Rubus occidentalis Ethanol Extract Attenuates Neuroinflammation and Cognitive Impairment in Lipopolysaccharide-Stimulated Microglia and Scopolamine-Induced Amnesic Mice

<b>Background/Objectives:</b> Neuroinflammatory mechanisms, primarily mediated by activated microglia, play a key role in the progression of conditions such as mild cognitive impairment associated with Alzheimer's disease. <i>Rubus occidentalis</i> (<i>R. occidentalis</i>), a black-fruited raspberry native to North America, is reported to possess antimicrobial, antidiabetic, and anticancer properties. This study investigated the neuroprotective and anti-neuroinflammatory effects of a 100% ethanol extract from premature <i>R. occidentalis</i> fruits (ROE) in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells and a scopolamine-induced amnesic mouse model. <b>Methods:</b> C57BL/6N mice were orally administered ROE (100 or 200 mg/kg/b.w.) and donepezil (DNZ, 5 mg/kg) for 9 days and intraperitoneally injected with scopolamine (2 mg/kg/b.w.) for two days. Spatial learning and cognitive function were assessed using the Y-maze and Morris water maze tests. Protein and mRNA levels were examined both in vitro and in vivo through Western blotting and RT-PCR analysis. <b>Results:</b> In vitro, ROE improved cell viability and reduced nitric oxide overproduction in LPS-stimulated BV-2 cells, attenuated LPS-induced phosphorylation and degradation of IκB-α (thereby limiting NF-κB p65 nuclear translocation), and suppressed phosphorylation of MAPK signaling components. In vivo, ROE administration enhanced spatial learning and memory in scopolamine-treated C57BL/6N mice, increased hippocampal levels of brain-derived neurotrophic factor (BDNF) and phosphorylated CREB, and reduced the expression of iNOS and COX-2. <b>Conclusions:</b> Collectively, these results suggest that ROE possesses neuroprotective properties mediated by inhibition of NF-κB and MAPK signaling, promotion of CREB/BDNF pathways, and amelioration of neuroinflammation and cognitive deficits. Thus, ROE may represent a promising therapeutic candidate for neuroinflammatory disorders.