Protective Properties of Marine Alkyl Glycerol Ethers in Chronic Stress.

In this paper we discuss the effect of alkyl glycerol ethers (AGs) from the squid Berryteuthis magister on a chronic stress model in rats. The study was performed on 32 male Wistar rats. Animals received AGs at a dose of 200 mg/kg through a gavage for six weeks (1.5 months), and were divided into four groups: group 1 (control), group 2 (animals received AGs), group 3 (stress control), group 4 (animals received AGs and were subjected to stress). Chronic immobilization stress was induced by placing each rat into an individual plexiglass cages for 2 h daily for 15 days. The serum lipid spectrum was evaluated by the content of total cholesterol, triglycerides, high-density lipoprotein cholesterol, low lipoprotein cholesterol and very low-density lipoprotein cholesterol. The atherogenic coefficient was calculated. The hematological parameters of peripheral blood were evaluated. The neutrophil-lymphocyte ratio was counted. The levels of cortisol and testosterone in blood plasma were determined. AGs at the selected dose did not have a significant effect on the body weight of rats in the preliminary period of the experiment. Under stress, the body weight gain, the concentrations of very low-density lipoprotein cholesterol and blood triglycerides decreased significantly. The neutrophil-lymphocyte ratio in animals treated with AGs shifted towards lymphocytes. A favorable increase in the percentage of lymphocytes was found in the stressed group of animals treated with AGs. So, for the first time, it was found that AGs prevent stress-induced suppression of the immune system. This confirms the benefit of AGs for the immune system under chronic stress. Our results prove the efficiency of the use of AGs for treating chronic stress, a serious social problem in modern society.

1-O-alkyl-glycerols from Squid Berryteuthis magister Reduce Inflammation and Modify Fatty Acid and Plasmalogen Metabolism in Asthma Associated with Obesity.

Asthma associated with obesity is considered the most severe phenotype and can be challenging to manage with standard medications. Marine-derived 1-O-alkyl-glycerols (AGs), as precursors for plasmalogen synthesis, have high biological activity, making them a promising substance for pharmacology. This study aimed to investigate the effect of AGs from squid Berryteuthis magister on lung function, fatty acid and plasmalogen levels, and cytokine and adipokine production in obese patients with asthma. The investigational trial included 19 patients with mild asthma associated with obesity who received 0.4 g of AGs daily for three months in addition to their standard treatment. The effects of AGs were evaluated at one and three months of treatment. The results of the study demonstrated that intake of AGs increased the FEV1 and FEV1/VC ratios, and significantly decreased the ACQ score in 17 of the 19 patients after three months of treatment. The intake of AGs increased concentration of plasmalogen and n-3 PUFA in plasma, and modified leptin/adiponectin production by adipose tissue. The supplementation of AGs decreased the plasma levels of inflammatory cytokines (TNF-α, IL-4, and IL-17a), and oxylipins (TXB2 and LTB4), suggesting an anti-inflammatory property of AGs. In conclusion, 1-O-alkyl-glycerols could be a promising dietary supplement for improving pulmonary function and reducing inflammation in obese asthma patients, and a natural source for plasmalogen synthesis. The study highlighted that the beneficial effects of AG consumption can be observed after one month of treatment, with gradual improvement after three months of supplementation.

Alkyl Glycerol Ethers as Adaptogens.

Τhis mini-review summarizes the hematopoietic and immunostimulating properties of alkyl glycerol ethers (AGs) reported earlier in the literature available to us. The role of AGs in the nervous system and aging of the body are also briefly described. We made an attempt to consider the data in terms of adaptation. The hematopoietic, immunostimulating and antioxidant properties of AGs in a variety of experimental situations, including stress, as well as the protective action of AGs against some adaptation diseases, allow us to consider them as substances that prevent some negative effects of stress and promote adaptation. The new approach to AGs as adaptogens seems promising and opens good opportunities for their new application.

