Perinatal choline supplementation prevents learning and memory deficits and reduces brain amyloid Aß42 deposition in AppNL-G-F Alzheimer's disease model mice.

Alzheimer's disease (AD) is characterized by cognitive and memory impairments and neuropathological abnormalities. AD has no cure, inadequate treatment options, and a limited understanding of possible prevention measures. Previous studies have demonstrated that AD model mice that received a diet high in the essential nutrient choline had reduced amyloidosis, cholinergic deficits, and gliosis, and increased neurogenesis. In this study, we investigated the lifelong effects of perinatal choline supplementation on behavior, cognitive function, and amyloidosis in AppNL-G-F AD model mice. Pregnant and lactating mice were given a diet containing either 1.1 g/kg (control) or 5 g/kg (supplemented) of choline chloride until weaning and subsequently, all offspring received the control diet throughout their life. At 3, 6, 9, and 12 months of age, animals were behaviorally tested in the Open Field Test, Elevated Plus Maze, Barnes Maze, and in a contextual fear conditioning paradigm. Immunohistochemical analysis of Aß42 was also conducted on the brains of these mice. AppNL-G-F mice displayed hippocampal-dependent spatial learning deficits starting at 3-months-old that persisted until 12-months-old. These spatial learning deficits were fully prevented by perinatal choline supplementation at young ages (3 and 6 months) but not in older mice (12 months). AppNL-G-F mice also had impaired fearful learning and memory at 9- and 12-months-old that were diminished by choline supplementation. Perinatal choline supplementation reduced Aß42 deposition in the amygdala, cortex, and hippocampus of AppNL-G-F mice. Together, these results demonstrate that perinatal choline supplementation is capable of preventing cognitive deficits and dampening amyloidosis in AppNL-G-F mice and suggest that ensuring adequate choline consumption during early life may be a valuable method to prevent or reduce AD dementia and neuropathology.

Natural antioxidant formula ameliorates lipopolysaccharide-induced impairment of hippocampal neurogenesis and contextual fear memory through suppression of neuroinflammation in rats.

This study investigated the ameliorating effects of a natural antioxidant formula (NAF) consisting of Ginkgo biloba leaf extract, docosahexaenoic acid/eicosapentaenoic acid, ferulic acid, flaxseed oil, vitamin E, and vitamin B12 on a lipopolysaccharide (LPS)-induced cognitive dysfunction model in rats. Six-week-old rats received a diet containing 0.5% (w/w) NAF for 38 days from Day 1, and LPS (1 mg/kg body weight) was administered intraperitoneally once daily on Days 8 and 10. On Day 11, LPS alone increased interleukin-1ß and tumor necrosis factor-α in the hippocampus and cerebral cortex and the numbers of M1-type microglia/macrophages and GFAP+ reactive astrocytes in the hilus of the hippocampal dentate gyrus. NAF treatment decreased brain proinflammatory cytokine levels and increased the number of M2-type microglia/macrophages. During Days 34-38, LPS alone impaired fear memory acquisition and the extinction learning process, and NAF facilitated fear extinction learning. On Day 38, LPS alone decreased the number of type-3 neural progenitor cells in the hippocampal neurogenic niche, and NAF restored the number of type-3 neural progenitor cells and increased the numbers of both immature granule cells in the neurogenic niche and reelin+ hilar interneurons. Thus, NAF exhibited anti-inflammatory effects and ameliorated LPS-induced adverse effects on hippocampal neurogenesis and fear memory learning, possibly through amplification of reelin signaling by hilar interneurons. These results suggest that neuroinflammation is a key factor in the development of LPS-induced impairment of fear memory learning, and supplementation with NAF in the present study helped to prevent hippocampal neurogenesis and disruptive neurobehaviors caused by neuroinflammation.

