iridoids and Cognitive-Dysfunction

In TgCRND8 (Tg) mice we checked the dose-response effect of diet supplementation with oleuropein aglycone (OLE) at 12.5 or 0.5 mg kg. Four month-old Tg mice were equally divided into four groups and treated for 8 weeks with a modified low fat (5.0%) AIN-76 A diet (10 g day. OLE supplementation at 12.5 mg kg. Our results extend previous data showing that the effects of OLE on behavioural performance and neuropathology are dose-dependent and not closely related to OLE by itself. In fact, diet supplementation with the same dose of a mix of polyphenols found in olive mill waste water resulted in comparable neuroprotection.

Topics: Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Behavior, Animal; Brain; Cognitive Dysfunction; Dietary Supplements; Disease Models, Animal; Dose-Response Relationship, Drug; Iridoid Glucosides; Iridoids; Mice, Transgenic; Olea; Peptide Fragments; Plaque, Amyloid; Polyphenols; Wastewater

Corni Fructus is a traditional Chinese herb and widely applied for treatment of age-related disorders in China. Iridoid glycoside was considered as the active ingredient of Corni Fructus. Loganin is one of the major iridoid glycosides and quality control components of Corni Fructus. Emerging evidence emphasized the beneficial effect of loganin on neurodegenerative disorders, such as Alzheimer's disease (AD). However, the detailed mechanism underlying the neuroprotective action of loganin remains to be unraveled.. To explore the improvement of loganin on cognitive impairment in 3 × Tg-AD mice and reveal the potential mechanism.. Eight-month 3 × Tg-AD male mice were intraperitoneally injected with loganin (20 and 40 mg/kg) for consecutive 21 days. Behavioral tests were used to evaluated the cognition-enhancing effects of loganin, and Nissl staining and thioflavine S staining were performed to analyze neuronal survival and Aβ pathology. Western blot analysis, transmission electron microscopy and immunofluorescence were utilized to explore the molecular mechanism of loganin in AD mice involved mitochondrial dynamics and mitophagy. Aβ. Loganin significantly mitigated the learning and memory deficit and amyloid β-protein (Aβ) deposition, and recovered synaptic ultrastructure in 3 × Tg-AD mice. Perturbed mitochondrial dynamics characterized by excessive fission and insufficient fusion were restored after loganin treatment. Meanwhile, loganin reversed the increase of mitophagy markers (LC3II, p62, PINK1 and Parkin) and mitochondrial markers (TOM20 and COXIV) in hippocampus of AD mice, and enhanced the location of optineurin (OPTN, a well-known mitophagy receptor) to mitochondria. Accumulated PINK1, Parkin, p62 and LC3II were also revealed in Aβ. Our observations confirmed that loganin enhanced cognitive function and alleviated AD pathology probably by promoting OPTN-mediated mitophagy,. Loganin might be a potential drug candidate for AD therapy via targeting mitophagy.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cognitive Dysfunction; Humans; Iridoids; Male; Mice; Mitophagy; Molecular Docking Simulation; Neuroblastoma; Protein Kinases; Ubiquitin-Protein Ligases

Topics: Alzheimer Disease; Animals; Cognitive Dysfunction; Disease Models, Animal; Female; Hippocampus; Iridoids; Mice; Mice, Transgenic; Morris Water Maze Test; Neuroprotective Agents; Proteome

The purpose of the present study was to elucidate the pharmacological effects of Geniposide (GEN) on high diet fed and streptozotocin (STZ)-caused diabetic cognitive impairment. The mice were fed with high fat diet (HFD) for 4 weeks and intraperitoneally injected with 60 mg/kg STZ for three times within 72 h. The mice with glucose level over 15 mmol/l were regarded as diabetic and selected for further studies. The animals were intragastrically treated with metformin or GEN once daily for 4 weeks. Afterwards, the animals were applied for Y maze, novel object recognition (NOR) test, step-through passive avoidance test, and Morris water maze (MWM) test. The blood glucose and body weight were examined. The SH-SY5Y cells were treated with GEN in the presence or absence of ibrutinib and stimulated with high-glucose culture medium. The tumor necrosis factor-a (TNF-α) and interleukin (IL)-6 in serum, hippocampus, and supernatant were measured using ELISA method. The protein expressions of Bruton's tyrosine kinase (BTK), Toll-like receptor 4 (TLR4), myeloid differentiating factor 88 (MyD88), nuclear factor kappa-B (NF-κB), p-NF-κB, brain-derived neurotrophic factor (BDNF), cAMP-response element binding protein (CREB), p-CREB, and glucagon-like peptide-1 receptor (GLP-1R) were detected by western blot analyses. As a result, the GEN treatment notably attenuated the body weight, blood glucose, and cognitive decline. GEN also inhibited the generations of inflammatory cytokines. Furthermore, the administrations of GEN ameliorated the alterations of BTK, TLR4, MyD88, NF-κB, and BDNF in HFD + STZ-induced mice. With the application of ibrutinib, the selective inhibitor of BTK, it was also found that BTK/TLR4/NF-κB pathway was associated with the GEN treatment in high glucose-induced SH-SY5Y cells. In summary, the results suggested that GEN exerted the protective effect on STZ-induced cognitive impairment possibly through the modulation of BTK/TLR4/NF-κB signaling.

