Search Results (124)

Mulberroside A (MsA) possesses neuroprotective effects, but whether it alleviates Alzheimer’s disease (AD)-like cognitive impairment through the microbiota–gut–brain axis remains unclear. Using a scopolamine-induced mouse model of acute cognitive impairment (male ICR mice, n = 10/group), we demonstrated that daily administration of MsA (10, 20, and 30 mg/kg/day) for 5 weeks significantly ameliorated cognitive performance in novel object recognition and Morris water maze tests. At the optimal dose (30 mg/kg/day), MsA suppressed hippocampal microglial activation, reduced pro-inflammatory cytokines (IL-6, IL-1β, TNF-α), and attenuated oxidative stress by decreasing malondialdehyde (MDA) while restoring superoxide dismutase (SOD) and glutathione (GSH) levels. MsA also strengthened intestinal barrier integrity (ZO-1, occludin) and significantly altered the gut microbiota, notably increasing the beneficial genus Dubosiella. Brain metabolomics indicated that MsA reversed scopolamine-induced metabolic disturbances, mainly restoring phospholipid balance. Correlation analysis demonstrated a strong gut–brain connection, with Dubosiella abundance positively associated with neuroprotective phospholipids and negatively with stress markers. Furthermore, fecal microbiota transplantation from MsA-treated donors successfully replicated these behavioral improvements in recipient mice, underscoring the functional involvement of the reshaped microbiome rather than a simple autonomous recovery. These results suggest that MsA alleviates AD-like cognitive impairment by reducing neuroinflammation and oxidative stress through microbiota remodeling, enhancing the intestinal barrier, and modulating the Dubosiella-associated gut–metabolite–brain axis, making MsA a promising multi-target nutraceutical for ameliorating AD-like cognitive deficits. Full article

Qin Bing eye drops, a traditional Chinese medicine-based in-hospital preparation, were historically indicated for the treatment of conjunctivitis, keratitis, and photokeratitis. This study aimed to develop Qin Pi extract (QP-E) using a proprietary extraction method, and to evaluate the therapeutic efficacy of QP-E alone, QP-E combined with Bing Pian (BP), and an ophthalmic formulation (QP-D) comprising both constituents in a preclinical model of dry eye disease (DED). DED was induced in mice via subcutaneous scopolamine administration alone, whereas a more robust dry eye phenotype was established in rats through combined treatment with scopolamine and environmental stressors. Ocular surface evaluation included measurement of tear secretion volume and corneal fluorescein staining scores. The results demonstrated that both QP-E monotherapy and the QP-E–BP combination significantly ameliorated key pathological features of DED, including tear film instability and corneal epithelial damage. QP-D—formulated with rationally optimized concentrations of QP-E and BP—significantly enhanced basal tear secretion and attenuated corneal epithelial injury in both murine and rat dry eye models. Mechanistic investigations revealed that QP-E treatment markedly inhibited VEGF-C secretion from classically activated (M1) macrophages, suppressed phosphorylation-dependent activation of the VEGF-C/VEGFR-3 signaling axis, and consequently impaired lymphatic endothelial cell migration and in vitro tube formation. These correlative findings indicate that QP-E may partially alleviate DED by suppressing lymphangiogenesis; however, direct causal evidence—such as genetic ablation of VEGF-C or pharmacological inhibition of VEGFR-3—was not established in the present study. Collectively, our data yield a testable mechanistic hypothesis and propose a novel therapeutic strategy targeting lymphatic remodeling for DED intervention. Full article

Cholinergic dysfunction and impaired synaptic plasticity are key mechanisms underlying cognitive decline in neurodegenerative conditions, including Alzheimer’s disease (AD). Schisandra chinensis pomace (SSP), a by-product of fruit processing, contains bioactive lignans and polyphenols with reported neuroprotective properties; however, its effects under cholinergic dysfunction have not been systematically investigated. In this study, the effects of SSP on scopolamine-induced cognitive impairment were evaluated using ex vivo electrophysiological and in vivo behavioral approaches. Multi-electrode array recordings demonstrated that SSP at 0.1 mg/mL significantly restored scopolamine-suppressed hippocampal long-term potentiation (LTP), whereas a higher concentration (1.0 mg/mL) did not restore hippocampal synaptic potentiation. In vivo, C57BL/6N mice received oral SSP (50 or 100 mg/kg/day) for six weeks, with scopolamine administered during the final three weeks. SSP at 50 mg/kg prevented scopolamine-induced body weight loss, attenuated hyperlocomotor activity, and significantly improved memory retention, as evidenced by enhanced performance in the passive avoidance and Morris water maze tests. Furthermore, SSP restored hippocampal brain-derived neurotrophic factor (BDNF) expression and reduced the p-JNK/JNK ratio, indicating modulation of neurotrophic and stress-responsive signaling pathways. Collectively, these findings suggest that SSP attenuates scopolamine-induced cholinergic dysfunction, accompanied by improved hippocampal synaptic plasticity and changes in BDNF and JNK signaling. These results support the potential of SSP as a neuroactive botanical resource under cholinergic challenge. Full article