Anoectochilus roxburghii flavonoids extract ameliorated the memory decline and reduced neuron apoptosis via modulating SIRT1 signaling pathway in senescent mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Anoectochilus roxburghii (A. roxburghii) is a precious herb and folk medicine in many Asian countries. It has been used traditionally to treat diabetes, etc., and also used as a dietary therapy to delay senescence. AIM OF THE STUDY: This study was to evaluate the neuroprotective effects of A. roxburghii flavonoids extract (ARF) and whether its effects were due to the regulation of SIRT1 signaling pathway in senescent mice and in D-galactose (D-gal) induced aging in SH-SY5Y cells. MATERIALS AND METHODS: 18-month-old mice were randomly divided into senescent model, low-dose ARF, high-dose ARF and vitamin E group. 2-Month-old mice were as a control group. After 8 weeks treatment, Morris water maze (MWM) was performed. The levels of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), monoamine oxidase (MAO) and acetylcholinesterase (ACh-E) in the cortex were determined. Hippocampus morphologic changes were observed with haematoxylin and eosin (H&E), Nissl, senescence-associated-galactosidase (SA-ß-gal) and terminal deoxynucleotidyl transferase nick-end labeling (TUNEL) staining. Apoptosis-related molecular expressions in the hippocampus were performed by western blotting. Furthermore, after stimulated by EX527 (a SIRT1 inhibitor), the SIRT1-dependent neuroprotective effects of ARF were determined by measuring SRIT1 and p53 expression in SH-SY5Y aging cells induced by D-gal. RESULTS: ARF could significantly ameliorate memory decline in senescent mice and reduce the generations of ROS, MDA and the activities of MAO and ACh-E, while increasing SOD activities in the cortex of aging mice. ARF obviously improved hippocampus pathological alterations, increased the number of Nissl bodies, while reducing senescent and apoptotic cells in senescent mice hippocampus. Further, ARF positively regulated SIRT1 expression, and reduced apoptosis-related molecules p53, p21 and Caspase-3 expression, while increasing the ratio of Bcl-2/Bax. In D-gal-induced SH-SY5Y cells, the effects of ARF on SIRT1 and p53, and the ability of scavenging ROS were mostly abolished after incubation with the EX527. CONCLUSIONS: ARF, in a SIRT1-dependent manner, exerted neuroprotection via modulating SIRT1/p53 signaling pathway against memory decline and apoptosis due to age-induced oxidative stress damage in senescent mice.

A novel nutritional mixture, MBN, prevents memory impairment via inhibiting NLRP3 inflammasome formation in 5xFAD transgenic mice.

OBJECTIVES: Amyloid beta (Aß)-induced abnormal neuroinflammation is recognized as a major pathological factor of Alzheimer's disease (AD), which results in memory impairment. Inhibition of excessive neuroinflammation mediated by Aß is considered a promising strategy to ameliorate AD symptoms. To regulate the inflammatory response, nutritional and dietary supplements have been used for centuries. Based on this idea, we investigated whether MBN, a novel nutritional mixture including cassia bark, turmeric root, and ginkgo leaf, can prevent AD progression through neuroinflammatory regulation. METHODS: MBN (10, 30, or 100 µg/ml) and Aß1-42 monomer were incubated together, and the degree of Aß aggregation was measured using Thioflavin T assay. The effects of MBN on Aß pathology in vivo were evaluated by orally administering MBN (40 mg/kg/day for 16 weeks) to five familial AD (5xFAD) mice. RESULTS: We found that treatment with MBN inhibited Aß aggregation in vitro. Next, MBN treatment significantly inhibited the activation of microglia induced by aggregated Aß in 5xFAD mice. Caspase-1 activation, which plays an important role in the maturation of interleukin-1ß, was markedly reduced by MBN. We also found that oral administration of MBN in 5xFAD mice alleviated memory decline. Taken together, our findings demonstrate that MBN suppresses neuroinflammation by downregulating the caspase-1 expression, thereby ameliorating memory impairment in 5xFAD mice. DISCUSSION: Based on these results, we suggest that MBN may be a preventive and therapeutic supplement for AD through the regulation of neuroinflammation.

The Role of Melatonin on Behavioral Changes and Concomitant Oxidative Stress in icvAß1-42 Rat Model with Pinealectomy.

