Background: Naltrexone is an opioid receptor antagonist commonly used to treat opioid and alcohol dependence. The use of low dose naltrexone (LDN) was found to have anti-inflammatory properties for treatment of diseases such as fibromyalgia, Crohn’s disease, multiple sclerosis and regional pain syndromes. Related to its anti-neuroinflammatory properties, the mechanism of action is possibly mediated via Toll-like receptor 4 antagonism, which is widely expressed on microglial cells. The aim of the present study was to assess the immunometabolic effects of naltrexone on microglia cells in in vitro conditions. Methods: All experiments were performed in the BV-2 microglial cell line. The cells were treated with naltrexone at 100 μM concentrations corresponding to low dose for 24 h. Cell viability was assessed for every drug dose. To induce additional activation, the cells were pretreated with LPS and IFN-γ. Immunofluorescence was used to analyse the classical microglial activation markers iNOS and CD206, while Seahorse was used for real-time cellular metabolic assessments. mTOR activity measured over the expression of a major direct downstream target S6K was assessed using western blot. Results: LDN induced a shift from highly activated pro-inflammatory phenotype (iNOS^highCD206^low) to quiescent anti-inflammatory M2 phenotype (iNOS^lowCD206^high) in BV-2 microglia cells. Changes in the inflammatory profile were accompanied by cellular metabolic switching based on the transition from high glycolysis to mitochondrial oxidative phosphorylation (OXPHOS). LDN-treated cells were able to maintain a metabolically suppressive phenotype by supporting OXPHOS with high oxygen consumption, and also maintain a lower energetic state due to lower lactate production. The metabolic shift induced by transition from glycolysis to mitochondrial oxidative metabolism was more prominent in cells pretreated with immunometabolic modulators such as LPS and IFN-γ. In a dose-dependent manner, naltrexone also modulated mTOR/S6K expression, which underlies the cell metabolic phenotype regulating microglia immune properties and adaptation. Conclusion: By modulating the phenotypic features by metabolic switching of activated microglia, naltrexone was found to be an effective and powerful tool for immunometabolic reprogramming and could be a promising novel treatment for various neuroinflammatory conditions.

With the progress of medicine, especially in the last century, life expectancy increased considerably. As a result, age-related diseases also increased, especially malignancies and degenerative diseases of the central nervous system. The incidence and prevalence of neurodegenerative diseases steadily increased over the years, but despite efforts to uncover the pathophysiological processes behind these conditions, they remain elusive. Among the many theories, oxidative stress was proposed to be involved in neurodegenerative processes and to play an important role in the morbidity and progression of various neurodegenerative disorders. Accordingly, a number of studies discovered the potential of natural plant constituents to have significant antioxidant activity. This review focused on several plant-based antioxidants that showed promising results in the prevention and treatment of neurodegenerative diseases. Laurus nobilis, Aronia melanocarpa, and celastrol, a chemical compound isolated from the root extracts of Tripterygium wilfordii and T. regelii, are all known to be rich in antioxidant polyphenols.

Apolipoprotein E (APOE) remains the most robust and widely replicated genetic risk factor for late-onset Alzheimer’s disease (AD) susceptibility, with the ε4 allele (APOE4) demonstrating profound associations with accelerated symptom manifestation, enhanced disease trajectory, and modified therapeutic responsiveness. This comprehensive review synthesizes contemporary evidence regarding the clinical utility of APOE4 genotyping, emphasizing its integration into personalized therapeutic frameworks and early diagnostic paradigms. The APOE4 variant exerts pathogenic influence through impaired amyloid-β clearance, enhanced tau pathology, and compromised neuronal repair mechanisms that alter disease phenotype. We systematically examine available genotyping methodologies, encompassing polymerase chain reaction (PCR) and next-generation sequencing (NGS) platforms, and evaluate their practical implementation within clinical environments. Recent investigations demonstrate that APOE4 status profoundly influences therapeutic efficacy, particularly with anti-amyloid interventions such as lecanemab, where carriers exhibit enhanced treatment response alongside increased adverse event susceptibility. Emerging gene therapeutic approaches show promise in mitigating APOE4-associated risks through targeted molecular interventions. The integration of APOE4 genotyping with fluid biomarkers and neuroimaging techniques enables refined patient stratification and enhanced diagnostic precision, facilitating earlier intervention windows that optimize therapeutic outcomes before irreversible neuronal damage occurs. This review underscores APOE4 testing as a transformative component of precision medicine in AD management, emphasizing its contribution to diagnostic refinement, clinical decision support, and targeted therapeutic interventions.