Background/Objectives: Dementia remains one of the major global health challenges of the modern era. Researchers worldwide continue to seek effective therapeutic strategies to combat this neurodegenerative condition. Silymarin is a natural compound with strong neuroprotective and antioxidant properties that holds great potential for dementia management; however, its poor aqueous solubility and limited ability to cross the blood–brain barrier (BBB) have restricted its clinical application. This study focused on the formulation and evaluation of a heparin–pullulan silymarin liposomal (HPSL) nano-gel to enhance the neuroprotective efficacy of silymarin, with potential for improved brain targeting effects. Methods: The HPSL nano-gel was synthesized using the thin-film hydration technique and optimized based on entrapment efficiency, particle size distribution, zeta potential, and in vitro release kinetics. The neuroprotective efficacy of the HPSL nano-gel was evaluated in mice using behavioral evaluations, biochemical quantification of oxidative stress markers, evaluation of cholinergic enzyme activity and detailed histopathological examination of brain tissues. Results: Morphological characterization using scanning electron microscopy (SEM) confirmed a uniform nano-scale structure. The optimized formulation (HPSL-3) exhibited a particle size of 406.07 ± 19.33 nm, zeta potential of −23.72 ± 7.64 mV and an entrapment efficiency of 73.53 ± 12.05%, indicating good colloidal stability and efficient drug loading. The in vitro release profile followed non-Fickian diffusion kinetics, suggesting sustained drug release behavior. Behavioral studies in scopolamine-induced amnesic mice (elevated plus maze, hole board, and light/dark paradigms) demonstrated significant (p ≤ 0.001) improvements in learning and memory retention. Biochemical analyses showed increased levels of ChAT, SOD, CAT, and GSH, along with decreased AChE and MDA levels, supporting the neuroprotective potential of the formulation. Histopathological evaluation revealed marked attenuation of neuronal degeneration, inflammation, and edema (HAI = 4) compared to the scopolamine-treated group (HAI = 11). Conclusions: Overall, the HPSL-2 formulation effectively enhanced silymarin delivery across the BBB, demonstrating potent antioxidant, neuroprotective, and cholinergic modulatory effects. These findings suggest that HPSL-2 represents a promising nano-carrier system for the management of dementia and other oxidative-stress-related neurological disorders. Full article

(1) Background: Bioactive peptides from marine and plant sources show neuroprotective potential, yet how their combination ratios affect memory regulation via the gut–brain axis remains unclear. This study investigated the effects of different ratios of marine peptide QMDDQ (Glutamine-Methionine-Aspartate-Aspartate-Glutamine) and plant peptide AGLPM (Alanine-Glycine-Leucine-Proline-Methionine) on scopolamine-induced memory impairment in mice. (2) Methods: Cognitive function was assessed using the Morris water maze and novel object recognition tests. Nissl staining, microplate-based assays for acetylcholine (ACh) content and acetylcholinesterase (AChE) activity, Western blotting for neurotrophic factors, LC-MS/MS-based intestinal peptide profiling, and HPLC-based brain amino acid analysis were performed. (3) Results: The 1:1 ratio most effectively restored learning and memory, regulated hippocampal cholinergic function, mitigated neuronal damage, and elevated BDNF, NGF, and NTF-3 expression. In the gut, peptides were hydrolyzed into glutamate- and proline-rich fragments, which influenced brain amino acid balance by elevating glutamate and proline levels while reducing NH₃-related signaling. (4) Conclusions: These results highlight the ratio-dependent efficacy of QMDDQ-AGLPM combinations and provide evidence for a gut peptide remodeling-brain metabolic link relevant to cognitive impairment. Full article