Anti-Inflammatory Activity of N-Docosahexaenoylethanolamine and N-Eicosapentaenoylethanolamine in a Mouse Model of Lipopolysaccharide-Induced Neuroinflammation.

The search for methods of cognitive impairment treatment and prevention in neurological and neurodegenerative diseases is an urgent task of modern neurobiology. It is now known that various diseases, accompanied by dementia, exhibit a pronounced neuroinflammation. Considering the significant docosahexaenoic and eicosapentaenoic polyunsaturated fatty acids' therapeutic potential, we decided to investigate and compare anti-inflammatory activity of their N-acylethanolamine derivatives. As a result, we found that both N-docosahexaenoylethanolamine (synaptamide) and N-eicosapentaenoylethanolamine (EPEA) prevents an LPS-mediated increase in the proinflammatory cytokines TNF-α and IL-6 production in the SIM-A9 microglia culture. In an in vivo experiment, synaptamide reversed an increase in LPS-mediated hippocampal TNF-α and IL-1ß, but EPEA did not. However, both compounds contributed to the microglia polarization towards the M2-phenotype. Synaptamide, rather than EPEA, inhibited the Iba-1-positive microglia staining area increase. However, both synaptamide and EPEA prevented the LPS-mediated astrogliosis. A study of BDNF immunoreactivity showed that synaptamide, but not EPEA, reversed an LPS-mediated decrease in BDNF production. Despite the more pronounced anti-inflammatory activity of synaptamide, both compounds were effective in maintaining a normal level of hippocampal long-term potentiation in neuroinflammation. The results indicate a high therapeutic potential for both compounds. However, some tests have shown higher activity of synaptamide compared to EPEA.

Protective action of alkylglycerols under stress.

The adaptogenic properties of alkylglycerols (AGs) after 1 month's treatment were investigated in a rat model of acute immobilization stress (AIS). The animals receiving AGs 157 mg/kg showed a body weight (BW) decrease in addition to a more pronounced increase in the adrenal glands index under stress conditions. Also, AGs at this dose prevented AIS-induced catalase inhibition. In addition, antiulcerative AG effects were already detected at a dose of 15 mg/kg. The data indicate that AGs promote adrenal gland activation in AIS. At the same time, AGs neutralize some of negative effects of stressful conditions, which include restoration of the oxidation-reduction balance, reduction of gastric mucosal stress lesion formation.LAY SUMMARYThe effect of alkylglycerols, ether lipids from marine organisms, was studied in stressed animals. AGs have antioxidant activity and can be useful in the complex therapy of stomach lesions.

N-Docosahexanoylethanolamine Reduces Microglial Activation and Improves Hippocampal Plasticity in a Murine Model of Neuroinflammation.

Chronic neuroinflammation is a common pathogenetic link in the development of various neurological and neurodegenerative diseases. Thus, a detailed study of neuroinflammation and the development of drugs that reduce or eliminate the negative effect of neuroinflammation on cognitive processes are among the top priorities of modern neurobiology. N-docosahexanoylethanolamine (DHEA, synaptamide) is an endogenous metabolite and structural analog of anandamide, an essential endocannabinoid produced from arachidonic acid. Our study aims to elucidate the pharmacological activity of synaptamide in lipopolysaccharide (LPS)-induced neuroinflammation. Memory deficits in animals were determined using behavioral tests. To study the effects of LPS (750 µg/kg/day, 7 days) and synaptamide (10 mg/kg/day, 7 days) on synaptic plasticity, long-term potentiation was examined in the CA1 area of acute hippocampal slices. The Golgi-Cox method allowed us to assess neuronal morphology. The production of inflammatory factors and receptors was assessed using ELISA and immunohistochemistry. During the study, functional, structural, and plastic changes within the hippocampus were identified. We found a beneficial effect of synaptamide on hippocampal synaptic plasticity and morphological characteristics of neurons. Synaptamide treatment recovered hippocampal neurogenesis, suppressed microglial activation, and significantly improved hippocampus-dependent memory. The basis of the phenomena described above is probably the powerful anti-inflammatory activity of synaptamide, as shown in our study and several previous works.

