Aerobic Exercise Ameliorates Cognitive Disorder and Declined Oxidative Stress via Modulating the Nrf2 Signaling Pathway in D-galactose Induced Aging Mouse Model.

The aim of this research was to explore the potential of treadmill exercise in preventing brain aging and neurodegenerative diseases caused by oxidative stress, by studying its effects on D-galactose-induced mice and the mechanisms involved. The results showed that C57BL/6 mice induced with D-gal exhibited cognitive impairment and oxidative stress damage, which was ameliorated by treadmill exercise. The Morris water maze also showed that exercise improved cognitive performance in aging mice and alleviated hippocampal and mitochondrial damage. The study also found that treadmill exercise increased the expression of nuclear factor Nrf2, p-GSK3ß, HO-1, NQO1, BDNF, and Bcl-2 proteins while decreasing the expression of Bax. Furthermore, there was a substantial increase in the levels of CAT, GSH-PX and SOD in the serum, along with a decrease in MDA levels. The outcomes propose that aerobic exercise has the potential to hinder oxidative stress and cell death in mitochondria through the modulation of the Nrf2/GSK3ß signaling pathway, thus improving cognitive impairment observed in the aging model induced by D-galactose. It appears that treadmill exercise could potentially serve as an effective therapeutic approach to mitigating brain aging and neurodegenerative diseases triggered by oxidative stress.

Gastrodin regulates the TLR4/TRAF6/NF-κB pathway to reduce neuroinflammation and microglial activation in an AD model.

BACKGROUND: Gastrodia elata (Orchidaceae) is a medicinal plant used in traditional Chinese medicine. The rhizomes contain numerous active components, of which Gastrodin (p-hydroxymethylphenyl-B-D-glucopyranoside) forms the basis of the traditional medicine Gastrodiae Rhizoma. Gastrodin is also found in other medicinal plants and has neuroprotective, antioxidant, and anti-inflammatory effects. Neuroinflammation plays a crucial role in neurodegeneration. Research indicates that consuming meals and drinks containing Gastrodiaelata can enhance cognitive functioning and memory in elderly patients. The mechanisms relevant to the problem have not been completely understood. PURPOSE: The aim was to examine the in vivo and in vitro anti-neuroinflammatory effects of Gastrodin. STUDY DESIGN: The neuroprotective effects of Gastrodin on the TLR4/TRAF6/NF-κB pathway and Stat3 phosphorylation in LPS-treated C57BL/6 mice and BV-2 cells were investigated. METHODS: 1. C57BL/6 mice were assigned to model, gastrodin, donepezil, and control groups (n = 10 per group). The Gastrodin group received 100 mg/kg/d for five days, and the Dopenezil group 1.3 mg/kg/d. A neuroinflammation model was established by administering intraperitoneal injections of 2 mg/kg LPS to all groups, excluding the control. To induce microglial activation in Gastrodin-treated mouse microglial BV-2 cells, 1 µg/ml LPS was introduced for 24 h Morris water mazes were utilized to evaluate learning and spatial memory. Expression and subcellular localization of TLR4/TRAF6/NF-κB axis-related proteins and p-Stat3, Iba-1, GFAP, iNOS, and CD206 were assessed by immunofluorescence, western blots, and ELISA. qRT-PCR was performed to determine and measure IL-1ß, TNF-α, cell migration, and phagocytosis. Overexpression of TRAF6 was induced by transfection, and the effect of Gastrodin on IL-1ß and p-NF-κB p65 levels was assessed. RESULTS: 1. In mice, gastrodin treatment mitigated LPS-induced deficits in learning and spatial memory, as well as reducing neuroinflammation in the hippocampus, expression of TLR4/TRAF6/NF-κB pathway proteins, activation of microglia and astrocytes, and phosphorylation of Stat3. 2. Gastrodin pretreatment improved LPS-induced inflammation in vitro, reducing expression of TLR4/TRAF6/NF-κB-associated proteins and p-Stat3, inducing microglial transformation from M1 to M2, and inhibiting migration and phagocytosis. Overexpression of TRAF6 inhibited the Gastrodin-induced effects. CONCLUSION: Gastrodin suppresses neuroinflammation and microglial activation by modifying the TLR4/TRAF6/NF-κB pathway and Stat3 phosphorylation.