Walnut peptide Lys-Gly-His-Leu-Phe-Pro-Asn (KG-7) is a food-derived bioactive peptide with a high antioxidant capacity. We systematically evaluated the ameliorative effects of KG-7 on scopolamine-induced memory deficits in mice and its intestinal absorption mechanisms through integrating motion behavior analysis, molecular biochemistry research, and fluorescence imaging technology. Morris water maze tests revealed that KG-7 significantly improved the behavioral performance of these mice. Further mechanistic investigations demonstrated that KG-7 restored cholinergic function by reducing acetylcholinesterase activity and increasing acetylcholine levels. Hematoxylin-eosin staining and hippocampal immunohistochemistry confirmed that KG-7 alleviated neuronal damage by downregulating Hes1 overexpression, clarifying its behavioral improvement mechanism. In vitro fluorescence imaging showed that KG-7 reached peak accumulation in brain tissue 8 h post-administration, confirming its brain delivery. To elucidate the absorption mechanism, immunohistochemistry and immunofluorescence revealed that KG-7 markedly reduced the expression of efflux transporter P-gp in the small intestine, thereby diminishing efflux activity, while weakened tight junction (Occludin, ZO-1) fluorescence indicated activation of the paracellular pathway. Western blot analysis confirmed that KG-7 enhanced paracellular absorption efficiency and reduced intestinal efflux by downregulating ZO-1, Occludin, and efflux transporters (P-gp, BCRP, and LRP1) alongside upregulating Claudin-2 expression. These findings provide a foundation for exploring walnut peptides that enhance memory and optimize absorption. Full article

Alzheimer’s disease and related neurodegenerative disorders are associated with progressive cognitive decline, primarily driven by cholinergic dysfunction and impaired synaptic signaling. Hericium erinaceus, also known as lion’s mane mushroom, has been reported to promote neuronal differentiation and synaptic plasticity. In this study, a standardized H. erinaceus extract powder (HEP) was prepared from fruiting bodies and quantified using hericene A as a marker compound. The neuroprotective effects of HEP were then evaluated in both cellular and animal models of scopolamine-induced cognitive dysfunction. Pretreatment of SH-SY5Y human neuroblastoma cells with HEP (5–25 μg/mL) significantly improved cell viability and reduced scopolamine-induced apoptosis, while enhancing the activation of neuroplasticity-related signaling proteins, including brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), and extracellular signal-regulated kinase (ERK). In vivo, oral administration of HEP (300 mg/kg) to scopolamine-treated ICR mice markedly improved cognitive performance, increasing the recognition index to 63.8% compared with 41.6% in the scopolamine group, and enhancing spontaneous alternation in the Y-maze test to 59.6%. These cognitive improvements were accompanied by preserved hippocampal neuronal structure and increased BDNF immunoreactivity. Additionally, HEP improved cholinergic function by restoring serum acetylcholine levels and reducing acetylcholinesterase activity. Collectively, these findings suggest that standardized HEP exerts neuroprotective and cognition-enhancing effects via modulation of cholinergic markers and activation of BDNF-mediated neuroplasticity, highlighting its potential as a functional food ingredient or nutraceutical for preventing cognitive decline related to cholinergic dysfunction. Full article

Background: Alzheimer’s disease (AD), a progressive brain disorder, is the most common form of dementia and necessitates the development of effective intervention strategies. Ginseng-Natto composite fermentation products (GN) have demonstrated beneficial bioactivities in mouse models of AD; however, the underlying mechanism of action through which GN ameliorates AD requires further elucidation. Methods: Mice received daily intragastric administration of low- or high-dose GN for 4 weeks, followed by intraperitoneal injection of scopolamine to induce the AD model. The pharmacological effects of GN were systematically evaluated using the Morris water maze test, ELISA, and H&E staining. To further investigate the underlying mechanisms, 16S rRNA gene sequencing and metabolomics were employed to analyze the regulatory effects of GN on the gut–brain axis. Additionally, Western blotting was performed to assess the impact of GN on blood–brain barrier (BBB) integrity. Results: GN intervention significantly ameliorated cognitive deficits and attenuated neuropathological injury in AD mice, restoring the brain levels of acetylcholine (ACh), acetylcholinesterase (AChE), superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GSH-Px), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) to normal ranges. GN reshaped the gut microbiota by promoting beneficial bacteria and inhibiting pro-inflammatory strains. It also regulated key metabolic pathways related to amino acid and unsaturated fatty acid metabolism. This metabolic remodeling restored the compromised BBB integrity by upregulating tight junction proteins (ZO-1, Occludin and Claudin-1). Conclusions: Our findings demonstrate that GN ameliorates AD through a gut-to-brain pathway, mediated by reshaping the microbiota-metabolite axis and repairing the BBB. Thus, GN may represent a promising intervention candidate for AD. Full article

