Fatty Acid-Derived <i>N</i>-acylethanolamines Dietary Supplementation Attenuates Neuroinflammation and Cognitive Impairment in LPS Murine Model

Neuroinflammation plays a critical role in the pathogenesis of most neurological and neurodegenerative diseases and therefore represents a potential therapeutic target. In this regard, accelerating the resolution process in chronic neuroinflammation may be an effective strategy to deal with the cognitive consequences of neuropathology and generalized inflammatory processes. N-acylethanolamine (NAE) derivatives of fatty acids, being highly active lipid mediators, possess pro-resolving activity in inflammatory processes and are promising agents for the suppression of neuroinflammation and its consequences. This paper is devoted to a study of the effects played by dietary supplement (DS), containing a composition of fatty acid-derived NAEs, obtained from squid Berryteuthis magister, on the hippocampal neuroinflammatory and memory processes. By detecting the production of pro-inflammatory cytokines and glial markers, a pronounced anti-inflammatory activity of DS was demonstrated both in vitro and in vivo. DS administration reversed the LPS-induced reduction in hippocampal neurogenesis and memory deterioration. LC-MS analysis revealed an increase in the production of a range of NAEs with well-documented anti-inflammatory activity in response to the administered lipid composition. To conclude, we found that tested DS suppresses the neuroinflammatory response by reducing glial activation, positively regulates neural progenitor proliferation, and attenuates hippocampal-dependent memory impairment

Synaptamide Modulates Astroglial Activity in Mild Traumatic Brain Injury

At present, the study of the neurotropic activity of polyunsaturated fatty acid ethanolamides (N-acylethanolamines) is becoming increasingly important. N-docosahexaenoylethanolamine (synaptamide, DHEA) is a highly active metabolite of docosahexaenoic acid (DHA) with neuroprotective, synaptogenic, neuritogenic, and anti-inflammatory properties in the nervous system. Synaptamide tested in the present study was obtained using a chemical modification of DHA isolated from squid Berryteuthis magister liver. The results of this study demonstrate the effects of synaptamide on the astroglial response to injury in the acute (1 day) and chronic (7 days) phases of mild traumatic brain injury (mTBI) development. HPLC-MS study revealed several times increase of synaptamide concentration in the cerebral cortex and serum of experimental animals after subcutaneous administration (10 mg/kg/day). Using immunohistochemistry, it was shown that synaptamide regulates the activation of GFAP- and S100&beta;-positive astroglia, reduce nNOS-positive immunostaining, and stimulates the secretion of neurotrophin BDNF. Dynamics of superoxide dismutase production in synaptamide treatment confirm the antioxidant efficacy of the test compound. We found a decrease in TBI biomarkers such as GFAP, S100&beta;, and IL-6 in the blood serum of synaptamide-treated experimental animals using Western blot analysis. The results indicate the high therapeutic potential of synaptamide in reducing the severity of the brain damage consequences

Modulation of Hippocampal Astroglial Activity by Synaptamide in Rats with Neuropathic Pain

The present study demonstrates that synaptamide (N-docosahexaenoylethanolamine), an endogenous metabolite of docosahexaenoic acid, when administered subcutaneously (4 mg/kg/day, 14 days), exhibits analgesic activity and promotes cognitive recovery in the rat sciatic nerve chronic constriction injury (CCI) model. We analyzed the dynamics of GFAP-positive astroglia and S100β-positive astroglia activity, the expression of nerve growth factor (NGF), and two subunits of the NMDA receptor (NMDAR1 and NMDAR2A) in the hippocampi of the experimental animals. Hippocampal neurogenesis was evaluated by immunohistochemical detection of DCX. Analysis of N-acylethanolamines in plasma and in the brain was performed using the liquid chromatography-mass spectrometry technique. In vitro and in vivo experiments show that synaptamide (1) reduces cold allodynia, (2) improves working memory and locomotor activity, (3) stabilizes neurogenesis and astroglial activity, (4) enhances the expression of NGF and NMDAR1, (5) increases the concentration of Ca2+ in astrocytes, and (6) increases the production of N-acylethanolamines. The results of the present study demonstrate that synaptamide affects the activity of hippocampal astroglia, resulting in faster recovery after CCI

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

Abstract 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 (IL1β, 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

Personalized regulation of glioblastoma cancer stem cells based on biomedical technologies : From theory to experiment (Review)

Glioblastoma multiforme (GBM) is one of the most aggressive brain tumors. GBM represents &gt;50% of primary tumors of the nervous system and similar to 20% of intracranial neoplasms. Standard treatment involves surgery, radiation and chemotherapy. However, the prognosis of GBM is usually poor, with a median survival of 15 months. Resistance of GBM to treatment can be explained by the presence of cancer stem cells (CSCs) among the GBM cell population. At present, there are no effective therapeutic strategies for the elimination of CSCs. The present review examined the nature of human GBM therapeutic resistance and attempted to systematize and put forward novel approaches for a personalized therapy of GBM that not only destroys tumor tissue, but also regulates cellular signaling and the morphogenetic properties of CSCs. The CSCs are considered to be an informationally accessible living system, and the CSC proteome should be used as a target for therapy directed at suppressing clonal selection mechanisms and CSC generation, destroying CSC hierarchy, and disrupting the interaction of CSCs with their microenvironment and extracellular matrix. These objectives can be achieved through the use of biomedical cellular products

Interaction of hematopoietic CD34(+) CD45(+) stem cells and cancer cells stimulated by TGF-beta 1 in a model of glioblastoma in vitro

The majority of modern treatment methods for malignant brain tumors are not sufficiently effective, with a median survival time varying between 9 and 14 months. Metastatic and invasive processes are the principal characteristics of malignant tumors. The most important pathogenic mechanism is epithelial-mesenchymal transition (EMT), which causes epithelial cells to become more mobile, and capable of invading the surrounding tissues and migrating to distant organs. Transforming growth factor-beta 1 (TGF-beta 1) serves a key role in EMT-inducing mechanisms. The current study presented the interaction between hematopoietic stem cells and glioblastoma cells stimulated by TGF-beta 1 in vitro. The materials for the study were hematopoietic progenitor cell antigen CD34(+) hematopoietic stem cells (HSCs) and U87 glioblastoma cells. Cell culture methods, automated monitoring of cell-cell interactions, confocal laser microscopy, flow cytometry and electron microscopy were used. It was demonstrated that U87 cells have a complex communication system, including adhesive intercellular contacts, areas of interdigitation with dissolution of the cytoplasm, cell fusion, communication microtubes and microvesicles. TGF-beta 1 affected glioblastoma cells by modifying the cell shape and intensifying their exocrine function. HSCs migrated to glioblastoma cells, interacted with them and exchanged fluorescent tags. Stimulation of cancer cells with TGF-beta 1 weakened the ability of glioblastoma cells to attract HSCs and exchange a fluorescent tag. This process stimulated cancer cell proliferation, which is an indication of the ability of HSCs to 'switch' the proliferation and invasion processes in glioblastoma cells