Epimedii Folium and Curculiginis Rhizoma ameliorate lipopolysaccharides-induced cognitive impairment by regulating the TREM2 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Neuroinflammation induced by microglia is closely related to a variety of neurodegenerative diseases including Alzheimer's disease (AD). Previous study has found that aqueous extract of Epimedii Folium and Curculiginis Rhizoma (EX) had anti-inflammatory effect on AD by activating the NLRP3 inflammasome and inhibiting NF-κB/MAPK pathway. However, whether the anti-neuroinflammatory effect of EX is related to microglia or not remains unclear. AIM OF THE STUDY: The present study aimed to investigate the protective effect of EX on cognitive impairment induced by LPS and explore the underlying mechanism of EX. MATERIALS AND METHODS: High performance liquid chromatography-tandem mass spectrometry (HPLC-MS) was performed to qualify the major components of EX, EX in the serum and cerebrospinal fluid. To evaluate the anti-inflammatory effects of EX in vivo, the mice were orally administrated with EX (2.34, 4.68 g kg-1•d-1) for 28 days before cotreatment with LPS (1 mg kg-1•d-1, i.p.). The leaning and memory abilities of mice were examined by Morris water maze test. The expression of inflammatory related proteins and the activation of microglia were detected by ELISA, immunofluorescence, real-time PCR and Western blotting. RESULTS: HPLC-MS analysis confirmed and quantified 9 components in EX, 5 components in the serum and 4 components in the cerebrospinal fluid. In a LPS-induced neuroinflammatory mouse model, EX was found to exert anti-inflammatory activity by reducing the levels of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1ß), regulating the expression of different phenotypes of microglia, and increasing the expression of proteins related with TREM2 in the hippocampus tissue. Moreover, LPS-induced microglia activation was markedly attenuated in the hippocampus. CONCLUSIONS: These findings demonstrate that EX exerts anti-neuroinflammatory effects via reducing the production of inflammatory mediators, regulating the conversion of microglia and activating the proteins related with TREM2. EX might become a novel herb pairs to treat neuroinflammatory diseases.

Combination of Polygoni Multiflori Radix Praeparata and Acori Tatarinowii Rhizoma Alleviates Learning and Memory Impairment in Scopolamine-Treated Mice by Regulating Synaptic-Related Proteins.

Polygoni Multiflori Radix Praeparata (ZhiHeShouWu, PMRP) and Acori Tatarinowii Rhizoma (ShiChangPu, ATR) and their traditional combination (PA) are frequently used in traditional Chinese medicine to prevent and treat Alzheimer disease (AD) based on the theory that PMRP tonifies the kidney and ATR dissipates phlegm. However, the components of PA and their mechanisms of action are not known. The present study analyzed the active components of PA, and investigated the protective effect of PA against cognitive impairment induced by scopolamine in mice along with the underlying mechanism.The aqueous extract of PA was analyzed by high-performance liquid chromatography-mass spectrometry (HPLC-MS) and gas chromatography (GC)-MS in order to identify the major components. To evaluate the protective effect of PA against cognitive dysfunction, mice were orally administered PA, PMRP, or ATR for 30 days before treatment with scopolamine. Learning and memory were assessed in mice with the Morris water maze test; neurotransmitter levels in the hippocampus were analyzed by HPLC-MS; and the expression of synapse-related proteins in the hippocampus was detected by western blotting and immunohistochemistry. Eight active compounds in PA and rat plasma were identified by HPLC-MS and GC-MS. Plasma concentrations of 2,3,5,4'-tetrahydroxystilbene-2-O-ß-d-glucoside, emodin, α-asarone, and asarylaldehyde were increased following PA administration; meanwhile, gallic acid, emodin-8-O-ß-d-glucopyranoside, ß-asarone, and cis-methyl isoeugenol concentrations were similar in rats treated with PA, PMRP, and ATR. In scopolamine-treated mice, PA increased the concentrations of neurotransmitters in the hippocampus, activated the brain-derived neurotrophic factor (BDNF)/extracellular signal-regulated kinase (ERK)/cAMP response element binding protein (CREB) signaling pathway, and increased the expression of p90 ribosomal S6 kinase (p90RSK) and postsynaptic density (PSD)95 proteins. Thus, PA alleviates cognitive deficits by enhancing synaptic-related proteins, suggesting that it has therapeutic potential for the treatment of aging-related diseases such as AD.