Microbiome-derived metabolites have emerged as key mediators of the gut–brain axis, influencing cognitive function and neuroprotection. This study investigated whether Lactobacillus delbrueckii subsp. lactis CKDB001 alleviates scopolamine-induced memory impairment through metabolic modulation, and how its effects compare with those of donepezil. ICR mice were administered CKDB001 or donepezil for 4–5 weeks and evaluated through behavioral, microbiome, metabolomic, and molecular analyses. CKDB001 significantly improved spatial working memory in a dose-dependent manner, with the high-dose group showing improvements comparable to those of the donepezil-treated group, while passive avoidance showed a non-significant but positive trend. Both CKDB001 and donepezil modulated gut microbial composition, leading to a partial divergence from the scopolamine-disrupted community structure, with CKDB001 inducing dose-dependent intestinal colonization. Metabolomic profiling revealed that both treatments increased tryptophan-derived indole metabolites and altered lipid and short-chain fatty acid metabolite profiles, although these effects were more pronounced in CKDB001-treated mice. At the molecular level, both CKDB001 and donepezil reduced hippocampal tau phosphorylation, downregulated glycogen synthase kinase-3 (GSK-3) signaling, enhanced intestinal tight-junction proteins, and partially normalized acetylcholinesterase activity, with CKDB001 restoring AChE levels more closely toward the normal control. Together, these findings suggest that CKDB001 mitigates cognitive deficits through coordinated modulation of microbial, metabolic, and neuronal pathways, offering a microbiome-based therapeutic approach that may provide benefits comparable to donepezil with potentially fewer limitations. Full article

Cognitive impairment is acknowledged as an early stage between normal aging and Alzheimer’s disease, emphasizing the need for prompt intervention. There is growing evidence that the gut–brain axis plays a role in regulating cognitive function, indicating that probiotics and their derivatives may impact cognitive functions through the brain–gut axis. In this study, we isolated and identified a novel bacterial strain Limosilactobacillus fermentum IOB802 (IOB802) from traditionally fermented pickles. This strain showed promising probiotic properties, and its postbiotic was also prepared. Both the probiotic IOB802 and its postbiotic preparation significantly improved memory and learning abilities by using a mouse model with cognitive impairment induced by scopolamine. In comparison to the scopolamine group, IOB802 and IOB802 postbiotic administration decreased acetylcholinesterase activity by 59.2% and 29.51%, increased antioxidant enzyme activity by 44.45% and 29.43%, and lowered lipid peroxidation by 44.19% and 32.53%, respectively. Moreover, IOB802 postbiotic notably boosted acetylcholine levels by 72.08%. In addition, the treatments preserved the integrity of neurons in specific regions of the hippocampus, as shown by histological analysis. The IOB802 postbiotic increased the expression of neurotrophic factors BDNF and NGF by 1.36- and 1.73-fold, while reducing the expression of inflammatory cytokines TNF-α, IL-6, and IL-1β by 2.05-, 1.85-, and 2.46-fold, respectively. Compared to the scopolamine group, IL-6 and IL-1β expression decreased by 1.32- and 2.37-fold in the IOB802 group. Additionally, IOB802, especially its postbiotic, was found to restore disrupted intestinal flora caused by scopolamine. These findings suggest that IOB802 and its postbiotic can improve cognitive function through enhancing cholinergic activity, reducing oxidative stress, providing neuroprotection, and restoring gut microbiota composition. Postbiotics, in particular, may represent a promising alternative to live probiotics for supporting cognitive health. Full article

Background/Objectives: 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. Rubus occidentalis (R. occidentalis), 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 R. occidentalis fruits (ROE) in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells and a scopolamine-induced amnesic mouse model. Methods: 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. Results: 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. Conclusions: 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. Full article

In our previous study, we demonstrated that a standardized ethanol extract of Perilla frutescens var. acuta (PE) alleviates memory deficits in an Alzheimer’s disease mouse model by inhibiting amyloid β (Aβ) aggregation and promoting its disaggregation. However, the extent to which PE exerts additional cognitive benefits independent of Aβ pathology remained unclear. Here, we aimed to evaluate the effects of PE on synaptic plasticity and learning and memory functions. Male ICR mice were used, and cognitive impairment was induced by scopolamine administration. PE was orally administered at doses determined from previous studies, and cognitive performance was assessed using the passive avoidance, Y-maze, and Morris water maze tests. In parallel, hippocampal slices were employed to examine the effects of PE on synaptic plasticity. PE (100 and 300 μg/mL) significantly enhanced long-term potentiation (LTP) in a concentration-dependent manner without altering basal synaptic transmission. This facilitation of LTP was blocked by scopolamine (1 μM), a muscarinic acetylcholine receptor (mAChR) antagonist, and IEM-1460 (50 μM), a calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (CP-AMPAR) inhibitor, indicating the involvement of mAChR and CP-AMPAR pathways. In vivo, PE (100, 250, and 500 mg/kg) treatment improved memory performance across all behavioral tasks and upregulated hippocampal synaptic proteins including GluN2B, PSD-95, and CaMKII. Collectively, these results demonstrate that PE ameliorates scopolamine (1 mg/kg)-induced cognitive impairment by enhancing synaptic plasticity, likely through modulation of mAChR, CP-AMPAR, and NMDA receptor signaling. These findings highlight the therapeutic potential of PE for memory deficits associated with cholinergic dysfunction. Full article