Technological approach of 1-O-alkyl-sn-glycerols separation from Berryteuthis magister squid liver oil.

Biological active compounds, 1-O-alkyl-sn-glycerols (AG), were isolated from liver oil of the squid Berryteuthis magister. The main components of the initial lipids were 1-O-alkyl-2,3-diacyl-sn-glycerols (38.50 %) and triacylglycerols (24.26 %). The first step of separation was the alkaline hydrolysis of oil to form a lipid mixture consisting of AG, free fatty acids and cholesterol. AG were separated by double recrystallization from acetone at -20 °C and 1 °C. A simple procedure is proposed for obtaining AG with a purity of 99.22 %, the main component of which is chimyl alcohol (94.39 %). Purity and structure of the obtained products were confirmed by GC and GC-MS technique. Isolated AG may be used in nutrition and cosmetics.

Microsurgical Clip Reconstruction of a True Posterior Communicating Artery Aneurysm.

Approximately 25% of intracranial aneurysms originate at the internal carotid artery and posterior communicating artery (PCoA) junction.1 In contrast to typical PCoA aneurysms, which are usually saccular, a subset known as true PCoA aneurysms arise directly from the PCoA. These represent about 1.3% of all intracranial aneurysms and 6.8% of PCoA aneurysms.1 The first report of a true PCoA aneurysm was in 1979.2Video 1 illustrates the microsurgical clipping of a true PCoA aneurysm in a 27-year-old man with subarachnoid hemorrhage and left-sided ophthalmoplegia. Computed tomography angiography revealed a large true patient consent, Our surgical strategy included 1) an extended pterional approach, 2) early brain relaxation through basal cisterns and third ventricle opening, 3) Sylvian fissure dissection, 4) partial uncus resection, 5) tracing the PCoA to the aneurysm, 6) pilot clipping and thrombectomy, and 7) careful aneurysm dissection and definitive clipping. The patient had an uncomplicated recovery and was discharged on postoperative day 5 with resolved third nerve dysfunction. A literature review from 2022 documented only 47 cases of true PCoA aneurysms, predominantly manifesting with rupture.3 Some studies suggest that these aneurysms may have a higher rupture risk than typical internal carotid artery-PCoA junction aneurysms.4 Microsurgical clipping is a primary treatment, often in cases associated with a fetal posterior cerebral artery variant.5 Ensuring the patency of the PCoA and thalamoperforating arteries is crucial, with careful visualization of the clip's distal ends to avoid impacting nearby neurovascular structures.

Anti-inflammatory Effect of Polyunsaturated Fatty Acid N-Acylethanolamines Mediated by Macrophage Activity In Vitro and In Vivo.

In recent years, there has been increasing interest in studying the anti-inflammatory activity of polyunsaturated fatty acid ethanolamides (N-acylethanolamines, NAE), which are highly active lipid mediators. The results of this study demonstrate that a dietary supplement (DS) of fatty acid-derived NAEs reduces LPS-induced inflammation. The processes of cell proliferation, as well as the dynamics of Iba-1-, CD68-, and CD163-positive macrophage activity within the thymus and spleen were studied. The production of pro-inflammatory cytokines (TNF, IL1ß, IL6, and INFγ), ROS, NO, and nitrites was evaluated in the blood serum, thymus, and LPS-stimulated RAW264.7 mouse macrophages. In vitro and in vivo experiments have shown that DS (1) prevents LPS-induced changes in the morphological structure of the thymus and spleen; (2) levels out changes in cell proliferation; (3) inhibits the activity of Iba-1 and CD68-positive cells; (4) reduces the production of pro-inflammatory cytokines (TNF, IL1ß, IL6, and INFγ), ROS, and CD68; and (5) enhances the activity of CD-163-positive cells. In general, the results of this study demonstrate the complex effect of DS on inflammatory processes in the central and peripheral immune systems.