One of the pathological hallmarks of Alzheimer's disease (AD) associated with its progression that contributes to ß-amyloid (Aß) generation is oxidative stress (OS). Clinical data suggest that melatonin is a potent antioxidant that might be effective in the adjunctive therapy of this neurodegenerative disease. The present study aimed to explore the role of melatonin on behavioral changes and markers of OS in three rat models, namely, pinealectomy (pin) model of melatonin deficit, intracerebroventricular (icv)Aß1-42 model of AD, and combination of both pin and Aß1-42 model (pin+icvAß1-42). The chronic injection with vehicle/melatonin (50 mg/kg, i.p. for 40 days) started on the same day of sham/pin and icv vehicle/Aß1-42 infusion procedures. Anxiety in the open field and the elevated plus-maze test and cognitive responses in the object recognition test were tested between the 30th-35th day after the surgical procedures. Markers of OS in the frontal cortex (FC) and hippocampus were detected by the ELISA method. Melatonin treatment corrected the exacerbated anxiety response only in the pin+icvAß1-42 model while it alleviated the cognitive impairment in the three models. Pinealectomy disturbed the antioxidant system via enhanced SOD activity and decreased GSH levels both in the FC and hippocampus. The Aß1-42 model decreased the SOD activity in the FC and elevated the MDA level in the two brain structures. The pin+icvAß1-42 model impaired the antioxidant system and elevated lipid peroxidation. Melatonin supplementation restored only the elevated MDA level of icvAß1-42 and pin+icvAß1-42 model in the hippocampus. In conclusion, our study reveals that the pin+icvAß1-42 rat model triggers more pronounced anxiety and alterations in markers of OS that may be associated with melatonin deficit concomitant to icvAß1-42-induced AD pathology.

Ligustrazine Attenuates Hyperhomocysteinemia-induced Alzheimer-like Pathologies in Rats.

Ligustrazine, an alkaloid extracted from the traditional Chinese herbal medicine Ligusticum Chuanxiong Hort, has been clinically applied to treat the cerebrovascular diseases. Hyperhomocysteinemia (Hhcy) is an independent risk factor for Alzheimer's disease (AD). Memory deficits can be caused by Hhcy via pathologies of AD-like tau and amyloid-ß (Aß) in the hippocampus. Here, we investigated whether homocysteine (Hcy) can induce AD-like pathologies and the effects of ligustrazine on these pathologies. The Hcy rat model was constructed by 14-day Hcy injection via vena caudalis, and rats were treated with daily intragastric administration of ligustrazine at the same time. We found that the pathologies of tau and Aß were induced by Hcy in the hippocampus, while the Hcy-induced tau hyperphosphorylation and Aß accumulation could be markedly attenuated by simultaneous ligustrazine treatment. Our data demonstrate that ligustrazine may be used as a promising neuroprotective agent to treat the Hcy-induced AD-like pathologies.

Maternal antioxidant treatment protects adult offspring against memory loss and hippocampal atrophy in a rodent model of developmental hypoxia.

Chronic fetal hypoxia is one of the most common outcomes in complicated pregnancy in humans. Despite this, its effects on the long-term health of the brain in offspring are largely unknown. Here, we investigated in rats whether hypoxic pregnancy affects brain structure and function in the adult offspring and explored underlying mechanisms with maternal antioxidant intervention. Pregnant rats were randomly chosen for normoxic or hypoxic (13% oxygen) pregnancy with or without maternal supplementation with vitamin C in their drinking water. In one cohort, the placenta and fetal tissues were collected at the end of gestation. In another, dams were allowed to deliver naturally, and offspring were reared under normoxic conditions until 4 months of age (young adult). Between 3.5 and 4 months, the behavior, cognition and brains of the adult offspring were studied. We demonstrated that prenatal hypoxia reduced neuronal number, as well as vascular and synaptic density, in the hippocampus, significantly impairing memory function in the adult offspring. These adverse effects of prenatal hypoxia were independent of the hypoxic pregnancy inducing fetal growth restriction or elevations in maternal or fetal plasma glucocorticoid levels. Maternal vitamin C supplementation during hypoxic pregnancy protected against oxidative stress in the placenta and prevented the adverse effects of prenatal hypoxia on hippocampal atrophy and memory loss in the adult offspring. Therefore, these data provide a link between prenatal hypoxia, placental oxidative stress, and offspring brain health in later life, providing insight into mechanism and identifying a therapeutic strategy.

