Omega-3 alleviates behavioral and molecular changes in a mouse model of stress-induced juvenile depression.

Introduction: Depression is increasingly diagnosed in adolescence, necessitating specific prevention and treatment methods. However, there is a lack of animal models mimicking juvenile depression. This study explores a novel model using ultrasound (US) stress in juvenile mice. Methods: We employed the US stress model in one-month-old C57/BL6 mice, exposing them to alternating ultrasound frequencies (20-25 kHz and 25-45 kHz) for three weeks. These frequencies correspond to negative and neutral emotional states in rodents and can induce a depressive-like syndrome. Concurrently, mice received either an omega-3 food supplement (FS) containing eicosapentaenoic acid (EPA; 0.55 mg/kg/day) and docosahexaenoic acid (DHA; 0.55 mg/kg/day) or a vehicle. Post-stress, we evaluated anxiety- and depressive-like behaviors, blood corticosterone levels, brain expression of pro-inflammatory cytokines, and conducted metabolome analysis of brain, liver and blood plasma. Results: US-exposed mice treated with vehicle exhibited decreased sucrose preference, a sign of anhedonia, a key feature of depression, increased anxiety-like behavior, elevated corticosterone levels, and enhanced TNF and IL-1ß gene expression in the brain. In contrast, US-FS mice did not display these changes. Omega-3 supplementation also reduced anxiety-like behavior in non-stressed mice. Metabolomic analysis revealed US-induced changes in brain energy metabolism, with FS increasing brain sphingomyelin. Liver metabolism was affected by both US and FS, while plasma metabolome changes were exclusive to FS. Brain glucose levels correlated positively with activity in anxiety tests. Conclusion: Chronic omega-3 intake counteracted depressive- and anxiety-like behaviors in a US model of juvenile depression in mice. These effects likely stem from the anti-inflammatory properties of the supplement, suggesting potential therapeutic applications in juvenile depression.

Aberrant Ganglioside Functions to Underpin Dysregulated Myelination, Insulin Signalling, and Cytokine Expression: Is There a Link and a Room for Therapy?

Gangliosides are molecules widely present in the plasma membranes of mammalian cells, participating in a variety of processes, including protein organization, transmembrane signalling and cell adhesion. Gangliosides are abundant in the grey matter of the brain, where they are critically involved in postnatal neural development and function. The common precursor of the majority of brain gangliosides, GM3, is formed by the sialylation of lactosylceramide, and four derivatives of its a- and b-series, GM1, GD1a, GD1b and GT1b, constitute 95% of all the brain gangliosides. Impairments in ganglioside metabolism due to genetic abnormalities of GM-synthases are associated with severe neurological disorders. Apart from that, the latest genome-wide association and translational studies suggest a role of genes involved in brain ganglioside synthesis in less pervasive psychiatric disorders. Remarkably, the most recent animal studies showed that abnormal ganglioside functions result in dysregulated neuroinflammation, aberrant myelination and altered insulin receptor signalling. At the same time, these molecular features are well established as accompanying developmental psychiatric disorders such as attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASD). This led us to hypothesize a role of deficient ganglioside function in developmental neuropsychiatric disorders and warrants further gene association clinical studies addressing this question. Here, we critically review the literature to discuss this hypothesis and focus on the recent studies on ST3GAL5-deficient mice. In addition, we elaborate on the therapeutic potential of various anti-inflammatory remedies for treatment of developmental neuropsychiatric conditions related to aberrant ganglioside functions.

Immunomodulatory effects of new phytotherapy on human macrophages and TLR4- and TLR7/8-mediated viral-like inflammation in mice.

Background: While all efforts have been undertaken to propagate the vaccination and develop remedies against SARS-CoV-2, no satisfactory management of this infection is available yet. Moreover, poor availability of any preventive and treatment measures of SARS-CoV-2 in economically disadvantageous communities aggravates the course of the pandemic. Here, we studied a new immunomodulatory phytotherapy (IP), an extract of blackberry, chamomile, garlic, cloves, and elderberry as a potential low-cost solution for these problems given the reported efficacy of herbal medicine during the previous SARS virus outbreak. Methods: The key feature of SARS-CoV-2 infection, excessive inflammation, was studied in in vitro and in vivo assays under the application of the IP. First, changes in tumor-necrosis factor (TNF) and lnteurleukin-1 beta (IL-1ß) concentrations were measured in a culture of human macrophages following the lipopolysaccharide (LPS) challenge and treatment with IP or prednisolone. Second, chronically IP-pre-treated CD-1 mice received an agonist of Toll-like receptors (TLR)-7/8 resiquimod and were examined for lung and spleen expression of pro-inflammatory cytokines and blood formula. Finally, chronically IP-pre-treated mice challenged with LPS injection were studied for "sickness" behavior. Additionally, the IP was analyzed using high-potency-liquid chromatography (HPLC)-high-resolution-mass-spectrometry (HRMS). Results: LPS-induced in vitro release of TNF and IL-1ß was reduced by both treatments. The IP-treated mice displayed blunted over-expression of SAA-2, ACE-2, CXCL1, and CXCL10 and decreased changes in blood formula in response to an injection with resiquimod. The IP-treated mice injected with LPS showed normalized locomotion, anxiety, and exploration behaviors but not abnormal forced swimming. Isoquercitrin, choline, leucine, chlorogenic acid, and other constituents were identified by HPLC-HRMS and likely underlie the IP immunomodulatory effects. Conclusions: Herbal IP-therapy decreases inflammation and, partly, "sickness behavior," suggesting its potency to combat SARS-CoV-2 infection first of all via its preventive effects.