Effect of Oleoylethanolamide-Based Dietary Supplement on Systemic Inflammation in the Development of Alimentary-Induced Obesity in Mice.

The complex effect of oleoylethanolamide-based dietary supplement (OEA-DS) was studied in a model of diet-induced obesity in mice. Physiological, biochemical, and immunohistochemical methods were used to reveal differences in the changes in the weight of experimental animals, morphological changes in the spleen tissues, and changes in the cytokine expression profile in the spleen, blood plasma, and macrophage cell culture. First, it is shown that a hypercaloric diet high in carbohydrates and cholesterol led to the development of systemic inflammation, accompanied by organ morphological changes and increased production of proinflammatory cytokines. In parallel, the use of OEA-DS reduced the intensity of cellular inflammatory reactions, accompanied by a decrease in markers of cellular inflammation and proliferation, such as CD68, Iba-1, and Ki67 in the spleen tissue, and stabilized the level of proinflammatory cytokines (IL-1ß, IL-6, TNFα) both in animals and in cell culture. In addition, in the macrophage cell culture (RAW264.7), it was shown that OEA-DS also suppressed the production of reactive oxygen species and nitrites in LPS-induced inflammation. The results of this study indicate the complex action of OEA-DS in obesity, which includes a reduction of systemic inflammation.

Action of alkyl glycerol ethers and n-3 polyunsaturated fatty acids diet on hematological parameters of blood and liver plasmalogen level in aged rats.

One of the ways to reduce age-related changes can be a diet correction by adding biologically active substances. We studied the effect of a diet including alkyl glycerol ethers (AGs) and n-3 polyunsaturated fatty acid (PUFA) concentrate isolated from the hepatopancreas of Berrytheuthis magister squid on hematological parameters and plasmalogens level in the liver of elderly rats. The senile animals showed decrease in hemoglobin, a three-fold decrease in leukocytes, a three-fold increase in platelet count, and a double decrease of blood coagulation time in the peripheral blood. Age-related changes in rats were characterized by the development of anemia, hypercoagulation, and a decrease in the number of immunocompetent cells. AGs, both separately and in combination with n-3 PUFAs, induced an increase in the number of red blood cells and hemoglobin, a decrease in the number of platelets, and an immunostimulating activity. Under the action of AGs and n-3 PUFAs, the concentration of plasmalogens and docosahexaenoic acid in the rat liver increased 2- and 1.5 folds, respectively. PRACTICAL APPLICATION: This study showed that the combined use of AGs and n-3 PUFAs improves the rheological properties of the blood and the state of the immune system during aging. The enrichment of diet with dietary supplements, whose structure contains AGs and n-3 PUFAs can increase the content of plasmalogens in the body.

N-docosahexaenoylethanolamine reduces neuroinflammation and cognitive impairment after mild traumatic brain injury in rats.

At present, there is a growing interest in the study of the neurotropic activity of polyunsaturated fatty acids ethanolamides (N-acylethanolamines). N-docosahexaenoylethanolamine (DHEA, synaptamide) is an endogenous metabolite and structural analogue of anandamide, a widely studied endocannabinoid derived from arachidonic acid. The results of this study demonstrate that DHEA, when administered subcutaneously (10 mg/kg/day, 7 days), promotes cognitive recovery in rats subjected to mild traumatic brain injury (mTBI). In the cerebral cortex of experimental animals, we analyzed the dynamics of Iba-1-positive microglia activity changes and the expression of pro-inflammatory markers (IL1ß, IL6, CD86). We used immortalized mouse microglial cells (SIM-A9) to assess the effects of DHEA on LPS-induced cytokines/ROS/NO/nitrite, as well as on CD206 (anti-inflammatory microglia) and the antioxidant enzyme superoxide dismutase (SOD) production. In vivo and in vitro experiments showed that DHEA: (1) improves indicators of anxiety and long-term memory; (2) inhibits the pro-inflammatory microglial cells activity; (3) decrease the level of pro-inflammatory cytokines/ROS/NO/nitrites; (4) increase CD206 and SOD production. In general, the results of this study indicate that DHEA has a complex effect on the neuroinflammation processes, which indicates its high therapeutic potential.