Transient forebrain ischemia under hyperthermic condition accelerates memory impairment and neuronal death in the gerbil hippocampus by increasing NMDAR1 expression.

Altered expression levels of N­methyl­D­aspartate receptor (NMDAR), a ligand­gated ion channel, have a harmful effect on cellular survival. Hyperthermia is a proven risk factor of transient forebrain ischemia (tFI) and can cause extensive and severe brain damage associated with mortality. The objective of the present study was to investigate whether hyperthermic preconditioning affected NMDAR1 immunoreactivity associated with deterioration of neuronal function in the gerbil hippocampal CA1 region following tFI via histological and western blot analyses. Hyperthermic preconditioning was performed for 1 h before tFI, which was developed by ligating common carotid arteries for 5 min. tFI­induced cognitive impairment under hyperthermia was worse compared with that under normothermia. Loss (death) of pyramidal neurons in the CA1 region occurred fast and was more severe under hyperthermia compared with that under normothermia. NMDAR1 immunoreactivity was not observed in the somata of pyramidal neurons of sham gerbils with normothermia. However, its immunoreactivity was strong in the somata and processes at 12 h post­tFI. Thereafter, NMDAR1 immunoreactivity decreased with time after tFI. On the other hand, NMDAR1 immunoreactivity under hyperthermia was significantly increased in the somata and processes at 6 h post­tFI. The change pattern of NMDAR1 immunoreactivity under hyperthermia was different from that under normothermia. Overall, accelerated tFI­induced neuronal death under hyperthermia may be closely associated with altered NMDAR1 expression compared with that under normothermia.

Aging-induced microbleeds of the mouse thalamus compared to sensorimotor and memory defects.

The aim of this study is to investigate the relationship between aging and brain vasculature health. Three groups of mice, 3, 17-18, and 24 months, comparable to young adult, middle age, and old human were studied. Prussian blue histology and fast imaging with steady precession T2∗-weighted magnetic resonance imaging were used to quantify structural changes in the brain across age groups. The novel object recognition test was used to assess behavioral changes associated with anatomical changes. This study is the first to show that the thalamus is the most vulnerable brain region in the mouse model for aging-induced vascular damage. Magnetic resonance imaging data document the timeline of accumulation of thalamic damage. Histological data reveal that the majority of vascular damage accumulates in the ventroposterior nucleus and mediodorsal thalamic nucleus. Functional studies indicate that aging-induced vascular damage in the thalamus is associated with memory and sensorimotor deficits. This study points to the possibility that aging-associated vascular disease is a factor in irreversible brain damage as early as middle age.