Alzheimer’s disease (AD) is a progressive neurological condition with limited effective pharmaceutical treatments, often accompanied by side effects. This has increased interest in plant-based alternatives. This study examined the cognitive effects of a Natural Polyherbal Extract (NPX) on scopolamine-induced memory deficits in mice. Male C57BL/6 mice (10 weeks old, n = 36) were divided into four groups: control (saline), scopolamine (1 mg/kg, i.p.), tacrine (10 mg/kg, oral), and NPX (1000 mg/kg, oral). NPX and tacrine were administered daily by oral gavage for two weeks. Cognitive function was assessed weekly using the Y-maze task. Brain tissues were collected for biochemical analysis, including AChE activity and immunohistochemical detection of neurodegeneration-related markers. Results: Mice treated with NPX demonstrated improved spontaneous alternation behavior compared to the scopolamine group. NPX also significantly reduced acetylcholinesterase activity. Immunohistochemistry revealed decreased expression of amyloid-beta (Aβ) and caspase-3, with enhanced choline acetyltransferase levels. These outcomes were comparable to those observed in the tacrine-treated group. Conclusions: NPX alleviated scopolamine-induced memory impairment through enhancement of cholinergic signaling and mitigation of neurodegenerative markers. The findings suggest that NPX may serve as a promising plant-derived candidate for managing memory-related disorders, including AD. Full article

Ochradenus baccatus (O. baccatus), a resilient medicinal plant native to arid regions, was systematically investigated for its neuroprotective potential against Alzheimer’s disease. Comprehensive phytochemical profiling of different plant parts revealed that the leaves possessed the highest levels of total phenolics (67.8 mg GAE/g) and flavonoids (49.2 mg QE/g), correlating with strong antioxidant activity (DPPH IC₅₀ = 19.8 µg/mL, FRAP = 832 µmol Fe²⁺/g). HPLC and GC-MS analyses identified multiple bioactive flavonoids and fatty acids. The leaf extract demonstrated potent in vitro AChE inhibition (IC₅₀ = 32.5 µg/mL) and significantly reduced amyloid-β aggregation (by 50%). In vivo, it ameliorated cognitive deficits in scopolamine-induced mice, as evidenced by improved performance in Morris Water Maze and Y-maze tests, and restored hippocampal neuronal density (CA3: +29.7%, DG: +30%). These findings highlight the therapeutic promise of O. baccatus leaves as a rich source of multifunctional anti-Alzheimer’s phytochemicals. Full article

Alzheimer’s disease is characterized by progressive cognitive decline associated with oxidative stress, neuroinflammation, and impaired neurotrophic signaling. Sulforaphane, a bioactive compound found in broccoli, has demonstrated neuroprotective effects by activating NRF2 and inhibiting NF-κB. However, the efficacy of whole-food-derived sulforaphane remains unclear. This study evaluated the neuroprotective potential of broccoli sprout extract using a scopolamine-induced mouse model of memory impairment. Mice were orally administered broccoli sprout extract once daily at doses of 100 mg/kg or 200 mg/kg for four weeks prior to behavioral and biochemical assessments. Treatment with broccoli sprout extract significantly improved scopolamine-induced deficits in long-term memory, as determined by the passive avoidance test. The spatial working memory remained unaffected. High doses of broccoli sprout extract restored hippocampal brain-derived neurotrophic factor levels and reduced cortical lipid peroxidation, suggesting antioxidant and neurotrophic benefits. Additionally, the low dose preserved striatal choline acetyltransferase expression and reduced systemic tumor necrosis factor-alpha and hippocampal cyclooxygenase-2 levels, indicating its anti-inflammatory and cholinergic protective effects. No significant changes in acetylcholinesterase activity or glutathione levels were observed. Overall, these results imply that broccoli sprout extract has multi-targeted neuroprotective effects, possibly involving redox and inflammatory regulation. Therefore, it may be a safe dietary strategy to support cognition in neurodegenerative conditions. Full article