Abstract Background Chronic inflammation within the central nervous system is a defining feature of many neurological and neurodegenerative disorders, including Alzheimer’s disease (AD). Astrocytes, the most abundant glial cell population in the brain, play a pivotal role in maintaining neuronal homeostasis, synaptic support, and metabolic regulation. Under pathological conditions, astrocytes undergo transformation, characterized by extensive cytokine release and impaired homeostatic functions, which can amplify inflammatory signaling and contribute to neuronal dysfunction. Although non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen are commonly employed to suppress inflammatory pathways, their clinical utility in neurodegeneration is constrained by limited brain availability and dose-dependent adverse effects. This has driven increasing interest in the development of novel anti-inflammatory compounds capable of effectively modulating glial reactivity with improved safety and sustained central activity. Aims & Objectives The aim of this study was to assess the anti-inflammatory and pro-resolving effects of ibuprofen (IBU) and a novel compound (TRP) in immune-stimulated primary astrocyte cultures derived from C57BL/6J wild-type (WT) mice as well as APPNL-F/NL-F knock-in mice (humanized model of AD). Method Primary astrocytes were isolated from the cerebral cortices of 1–2-day-old mice and exposed to IBU or TRP (10 μM) for 1 h, followed by inflammatory stimulation with lipopolysaccharide (LPS; 100 ng/mL) for 24 h. Astrocytic viability was evaluated using the LDH release assay. Nitric oxide production was quantified using the Griess method, while the release of selected pro-inflammatory (IL-1β, IL-6, CCL2) and anti-inflammatory (IL-10, IL-4) cytokines was determined by ELISA. Results Treatment with both IBU and TRP significantly improved astrocyte survival under inflammatory conditions, as indicated by reduced LDH release. LPS exposure markedly increased nitric oxide production and the secretion of pro-inflammatory mediators, whereas TRP treatment effectively suppressed NO, IL-1β, and CCL2 levels in stimulated astrocytes. These effects were observed in cultures derived from both WT and AD-model mice. Discussion & Conclusions The present findings demonstrate that TRP attenuates astrocyte-mediated inflammatory responses and confers protection against LPS-evoked cellular damage. Hence, TRP emerges as a promising candidate for further investigation as a modulator of astrocyte-driven neuroinflammation and/or Alzheimer’s disease. The study was supported by a programme coordinated by the Medical Research Agency, co-financed by the European Union under the NextGeneration EU initiative, within the framework of the National Recovery Plan, Component D, Investment D3.1.1 (project no. 2024/ABM/03/KPO/KPOD.07.07-IW.07-0173/24-00).
A. Basta-Kaim, E. Trojan, K. Kamińska et al.· International Journal of Neu...· 0 citations
Abstract Background Neuroinflammation is a hallmark of central nervous system (CNS) disorders and plays a critical role in the progression of neurodegenerative diseases, including Alzheimer’s disease. Microglia, the resident immune cells of the CNS, act as key regulators of inflammatory responses and are rapidly activated in response to pathological stimuli such as amyloid-β accumulation, neuronal injury, and synaptic dysfunction. While acute microglial activation is essential for tissue homeostasis and debris clearance, sustained or dysregulated activation contributes to chronic inflammation and neurodegeneration. Non-steroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, are widely used to attenuate neuroinflammatory processes. Although ibuprofen exhibits anti-inflammatory and neuroprotective properties, achieving therapeutic concentrations in the brain requires prolonged dosing, which exacerbates various peripheral and central side effects. Therefore, there is a critical need to develop novel anti-inflammatory compounds with improved brain bioavailability and safer therapeutic profiles in order to effectively modulate neuroinflammation and in consequently, neurodegeneration. Aims & Objectives We propose as a goal of the present study a comparative evaluation of the anti-inflammatory and pro-resolution potential of ibuprofen (IBU) and a novel compound (TRP) in immune-activated primary microglial cell cultures derived from C57BL/6J (WT) and APPNL-F/NL-F knock-in mice (KI, animal model of AD). Method Primary Microglial cells were prepared from the cortices of 1-2-day-old mouse brains. The cells were treated for 1 h with IBU or TRP (10 μM) and then stimulated for 24 h with bacterial endotoxin (lipopolysaccharide, LPS, 100 ng/mL). We measured the cell death parameters (lactate dehydrogenase, LDH assay), the secretion of nitric oxide (NO) synthesis by Griess reaction, and pro- (IL-1β, IL-6, CCL2) and anti-inflammatory cytokines (IL-10, IL-4) profile release in control and AD-derived microglia cells using ELISA kits. Results Exposure to IBU and TRP significantly reduced LPS-induced microglial cell death, as evidenced by decreased LDH release. Moreover, LPS stimulation led to an upregulation of NO, and IL-1β, IL-6, and IL-10 release as well as CCL-2 production, more evident in microglia cells derived from KI mice. Most of the pro-inflammatory markers released were attenuated by TRP administration. Interestingly, TRP treatment preserved the LPS-induced elevation of IL-10, which may suggest not only an anti-inflammatory but also a pro-resolving profile of TRP action in primary microglia cultures obtained also from the AD model. Discussion & Conclusions Our findings suggest that TRP modulates microglial activation in a varied manner. Its simultaneous ability to influence the proinflammatory and anti-inflammatory profiles of microglial cells in an AD model positions this compound as a promising candidate for further investigation in the context of neuroimmune dysregulation and a tool for pharmacotherapy of resolution. The study was supported by a programme coordinated by the Medical Research Agency, co-financed by the European Union under the NextGeneration EU initiative, within the framework of the National Recovery Plan, Component D, Investment D3.1.1 (project no. 2024/ABM/03/KPO/KPOD.07.07-IW.07-0173/24-00).
E. Trojan, K. Kamińska, M. Leśkiewicz et al.· International Journal of Neu...· 0 citations
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