Sesame oil mitigates memory impairment, oxidative stress, and neurodegeneration in a rat model of Alzheimer's disease. A pivotal role of NF-κB/p38MAPK/BDNF/PPAR-γ pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Sesame (Sesamum indicum, L., Family: Pedaliaceae) is a notable folk medicine in Middle East, Asia and Africa. Many traditional and pharmacological studies have documented the unique nature of sesame oil (SO). SO has been reported to have many pharmacological effects related to the anti-inflammatory and antioxidant capacity of its components. Neuroinflammation and oxidative stress have been the predominant pathogenic events in Alzheimer's disease (AD) which is one of the most common neurodegenerative diseases. AIM OF STUDY: we aimed to explore the neuroprotective effect and the probable mechanisms of SO against aluminium chloride (AlCl3)-induced AD symptoms. MATERIALS AND METHODS: Rats were treated daily with AlCl3 (100 mg/kg/i.p.) either alone or with SO (two different doses) for six weeks. Behavioral (Open-field and Morris water maze tests), histopathological, and biochemical examinations were used to evaluate the neuroprotective effect and the underlying mechanisms of SO against AlCl3-induced AD symptoms. RESULTS: Our results indicated that SO significantly improved learning and memory impairments induced by AlCl3. Indeed, SO treatment significantly restored the elevated level of acetylcholinesterase (AChE) and amyloid beta (Aß) overexpression. Moreover, AlCl3 treatment afforded histopathological changes, increase the expression of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1ß) in addition to mitigation of oxidative stress status in the brain. SO abolished all these abnormalities. Meanwhile, AlCl3 induced activation of p38 mitogen-activated protein kinase (p38MAPK) and decreased brain-derived neurotrophic factor (BDNF) which were inhibited by SO. Furthermore, SO administration modulated the expression of the peroxisome proliferator-activated receptor gamma (PPAR-γ) and nuclear factor kappa B (NF-κB). CONCLUSIONS: In conclusion, the neuroprotective effect of SO involved the modulation of different mechanisms targeting oxidative stress, neuroinflammation, and cognitive functions. SO may modulate different molecular targets involved in AD pathogenesis by alterations of NF-κB/p38MAPK/BDNF/PPAR-γ signalling and this may be attributed to the synergistic effect of their active components.

NaoXinTong Capsule ameliorates memory deficit in APP/PS1 mice by regulating inflammatory cytokines.

Alzheimer's disease (AD) is the most common neurodegenerative disease in aging population. Neuroinflammation, hyperphosphorylated Tau (p-Tau) and the imbalance between production and clearance of ß-amyloid peptide (Aß) are the major causes for AD development. NaoXinTong Capsule (NXT), a traditional Chinese medicine, is wildly used for treatment of cardiovascular and cerebrovascular diseases. Hence, we used the double transgenic mice expressing chimeric human amyloid precursor protein and mutant human presenilin 1 (APP/PS1) and HT-22 cells to determine the neuroprotective effects of NXT in AD development and the involved mechanisms. The 3-month-old APP/PS1 mice were randomly divided into 3 groups and received following treatment: Control group, mice were fed normal chow; NXT groups, mice were fed normal chow containing NXT at a normal and a high dose, respectively. While the age-matched C57BL/6J mice fed normal chow were used as the normal control. The NXT treatment was lasted for 5 months. We found that NXT treatment improved spatial memory impairment and cognitive decline in APP/PS1 mice by decreasing p-Tau levels and Aß accumulation in the brain. Mechanistically, we observed that NXT inhibited neuron atrophy and apoptosis by downregulating inflammatory cytokines, interleukin 1ß (IL-1ß), IL-6 and tumor necrosis factor α (TNF-α), and inflammation mediators, nuclear factor κB (NF-κB) and toll-like receptor 4 (TLR4) in the brain. Consistently, NXT blocked l-glutamic acid-induced reactive oxygen species production, inflammation and apoptosis in HT-22 cells partially by inhibiting TLR4/NF-κB/IL-1ß signaling pathway. Our study demonstrates that NXT ameliorates AD by reducing p-Tau, Aß accumulation, inflammation and neuron apoptosis via regulation of TLR4-mediated inflammatory system. It also suggests the potential application of NXT for AD treatment.

Matcha Improves Metabolic Imbalance-Induced Cognitive Dysfunction.

This study was conducted to assess the protective effect of extract of match (EM) on high-fat diet- (HFD-) induced cognitive deficits in male C57BL/6 mice. It was found that EM improved glucose tolerance status by measuring OGTT and IPGTT with HFD-induced mice. EM protected behavioral and memory dysfunction in Y-maze, passive avoidance, and Morris water maze tests. Consumption of EM reduced fat mass, dyslipidemia, and inflammation in adipose tissue. Also, EM ameliorated hepatic and cerebral antioxidant systems. EM improved the cerebral cholinergic system by regulating ACh contents and expression of AChE and ChAT. Also, EM restored mitochondrial function in liver and brain tissue. EM attenuated hepatic inflammatory effect, lipid synthesis, and cholesterol metabolism by regulating the protein expression of TNF-α, TNFR1, p-IRS-1, p-JNK, IL-1ß, iNOS, COX-2, HMGCR, PPARγ, and FAS. Finally, EM regulated cognitive function and neuroinflammation in the whole brain, hippocampus, and cerebral cortex by regulating the protein expression of p-JNK, p-Akt, p-tau, Aß, BDNF, IDE, COX-2, and IL-1ß. These findings suggest that EM might be a potential source of functional food to improve metabolic disorder-associated cognitive dysfunction.