1-O-alkylglycerols from the hepatopancreas of the crab Paralithodes camtschaticus, liver of the squid Berryteuthis magister, and liver of the skate Bathyraja parmifera, and their anticancer activity on human melanoma cells.

1-O-alkylglycerols (AKG) are a class of natural ether lipids derived from 1-O-alkyl-2,3-diacyl-sn-glycerols by deacylation. In this study, 1-O-alkylglycerol (AKG) composition was investigated in the hepatopancreas lipids of the crab Paralithodes camtschaticus and the liver lipids of the squid Berryteuthis magister and the skate  Bathyraja parmifera. One of the principal AKG in marine organisms was 1-O-hexadecyl-sn-glycerol (AKG 16:0). To assess AKG influence on melanoma, we evaluated the cytotoxicity and antiproliferative actions of natural AKG 16:0 and synthetic 1-O-octyl-sn-glycerol (AKG 8:0) on three human melanoma cell lines SK-Mel-5, SK-Mel-28, and RPMI-7951. Natural AKG 16:0 in concentration up to 20 µM was not toxic to all cell lines. AKG 8:0 showed no toxicity to cells SK-Mel-5 and SK-Mel-28 in concentrations up to 20 µM but had moderate cytotoxicity to RPMI-7951 cells with an IC50 of 13 µM. Both investigated substances inhibited the proliferation, formation, and growth of cell colonies of RPMI-7951. PRACTICAL APPLICATIONS: AKG exhibit a variety of biological activities, including anticancer effects. In this study, the liver lipids of the skate B. parmifera and the hepatopancreas lipids of crab P. camtschaticus were shown to be sources of AKG. Our data showed that AKG can be used to prevent the formation of new colonies of malignant cells in combination therapy against melanoma. The results will be useful for future studies involving marine ether lipids and the examination of their anticancer properties against malignant cells.

Adult hippocampal neurogenesis in neuropathic pain and alkyl glycerol ethers treatment.

Neuropathic pain manifested by a number of sensory symptoms is often accompanied by disorders of higher nervous activity, such as memory impairment, depression, anxiety, anhedonia, etc. This emphasizes the involvement of supraspinal structures including the hippocampus in neuropathic pain pathogenesis. In the present study, we focused on the impact of chronic neuropathic pain on hippocampal neurogenesis and microglial state. In addition, we test the effect of alkyl glycerol ethers on hippocampal neuronal and microglial plasticity as well as behavioral parameters. Neuropathic pain was induced using the model of sciatic nerve chronic constriction injury. We found an impairment of working memory and locomotor activity in animals with neuropathic pain, which was prevented by alkyl glycerol ethers treatment. Sciatic nerve ligation in mice contributed to the decrease in hippocampal neurogenesis intensity. Alkyl glycerol ethers administration significantly reduced this effect. Neuropathic pain-associated neurogenesis reduction was accompanied by an increased percentage of Iba1-labeled area in the CA1 hippocampal region on the 14th and 28th days after surgery. In addition, we observed a decrease in hippocampal pro-inflammatory microglia marker CD86 immunostaining on day 28 after surgery in alkyl glycerol ethers-treated mice with sciatic nerve ligation. These results are consistent with data on pro- and anti-inflammatory cytokines expression in the hippocampus. Alkyl glycerol ethers administration increased IL-10 and decreased IL-1ß hippocampal expression in animals with neuropathic pain. Taken together, these data suggest that neuropathic pain-behavior in rodents is accompanied by changes in microglia polarization, thereby contributing to neurogenesis impairment and cognitive disturbances. Alkyl glycerol ethers prevented M1 microglial activation, contributing to the maintenance of normal neurogenesis levels within the hippocampus and normalizing working memory.