Omega-3 PUFAs Suppress IL-1ß-Induced Hyperactivity of Immunoproteasomes in Astrocytes.

The role of immunoproteasome (iP) in astroglia, the cellular component of innate immunity, has not been clarified. The results so far indicate that neuroinflammation, a prominent hallmark of Alzheimer's disease, strongly activates the iP subunits expression. Since omega-3 PUFAs possess anti-inflammatory and pro-resolving activity in the brain, we investigated the effect of DHA and EPA on the gene expression of constitutive (ß1 and ß5) and inducible (iß1/LMP2 and iß5/LMP7) proteasome subunits and proteasomal activity in IL-1ß-stimulated astrocytes. We found that both PUFAs downregulated the expression of IL-1ß-induced the iP subunits, but not the constitutive proteasome subunits. The chymotrypsin-like activity was inhibited in a dose-dependent manner by DHA, and much strongly in the lower concentration by EPA. Furthermore, we established that C/EBPα and C/EBPß transcription factors, being the cis-regulatory element of the transcription complex, frequently activated by inflammatory mediators, participate in a reduction in the iP subunits' expression. Moreover, the expression of connexin 43 the major gap junction protein in astrocytes, negatively regulated by IL-1ß was markedly increased in PUFA-treated cells. These findings indicate that omega-3 PUFAs attenuate inflammation-induced hyperactivity of iPs in astrocytes and have a beneficial effect on preservation of interastrocytic communication by gap junctions.

Docosahexaenoic Acid (DHA) Inhibits FADS2 Expression in Astrocytes but Increases Survival of Neurons Co-cultured with DHA-enriched Astrocytes.

Docosahexaenoic acid (DHA), the most abundant n-3 polyunsaturated fatty acid (n-3PUFA) in the brain, has attracted great importance for a variety of neuronal functions such as signal transduction through plasma membranes, neuronal plasticity, and neuroprotection. Astrocytes that provide structural, functional, and metabolic support for neurons, express ∆6- desaturase encoded by FADS2 gene that can be, next to the plasma DHA pool, additional source of DHA in the brain. Furthermore, the genetic variations of FADS gene cluster has been found in children with developmental disorders, and are associated with cognitive functions. Since, the regulation of DHA biosynthesis in astrocytes remains poorly studied the aim of this study was to determine the effect of palmitic acid (PA), α-linolenic acid (ALA) or docosahexaenoic acid (DHA), on the transcription of FADS2 gene in astrocytes and survival of neurons challenged with oxidative compounds after co-culture with astrocytes exposed to DHA. The lipid profile in cell membranes after incubation with fatty acids was determined by gas chromatography, and FADS2 expression was analyzed using real-time PCR. The viability of neurons cocultured with PUFA-enriched astrocytes was investigated by flow cytometry after staining cells with annexin V-FITC and PI. The results showed that DHA suppressed (P <0.01), PA stimulated (P <0.01), while ALA did not change the FADS2 gene expression after 24 h incubation of astrocytes with fatty acids. Although FADS2 mRNA was down-regulated by DHA, its level in astrocytic membranes significantly increased (P <0.01). Astrocytes with DHA-enriched membrane phospholipids markedly enhanced neuronal resistance to cytotoxic compounds and neuronal survival. These results suggest that beneficial effects of supplementation with n-3 PUFA in Alzheimer disease and in psychiatric disorders is caused, in part, by increased efficacy of DHA-enriched astrocytes to protect neurons under adverse conditions in the brain.

Polyunsaturated fatty acids levels and initial presentation of somatic symptoms induced by interferon-alpha therapy in patients with chronic hepatitis C viral infection.

OBJECTIVES: Somatic symptoms are common in depressive disorder and are similar to sickness behaviors due to inflammatory activation after cytokine administration. Omega-3 polyunsaturated fatty acids (PUFAs) are natural anti-inflammatory agents and may reduce inflammation-induced behavioral changes. The aim of this study was to investigate the role of PUFAs on the development of somatic symptoms and depression in patients of hepatitis C virus infection (HCV) receiving interferon-alpha therapy (IFN-α) in a prospective manner. METHODS: In this 24-week, prospective cohort study, 43 patients with chronic HCV ongoing IFN-α therapy were assessed with the mini-international neuropsychiatric interview for major depressive episodes and neurotoxicity rating scale (NRS) for somatic symptoms. RESULTS: One-third later developed IFN-α-induced depression (depression (DEP) group). As compared to subjects without depression, DEP group had higher NRS scores (P < 0.001), lower eicosapentaenoic acid (EPA) levels (P = 0.038) at week 2. Somatic symptoms, regardless of painful/non-painful characteristics, had positive association with arachidonic acid (P < 0.05), and negative association with EPA (P < 0.05). CONCLUSION: This study implies that early intervention with omega-3 PUFAs might be a promising strategy to prevent depression and somatic symptoms in patients receiving cytokine therapy.

[The role of docosahexaenoic acid in neuronal function]. / Rola kwasu dokozaheksaenowego w czynnosci komórek nerwowych.

Docosahexaenoic acid (DHA, C22: 6n-3) is the most abundant polyunsaturated fatty acid in neuronal phospholipids, particularly in the cortex. The main source of DHA for neural cells is food, and hepatic and astroglia DHA synthesis from essential a-linolenic acid (C18: 3n-3). Accretion of DHA in the brain is most intensive during fetal life and the first two years of life. An adequate level of DHA in cell membranes is important for many functions of neural cells and this is presumably the reason for DHA saving in the adult mammalian brain during dietary a-linolenic acid deficiency. DHA-containing phospholipids in membranes are flexible and membranes possessing a high content of them are quite thin, more permeable to ions and small molecules, have looser lipid packing, and finally are more "dynamic" than membranes composed of other fatty acid containing phospholipids. Furthermore, these membranes create an appropriate environment for integral proteins highly condensed in neurons, such as receptors, ion channels, enzymes, and peripheral proteins. The quantity of phosphatidylserine in the inner membrane lipid layer depends on the availability of DHA to neurons. Phosphatidylserine promotes neuronal survival by translocation/activation of kinase Akt and Raf-1/MEK. DHA present in membrane phospholipids facilitates v-SNARE/t-SNARE complex formation, which is necessary for fusion of synaptic vesicles and plasma membranes necessary for transmitter exocytosis, and neurite outgrowth-dependent plasticity. DHA plays an important neuroprotective role. DHA has been shown to inhibit PGE2 synthesis and COX-1 expression in astrocytes, and DHA derivatives, especially neuroprotectins D, can suppress inflammatory responses, preventing neuronal damage or apoptosis. The results of high DHA content in neuronal membranes and formation of DHA derivates, as well as the function of DHA-dependent phosphatidylserine, may explain the promising results supporting beneficial DHA supplementation in neurodegenerative diseases and improvement of brain function.