Effect of desalted Salicornia europaea L. ethanol extract (PM-EE) on the subjects complaining memory dysfunction without dementia: a 12 week, randomized, double-blind, placebo-controlled clinical trial.

Desalted Salicornia europaea L. (SE) inhibits acetylcholine esterase, attenuates oxidative stress and inflammatory cytokines, and activates neurotrophic pathway. We performed 12-week, randomized, double-blind, placebo-controlled study to evaluate the efficacy of PhytoMeal(a desalted SE)-ethanol extract (PM-EE), in improving the cognitive performance in patients with subjective memory impairment. 63 participants complaining memory dysfunction without dementia (Korean Mini-Mental State Examination [K-MMSE] score ≥ 23) were assigned to PM-EE 600 mg/day or placebo. The cognitive domain of the Alzheimer's disease assessment scale-Korean version (ADAS-K) was set as the primary outcome. After 12 weeks, there was no differences in the changes in the primary outcome or the frequency of adverse events between the groups. In the subgroup analysis for the 30 subjects with mild cognitive impairment (MCI, baseline K-MMSE scores ≤ 28), PM-EE significantly improved the color-reading score of the Korean color-word stroop test (8.2 ± 25.0 vs. - 4.7 ± 13.2, P = 0.018). Our findings suggest that PM-EE is safe but might not be effective in this setting of this study. However, PM-EE may improve the frontal executive function in the patients with MCI. Further large-sized studies with longer follow-up period is warranted (trial registration number KCT0003418).

Acute EPA-induced learning and memory impairment in mice is prevented by DHA.

Eicosapentaenoic acid (EPA), an omega-3 fatty acid, has been widely used to prevent cardiovascular disease (CVD) and treat brain diseases alone or in combination with docosahexaenoic acid (DHA). However, the impact of EPA and DHA supplementation on normal cognitive function and the molecular targets of EPA and DHA are still unknown. We show that acute administration of EPA impairs learning and memory and hippocampal LTP in adult and prepubescent mice. Similar deficits are duplicated by endogenously elevating EPA in the hippocampus in the transgenic fat-1 mouse. Furthermore, the damaging effects of EPA are mediated through enhancing GABAergic transmission via the 5-HT6R. Interestingly, DHA can prevent EPA-induced impairments at a ratio of EPA to DHA similar to that in marine fish oil via the 5-HT2CR. We conclude that EPA exhibits an unexpected detrimental impact on cognitive functions, suggesting that caution must be exercised in omega-3 fatty acid supplementation and the combination of EPA and DHA at a natural ratio is critical for learning and memory and synaptic plasticity.

Combination effect of exercise training and eugenol supplementation on the hippocampus apoptosis induced by chlorpyrifos.

The aim of this study was to investigate the combination effect of exercise training and eugenol supplementation on the hippocampus apoptosis induced by CPF. 64 adult male albino rats were randomly selected and devided into eight groups of eight including: control, exercise (EXE), chlorpyrifos (CPF), Control + Oil (Co + Oil), Control + DMSO (Co + DMSO), chlorpyrifos + eugenol (CPF + Sup), chlorpyrifos + exercise (CPF + Exe) and, chlorpyrifos + exercise + eugenol (CPF + Exe + Eu). Four experimental groups received intraperitoneal injection (5 days a week) of 3.0 mg/kg body weight CPF in DMSO for 6 consecutive weeks. The exercise groups performed aerobic 5 days per week over 4 weeks. Eugenol were administered by gavage. Finally, the animals were sacrificed using CO2 gas (a half of the rats were anesthetized with ketamine and xylazine and then perfused) to evaluate hippocampus histology and parameters. The results of this study showed that CPF injection significantly decreased BDNF, AChE and ATP in CA1 area of the hippocampus (p ˂ 0.05). Also, CA1 apoptosis by tunnel assay, it was found that CPF receiving groups with different dosage, showed a significant increase compared to other groups, which was confirmed by increasing cytochrome C and procaspase-3 in CPF groups (p ˂ 0.05). The result of this study show that 4 weeks of exercise training and eugenol supplementation does not improve the destructive effects of CPF in CA1 area of the hippocampus. As a result, it is recommended that future studies longer periods for treatment with exercise and eugenol supplementation.