Topics: Agammaglobulinaemia Tyrosine Kinase; Animals; Blood Glucose; Cell Line, Tumor; Cognitive Dysfunction; Diabetes Mellitus; Dose-Response Relationship, Drug; Humans; Iridoids; Male; Mice; Mice, Inbred ICR; NF-kappa B; Random Allocation; Signal Transduction; Streptozocin; Toll-Like Receptor 4; Treatment Outcome

The aim of this study is to investigate the protective effects as well as the underlying molecular mechanisms of geniposide in APP/PS1 transgenic mice.. APP/PS1 mice were subjected to intragastric administration of geniposide (50 mg/kg/d) for 8 weeks (including a 2-week behavior test). The novel object recognition (NOR) and the Morris water maze (MWM) tests were used for behavioral assessments. Aβ1-40 plaques in mice cortices and hippocampi are visualized with immunohistochemistical staining. ELISA was used to quantify the levels of soluble Aβ1-40 and Aβ1-42 in the hippocampus. Western blot was used to detect p-Akt/Akt, p-mTOR/mTOR and p-4E-BP1/4E-BP1 levels. The relative mRNA levels of Akt, mTOR and 4E-BP1 were quantified using real-time PCR (RT-PCR).. Geniposide alleviated cognitive impairment by improving the ability of novel object exploration, spatial memory, and reduced the level of Aβ in the brain of APP/PS1 mice. Geniposide possibly regulates mTOR-related proteins through modification of phosphorylation. Geniposide markedly lowered p-mTOR and p-Akt expressions while elevating p-4E-BP1 expression. Geniposide obviously reduced the relative mRNA levels of Akt and mTOR and increased the relative mRNA level of 4E-BP1.. Geniposide is able to alleviate cognitive impairments and cerebral damage in APP/PS1 mice, with its neuroprotective effects likely mediated via modulation of the mTOR signaling pathway.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cerebral Cortex; Cognitive Dysfunction; Disease Models, Animal; Hippocampus; Iridoids; Male; Mice, Inbred C57BL; Mice, Transgenic; Neuroprotective Agents; Peptide Fragments; Plaque, Amyloid; Signal Transduction; TOR Serine-Threonine Kinases

Geniposide, an iridoid glycoside extract from the gardenia fruit, is used in traditional Chinese medicine to alleviate symptoms of liver and inflammatory diseases. Geniposide activates GLP-1 receptors, known to modulate the activity of mechanistic target of rapamycin (mTOR), a key kinase regulating energy balance, proliferation, and survival in cells. mTOR activation inhibits autophagy, which is often disrupted in age-related diseases. Modulation of mTOR function to increase autophagy and inhibit apoptosis is involved in the protective effects of pharmacologic agents targeting diabetes and Alzheimer's disease (AD). We investigated whether such mechanism could mediate geniposide's neuroprotective effects in the APP/PS1 mouse model of AD. Eight-week treatment with geniposide improved cognitive scores in behavioral tests, reduced amyloid-β 1-40 plaque deposition, and reduced soluble Aβ1-40 and Aβ1-42 levels in the APP/PS1 mouse brain.This also showed increased p-Akt/Akt, p-mTOR/mTOR and decreased p-4E-BP1/4E-BP1 expression, and these patterns were partially reversed by geniposide. Evidence for enhanced autophagy, denoted by increased expression of LC3-II and Beclin1, was also seen after treatment with geniposide. Our data suggests that down regulation of mTOR signaling, leading to enhanced autophagy and lysosomal clearance of Aβ fibrils, underlies the beneficial effects of geniposide against neuropathological damage and cognitive deficits characteristic of AD.