Caffeine-related effects on cognitive performance: Roles of apoptosis in rat hippocampus following sleep deprivation.

Caffeine is a common stimulant widely existed in food and has stimulatory effects on the central nervous system, shift-work individuals often rely on caffeine to maintain attention and keep awake. Although sleep deprivation (SD) is widely considered as an independent risk factor for cognition retardations, however, little is well understood about the synergistic role of caffeine dosage and SD for cognitive performance. This research intended to investigate the underlying molecular mechanism of varying caffeine doses on cognitive function after sleep deprivation. The results revealed that SD attenuated the cognitive dysfunction, associated with ultrastructure damage and pyramidal neuron loss in the hippocampus, decreased in the level of VIP and AVP. SD also significantly accelerated the neuropeptide-associated apoptosis in the hippocampus, which may modulate via the cAMP-PKA-CREB signal path axis and activation of the downstream apoptosis genes. Additionally, the data indicated that low-dose caffeine (LC) contributed to cognitive enhancement, and high-dose caffeine (HC) aggravated cognitive impairment by modulating hippocampal neuronal apoptosis. Our studies suggest that caffeine, particularly in high dosage, may be a potential factor to influence the neurocognitive outcome caused by sleep loss, and the appropriate amount of caffeine ingested after sleep deprivation deserves serious consideration.

Preventive Effects of Escitalopram Against Anxiety-Like Depressive Behaviors in Monosodium Glutamate-Teated Rats Subjected to Partial Hepatectomy.

The reasons for the relationship between depression and chronic liver disease (CLD) are complex and multifactorial. Further research is needed to decipher the etiology and establish an optimal management approach for depression in patients, including the potential role of non-pharmacological treatments. monosodium glutamate (MSG)-treated rats are more likely to develop anxiogenic- and depressive-like behaviors, which could be related to the dysfunction of serotonergic system. In this study, partial hepatectomy (PH) was performed in MSG-treated rats and the histopathological changes were observed in orbitofrontal cortex (OFC) and liver. The effect of escitalopram, a widely used antidepressant, on neural and liver injury in this model was also examined. The MSG + PH-treated rats displayed decreased distances traveled in total, in center arena, and in the left side of arena in inner open field test (OFT), as compared to saline, saline + PH, and MSG-treated animals. The present study established that PH aggravated anxiety-like depressive behaviors in MSG-treated rats, concordant with damaged Nissl bodies (and neurites), decreased IBA-1 and Sox-2 expression in OFC and neurotransmitter disorder. Escitalopram treatment could alleviate these pathological changes as well as reduce hepatic steatosis and lipid metabolism.

Protective Effects of Liu Wei Di Huang Wan on the Liver, Orbitofrontal Cortex Nissl Bodies, and Neurites in MSG+PH-Induced Liver Regeneration Rat Model.