Matrine ameliorates cognitive deficits via inhibition of microglia mediated neuroinflammation in an Alzheimer's disease mouse model.

Amyloid ß (Aß) induced microglial activation and attendant neuroinflammation play pivotal roles in Alzheimer's disease (AD) pathogenesis. Matrine is a natural anti-inflammation compound from the Chinese herbal medicine Sophora flavescens Ait. (Kushen). This study aimed to investigate the effects of matrine on memory deficit and neuroinflammation in an oligomeric Aß (oAß)-induced AD mice model. Whether microglial activation and NADPH oxidase were involved in these effects were further studied. Different doses of matrine (10, 20, or 40 mg/kg) were intragastrically administered once a day after intracerebroventricular oAß injection (2.5 µg/µl, 4 µl). 15 days after the oAß injection, behavioral experiments including novel object recognition (NOR) test and Morris water maze (MWM) test were performed. 21 days after the oAß injection, concentration of ROS, TNF-α, IL-1ß and IL-6 as well as expression of NADPH oxidase subunits gp91phox and p47phox in mice hippocampal tissues were assessed, and microglial activation were evaluated by Iba-1 immunohistochemical staining. Results of NOR test and MWM test revealed that oAß injection could remarkably impair learning and memory function in AD mice, and matrine administration could significantly ameliorate the impairment. ROS, TNF-α, IL-1ß and IL-6 levels increased after oAß injection, while matrine could significantly reduce the concentrations of these inflammatory factors. OAß induced protein expression of NADPH oxidase subunits gp91phox and p47phox were also significantly reduced by matrine. Iba-1 immunohistochemistry results showed less activated microglia in matrine-treated mice brain. These results indicate that matrine could ameliorate learning and memory impairment and neuroinflammation induced by oAß injection. These effects were found to be mediated through inhibition of microglial activation and NADPH oxidase expression in hippocampal tissue. The results suggest that matrine may be a valuable natural compound with therapeutic potential against AD.

Effect of the King Oyster Culinary-Medicinal Mushroom Pleurotus eryngii (Agaricomycetes) Basidiocarps Powder to Ameliorate Memory and Learning Deficit in Ability in Aß-Induced Alzheimer's Disease C57BL/6J Mice Model.

One of the major causes of Alzheimer's disease (AD) is oxidative stress, which accelerates ß-amyloid peptide (AP) plaque and neurofibrillary tangle accumulation in the brain. Pleurotus eryngii is known to be rich in antioxidants, including ergothioneine, adenosine, and polyphenol, which can reduce oxidative stress-related aging. The aim of this study was to investigate the proximate and functional composition of P. eryngii, and evaluate the cognitive effects of low (LPE), medium (MPE), and high (HPE) P. eryngii dosages in an Aß-induced Alzheimer's disease C57BL/6J mouse model. Mice fed P. eryngii for six weeks showed no adverse effects on body weight gain, food intake efficiency, serum biochemical parameters, and liver and kidney histopathological features. The relative brain weight was significantly lower in Aß-injected mice (p < 0.05). Further, P. eryngii was shown to delay brain atrophy. Reference memory behavioral tasks showed that LPE, MPE, and HPE significantly decreased escape latency (49-85%) and distance (53-69%, p < 0.05). Probe and T-maze tasks showed that P. eryngii potently ameliorated memory deficit in mice. An AD pathology index analysis showed that P. eryngii significantly decreased levels of brain phosphorylated τ-protein, Aß plaque deposition, malondialdehyde, and protein carbonyl (p < 0.05). P. eryngii may therefore promote memory and learning capacity in an Aß-induced AD mouse model.