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Protein Precursor; Animals; Autophagy; Behavior, Animal; Cognitive Dysfunction; Down-Regulation; Gene Expression Regulation; Humans; Iridoids; Mice; Mice, Transgenic; Peptide Fragments; Plaque, Amyloid; Random Allocation; TOR Serine-Threonine Kinases

The present study was designed to evaluate the antioxidant effects of oleuropein against oxidative stress in the hippocampal area of rats. We used seven experimental groups as follows: Control, Propofol, Propofol-Ketamine (Pro.-Ket.), Xylazine-Ketamine (Xyl.-Ket.), and three oleuropein-pretreated groups (Ole.-Pro., Ole.-Pro.-Ket. and Ole.-Xyl.-Ket.). The oleuropein-pretreated groups received oleuropein (15 mg/kg body weight as orally) for 10 consecutive days. Propofol 100 mg/kg, xylazine 3 mg/kg, and ketamine 75 mg/kg once as ip was used on the 11th day of treatment. Spatial memory impairment and antioxidant status of hippocampus were measured via Morris water maze, lipid peroxidation marker, and antioxidant enzyme activities. Spatial memory impairment and lipid peroxidation significantly increased in Xyl.-Ket.-treated rats in comparison to the control, propofol, Ole.-Pro. and Ole.-Pro.-Ket. groups. Oleuropein pretreatment significantly reversed spatial memory impairment and lipid peroxidation in the Ole.-Xyl.-Ket. group as compared to the Xyl.-Ket.-treated rats. There was no significant difference between the control and the propofol group in lipid peroxidation and spatial memory status. Superoxide dismutase and catalase activities both significantly decreased in Xyl.-Ket.-treated rats when compared to the control, propofol, Ole.-Pro., Ole.-Pro.-Ket., and Ole.-Xyl.-Ket. groups. In contrast, glutathione peroxidase activity in Xyl.-Ket.-treated rats significantly increased as compared to the control, propofol, Pro.-Ket., Ole.-Pro., and Ole.-Pro.-Ket. groups. We concluded that xylazine in combination with ketamine is an oxidative anesthetic drug and oleuropein pretreatment attenuates cognitive dysfunction and oxidative stress induced by anesthesia in the hippocampal area of rats. We also confirmed the antioxidant properties of propofol as a promising antioxidant anesthetic agent.

Topics: Anesthetics; Animals; Antioxidants; Catalase; Cognitive Dysfunction; Glutathione Peroxidase; Hippocampus; Iridoid Glucosides; Iridoids; Ketamine; Lipid Peroxidation; Male; Oxidative Stress; Propofol; Rats; Rats, Sprague-Dawley; Spatial Memory; Superoxide Dismutase; Xylazine

Alzheimer's disease is a progressive neurodegenerative disorder with decline in memory. The role of oxidative stress is well known in the pathogenesis of the disease. The purpose of this study was to evaluate pretreatment effects of oleuropein on oxidative status and cognitive dysfunction induced by colchicine in the hippocampal CA1 area. Male Wistar rats were pretreated orally once daily for 10 days with oleuropein at doses of 10, 15 and 20 mg/kg. Thereafter, colchicine (15 μg/rat) was administered into the CA1 area of the hippocampus to induce cognitive dysfunction. The Morris water maze was used to assess learning and memory. Biochemical parameters such as glutathione peroxidase and catalase activities, nitric oxide and malondialdehyde concentrations were measured to evaluate the antioxidant status in the rat hippocampus. Our results indicated that colchicine significantly impaired spatial memory and induced oxidative stress; in contrast, oleuropein pretreatment significantly improved learning and memory retention, and attenuated the oxidative damage. The results clearly indicate that oleuropein has neuroprotective effects against colchicine-induced cognitive dysfunction and oxidative damage in rats.

Topics: Animals; Behavior, Animal; CA1 Region, Hippocampal; Caspase 3; Catalase; Cognitive Dysfunction; Colchicine; Glutathione Peroxidase; Iridoid Glucosides; Iridoids; Lipid Peroxidation; Male; Malondialdehyde; Neuroprotective Agents; Nitric Oxide; Oxidative Stress; Rats; Rats, Wistar; Spatial Learning; Spatial Memory