective, trials with IGF-1, sodium valproate, coenzyme Q or glatiramer acetate have failed to demonstrate any beneficial effect. A study published in 2008 argued that lithium may have a neuroprotective effect in ALS mice and also in patients. However, two preclinical studies failed to replicate the neuroprotective effect of lithium in ALS mice. Therapeutic trials have been performed or are currently ongoing in Europe and North America. Their results have not yet been published.

Docosahexaenoic acid neurolipidomics.

Mediator lipidomics is a field of study concerned with the characterization, structural elucidation and bioactivity of lipid derivatives actively generated by enzymatic activity. It is well known that omega-3 fatty acids are beneficial for brain function. Docosahexaenoic acid [DHA; 4 22:6(n-3)] is the most abundant essential omega-3 fatty acid present in the brain and it has multiple mechanisms of exerting protective effects after cellular injury. Certain lipid species produced from DHA early during the reperfusion stage of brain ischemia-reperfusion injury are generated in order to help the cell cope as the injury progresses. We explore these newly discovered lipid mediators in order to understand their role in the cell. We have identified one of these potentially protective lipid mediators as a novel stereospecific DHA-derived fatty acid, called neuroprotectin D1 (NPD1; 10R,17S-dihydroxy-docosa-4Z,7Z,11E,15E,19Z hexaenoic acid). DHA also has important roles in pro-survival signaling cascades after ischemia-reperfusion in injury. It has been shown to accelerate AKT translocation and activation and has binding affinity with an important PPAR-gamma family of ligand-activated nuclear receptors that have been implicated in various aspects of lipid metabolism and have been shown to have anti-inflammatory actions. Here we present an overview of these mechanisms and discuss the potential of using DHA signaling in the development of treatments for the large population of patients suffering from the devastating consequences of stroke.

Hot tub, whirlpool, and spa-related injuries in the U.S., 1990-2007.

BACKGROUND: Recreational use of hot tubs, whirlpools, and spas has increased within the past 3 decades. Injuries due to hot tubs, whirlpools, and spas can affect people of all ages and can result in serious disabilities. PURPOSE: This study examines nonfatal hot tub, whirlpool, and spa-related injuries on a national level. METHODS: The National Electronic Injury Surveillance System database was used to examine cases of nonfatal hot tub, whirlpool, and spa-related injuries treated in U.S. emergency departments from January 1, 1990, through December 31, 2007. Analysis was conducted from November 2008 to March 2009. RESULTS: An estimated 81,597 patients, aged <1-102 years, were treated in U.S. emergency departments for hot tub, whirlpool, and spa-related injuries, with the number increasing 160% over the 18-year study period (p<0.001). Nearly 73% of injuries occurred in patients aged >or=17 years. Lacerations were the most common diagnosis (27.8%) and accounted for 58% of all head injuries. Slips and falls were the most common mechanism of injury (47.6%); were more likely to result in an injury to the trunk than other body parts (OR=2.49, 95% CI=1.83, 3.39); and were more likely to result in concussions and fractures/dislocations than any other diagnosis (OR=7.813, 95% CI=2.194, 27.823 and OR=3.017, 95% CI=2.057, 4.425, respectively). CONCLUSIONS: Given the increase in hot tub, whirlpool, and spa ownership and the 160% increase in injuries during the study period, more research is needed to identify the cause of the increase in hot tub, whirlpool, and spa-related injuries and what injury-prevention solutions and policies may be appropriate.

Robust docosahexaenoic acid-mediated neuroprotection in a rat model of transient, focal cerebral ischemia.

BACKGROUND AND PURPOSE: Docosahexaenoic acid (DHA; 22:6n-3), an omega-3 essential fatty acid family member, is the precursor of neuroprotectin D1, which downregulates apoptosis and, in turn, promotes cell survival. This study was conducted to assess whether DHA would show neuroprotective efficacy when systemically administered in different doses after middle cerebral artery occlusion (MCAo) in rats. METHODS: Sprague-Dawley rats were anesthetized with isoflurane and subjected to 2 hour of MCAo. Animals were treated with either DHA (low doses=3.5 or 7 mg/kg; medium doses=16 or 35 mg/kg; and high dose=70 mg/kg) or an equivalent volume of saline intravenously 3 hours after MCAo onset. Neurologic status was evaluated during occlusion (60 minutes) and on days 1, 2, 3, and 7 after MCAo. Seven days after MCAo, brains were perfusion-fixed, and infarct areas and volumes were determined. RESULTS: Only the low and medium doses of DHA significantly improved the neurologic score compared with vehicle-treated rats at 24 hours, 48 hours, 72 hours, and 7 days. DHA markedly reduced total corrected infarct volume in all treated groups compared with vehicle-treated rats (3.5 mg/kg, 26+/-9 mm(3); 7 mg/kg, 46+/-12 mm(3); 16 mg/kg, 37+/-5 mm(3); and 35 mg/kg, 34+/-15 mm(3) vs vehicle, 94+/-12 mm(3)). Cortical and striatal infarct volumes were also significantly reduced by treatment with DHA. No neuroprotective effects were observed with 70 mg/kg DHA. CONCLUSIONS: We conclude that DHA experimental therapy at low and medium doses improves neurologic and histologic outcomes after focal cerebral ischemia and might provide benefits in patients after ischemic stroke.

Omega-3 fatty acids, pro-inflammatory signaling and neuroprotection.

PURPOSE OF REVIEW: To summarize recent findings that docosahexaenoate (DHA) is the precursor of stereospecific derivatives with anti-inflammatory and cytoprotective properties. RECENT FINDINGS: The docosahexaenoate-derived mediator neuroprotectin D1 is formed in retinal pigment epithelial cells when confronted with oxidative stress, in the brain during experimental stroke, and in the human brain from Alzheimer's disease patients as well as in human brain cells in culture. Neuroprotectin D1 displays potent anti-inflammatory and neuroprotective bioactivity. SUMMARY: Here, we summarize recent studies demonstrating that in brain ischemia-reperfusion and in retinal pigment epithelial cells exposed to oxidative stress stereospecific docosahexaenoate-oxygenation pathways are activated and lead to the formation of docosanoid messengers. Two docosahexaenoate-oxygenation pathways were identified: the first is responsible for the formation of the messenger neuroprotectin D1 and the second pathway, which is active in the presence of aspirin, leads to the formation of the resolvin-type mediators (17R-DHA). Neuroprotectin D1 induces antiapoptotic, anti-inflammatory signaling and is neuroprotective.

Synthesis and in vivo evaluation of non-hepatotoxic acetaminophen analogs.

A series of acetaminophen (APAP) analogs, 2-(1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)-N-(4-hydroxyphenyl)alkanecarboxamides, bearing a heterocyclic moiety linked to the p-acylaminophenol fragment, were prepared in a general project to develop APAP analogs with modulated pharmacokinetic profiles. Unexpectedly, the products described maintained the in vivo analgesic profile, while the characteristic hepatotoxicity of APAP was consistently reduced. One of the products, 5a, was studied in vivo in comparison with APAP. Compound 5a displayed an analgesic efficacy comparable to that of APAP. A relatively high acute oral dose of 5a (6 mmol/kg) produced no measurable toxicity, whereas the equimolar dose of APAP increased transaminase activity, depleted hepatic and renal glutathione, and resulted in mortality. In human hepatocytes (HEPG-2) and in human primary cultures of normal liver cells, APAP, but not 5a, was associated with apoptotic cell death, Fas-ligand up-regulation, and CAR (constitutive androstane receptor) activation, contributing to a favorable safety profile of 5a as an orally delivered analgesic.