Introduction. To examine the protective effects of Liu Wei Di Huang Wan formula (LWDH) on liver and orbitofrontal cortex (OFC) injuries in monosodium glutamate (MSG) and partial hepatectomy (PH) rat model. Methods. Neonatal Wistar rats were given MSG or saline on postnatal days 2, 4, 6, 8, and 10. The rats were caged into five groups and treated accordingly at six weeks old as follows: Saline group, Saline+PH group, MSG group, MSG+PH group, and LWDH group (MSG+PH+LWDH). The PH was performed during week 8 by excision of the left and median hepatic lobes (occupying about 68% of whole liver).On day 8 after the PH, the rats were subjected to an inner OFT before being sacrificed. The liver and OFC were stained using H&E, ORO, or Nissl staining. The expression of neurotrophic factors (ß-NGF, BDNF) was examined in the OFC lysates by ELISA. Serum levels of cytokines (IL-1ß, VEGF) were examined using the Bio-Plex suspension array. Results. LWDH increased the total distance traveled by the animals (p<0.05), and LWDH improved the integrity of the Nissl bodies in the OFC (mean area of the Nissl bodies, p<0.01; mean diameter, p<0.05; mean density, p<0.05; and IOD, p<0.01). There were less white area in the liver (p>0.05) and decreased hepatic steatosis (p<0.01) in LWDH group. LWDH administration decreased the expression of serum levels of IL-1ß (p>0.05), while it increased VEGF (p>0.05) expression. LWDH administration increased the expression of BDNF (p>0.05) and ß-NGF (p>0.05) in the OFC, all as compared to the MSG+PH group. Conclusion. LWDH partly protected the animals from depressive-like behaviors in the MSG+PH-induced liver regeneration neonatal rat model. LWDH alleviated hepatic injury and steatosis and, furthermore, protected the Nissl body integrity and the growth of neurites.

The protective effect of Epimedii Folium and Curculiginis Rhizoma on Alzheimer's disease by the inhibitions of NF-κB/MAPK pathway and NLRP3 inflammasome.

The purpose of the current study was to explore the effects of the water extracts of Epimedii Folium and Curculiginis Rhizoma (EX) on Aß-induced Alzheimer's disease. Aß1-42 was stereotaxically injected bilaterally into the dorsal hippocampus, and then the rats were orally received EX at the doses of 2 g/kg and 6 g/kg for 30 days. Behavior was monitored through Morris water maze test. The neuroprotective effect of EX were examined with methods of histochemistry and biochemistry. EX reduced the contents of pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß) and interleukin-6 (IL-6) in hippocampus and cortex. EX also reduced the levels of malondialdehyde (MDA) and increased superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and glutathione peroxidase (GSH-Px) in the serum. Immunohistochemical analysis demonstrated that EX inhibited the expressions of NLRP3. In addition, we further confirmed that EX suppressed the expression of the NLRP3 inflammasome. EX inhibited the phosphorylations MAPKs, nuclear factor κB (NF-κB), myeloid differentiation factor 88(MyD88), cathepsin B. In conclusion, these results suggest that EX may be a potential agent for treating Alzheimer's disease.

Role of Sinomenine on Complete Freund's Adjuvant-Induced Arthritis in Rats.

The investigation was undertaken to evaluate the effect of sinomenine (Sin) on experimental adjuvant arthritis rats stimulated by Freund's complete adjuvant and explore the corresponding potential molecular mechanism. The content of proinflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1 beta and interleukin-6 were detected. Besides, canonical nuclear factor kappa B (NF-κB) pathway was also assessed to evaluate the antiarthritic potential of sinomenine. Pathological sections of rat paws showed sinomenine and diclofenac sodium significantly alleviated articular cartilage lesion, cellular infiltration, epithelial cell degeneration, synovial tissue vasodilation and congestion. The phosphorylations of inhibitor of kappaB alpha and NF-κB subunit p65 were downregulated with the treatment of sinomenine in dose dependent manners, as well as proinflammatory cytokines. Therefore, it was assumed that sinomenine might be a new therapeutic candidate to treat arthritis. © 2016 IUBMB Life, 68(6):429-435, 2016.