A high-fat diet rich in corn oil exaggerates the infarct size and memory impairment in rats with cerebral ischemia and is associated with suppressing osteopontin and Akt, and activating GS3Kß, iNOS, and NF-κB.

The increase in osteopontin (OPN) levels after stroke induces neural protection by activating Akt signaling and inhibiting GS3Kß, iNOS, and NF-κB. This study investigated the effect of a high-fat diet rich in corn oil (CO-HFD) on infarct size and memory function in rats after induction of cerebral ischemia in rats and investigated its effect on the expression of OPN/Akt/iNOS/NF-κB signaling pathways. Rats were initially fed a standard diet (STD, 3.82 kcal/g; 9.4%, from fat) or a CO-HFD (5.4 kcal/g, 40% from fat) for 12 weeks. Then, both groups were further subdivided into either sham group or group exposed to cerebral ischemia by the middle cerebral artery occlusion (MCAO) protocol. Compared with sham-operated rats fed STD diet, neurological scores and both short- and long-term memory functions were significantly impaired in sham-operated CO-HFD-fed rats. In addition, brains collected from CO-HFD-fed rats showed lower protein levels of OPN, p-Akt (Thr308), p-GS3Kß (Ser9), and Bcl-2 and had higher protein levels of iNOS, cleaved caspase-3, nuclear NF-κB p65, and cytoplasmic cytochrome C. However, once exposed to MCAO surgery, similar but more profound alterations of all these biochemical parameters with more severe impairment in short- and long-term memory functions and larger infarct size were noticed in the brains of CO-HFD-fed rats as compared with STD-fed rats exposed to MCAO. In conclusion, chronic consumption of CO-HFD induces memory impairments and worsens memory function recovery and infarct size after cerebral ischemia in rats by reducing levels of OPN, inhibiting the activation of Akt and activating iNOS and NF-κB.

Traditional Korean herbal formulae, Yuk-Mi-Ji-Hwang-Tang, ameliorates impairment of hippocampal memory ability by chronic restraint stress of mouse model.

ETHNOPHARMACOLOGICAL RELEVANCE: Yuk-Mi-Jihwang-Tang (YJT) has been popularly prescribed to treat aging related disorders over than hundreds of years in East Asia countries. AIM OF THE STUDY: To investigate possible modulatory actions of YJT on chronic restraint stress (CRS)-induced neurodegeneration on hippocampus neuronal injuries. MATERIALS AND METHODS: Mice were orally administered with YJT (100, 200, or 400 mg/kg) or ascorbic acid (100 mg/kg) before 4 h of stress for 28 days. Morris water maze task was completed from day 24th to 28th, and stress hormones and biochemical analyzes were measured. RESULTS: Four weeks of the CRS abnormally affected memory impairments by measurement of escape latency and time spent in the target quadrant. Additionally, neurotransmitters were also drastically altered in serum or hippocampus protein levels by CRS. Gene expressions for 5-hydroxytryptamine (5-HT) receptor, 5-HT-transport, and tryptophan hydroxylase were also altered, whereas YJT led to normalize the above alterations. Additionally, YJT also beneficially worked on endogenous redox system as well as inflammatory reactions in the hippocampal neurons. We observed that hippocampal excitotoxicity was induced by CRS which were evidenced by depletion of phosphor-cAMP response element-binding protein, brain-derived neurotrophic factor, nuclear factor erythroid-2-related factor 2, heme oxygenase-1 and abnormally increases of acetylcholine esterase activities in hippocampus protein levels; however, YJT considerably improved the above pathological conditions. CONCLUSIONS: Our findings supported YJT enhance memory function via regulation of hippocampal excitotoxicity-derived memory impairment, stress hormone, and endogenous redox, respectively.