Cognitive Dysfunction In Mice Research Articles

Amentoflavone Ameliorates Memory Deficits and Abnormal Autophagy in Aβ25-35-Induced Mice by mTOR Signaling.

Alzheimer's disease (AD) is a neurodegenerative disease in which autophagy plays a crucial role. Amentoflavone is a flavonoid obtained from various plants and has been shown to have AD-resistant neuroprotective effects. This study investigated the role of amentoflavone on memory impairment and abnormal autophagy in amyloid-β25-35 (Aβ25-35)-induced mice to elucidate the mechanisms by which it exerts neuroprotective effects. In this experiment, the AD mouse model was established by intracerebroventricular (ICV) injection of Aβ25-35 peptides, and amentoflavone was administered orally for 4 weeks. Behavioral changes in mice and pathological changes in the hippocampus were observed, and levels of inflammation, oxidative stress, and autophagy in the brain were detected and analyzed. PC-12 and APPswe-N2a cells were used in vitro to further investigate the effect of amentoflavone on the level of intracellular autophagy. Molecular docking was used to determine the action sites of amentoflavone. The results showed that amentoflavone improved memory function, eased anxiety symptoms in Aβ25-35-induced mice, and reduced atrophic degeneration of neurons in the hippocampus. Moreover, amentoflavone lessened the oxidative stress and inflammation in the brains of mice. Through in vivo and in vitro experiments, we found that amentoflavone may enhance autophagy, by way of binding to the ATP site of the mTOR protein kinase domain. Amentoflavone not only interacted with mTOR, but also improved Aβ25-35-induced cognitive dysfunction in mice by enhancing autophagy, attenuating levels of inflammation and oxidative stress, and reducing apoptosis in brain cells.

Neurotrophic factor-\u03b11, a novel tropin is critical for the prevention of stress-induced hippocampal CA3 cell death and cognitive dysfunction in mice: comparison to BDNF

Stress leads to brain pathology including hippocampal degeneration, cognitive dysfunction, and potential mood disorders. Hippocampal CA3, a most stress-vulnerable region, consists of pyramidal neurons that regulate cognitive functions e.g. learning and memory. These CA3 neurons express high levels of the neuroprotective protein, neurotrophic factor-α1 (NF-α1), also known as carboxypeptidase E (CPE), and receive contacts from granule cell projections that release BDNF which has neuroprotective activity. Whether NF-α1-CPE and/or BDNF are critical in protecting these CA3 neurons against severe stress-induced cell death is unknown. Here we show that social combined with the physical stress of maternal separation, ear tagging, and tail snipping at weaning in 3-week-old mice lacking NF-α1-CPE, led to complete hippocampal CA3 degeneration, despite having BDNF and active phosphorylated TrkB receptor levels similar to WT animals. Mice administered TrkB inhibitor, ANA12 which blocked TrkB phosphorylation showed no degeneration of the CA3 neurons after the weaning stress paradigm. Furthermore, transgenic knock-in mice expressing CPE-E342Q, an enzymatically inactive form, replacing NF-α1-CPE, showed no CA3 degeneration and exhibited normal learning and memory after the weaning stress, unlike NF-α1-CPE-KO mice. Mechanistically, we showed that radio-labeled NF-α1-CPE bound HT22 hippocampal cells in a saturable manner and with high affinity (Kd = 4.37 nM). Subsequently, treatment of the HT22cpe−/− cells with NF-α1-CPE or CPE-E342Q equivalently activated ERK signaling and increased BCL2 expression to protect these neurons against H2O2-or glutamate-induced cytotoxicity. Our findings show that NF-α1-CPE is more critical compared to BDNF in protecting CA3 pyramidal neurons against stress-induced cell death and cognitive dysfunction, independent of its enzymatic activity.

Resveratrol and organic selenium-rich fermented milk reduces D-galactose-induced cognitive dysfunction in mice.

Recently, dietary intervention has been considered as a prospective strategy in treating age-related cognitive dysfunction and brain plasticity degeneration. In this study, we developed a kind of functional fermented milk rich in resveratrol and organic selenium, and explored the effects on cognitive behavior, hippocampal neurogenesis and the neurotrophic signaling pathway in d-galactose model mice. Behavioral tests showed that the functional fermented milk significantly reversed spatial memory loss and showed a recognition behavior reduction in a novel object recognition task. Immunohistochemistry analysis demonstrated that the functional fermented milk significantly increased hippocampal neurogenesis. Moreover, walnut diets with dairy products reserved a d-galactose induced decrease of hippocampal p-ERK/ERK, p-CREB/CREB, and BDNF expression in the protein level. These findings confirmed that dietary treatment with the functional fermented milk could ameliorate cognitive dysfunction in d-galactose model mice, and yoghurt rich in resveratrol and organic selenium has the potential in treating age-related diseases.

Ganoderic acid improves 5-fluorouracil-induced cognitive dysfunction in mice.

5-Fluorouracil (5-FU) is a chemotherapeutic drug with a good anti-cancer effect on various types of cancers, such as colorectal cancer and breast cancer. However, previous studies have found that 5-FU could induce cognitive deficit in clinics. As ganoderic acid, isolated from Ganoderma lucidum, has a protective effect on neurons, this study investigated the effects of ganoderic acid (GA) against 5-FU-induced cognitive dysfunction with a series of behavioral tests and related indicators. Experimental results showed that GA significantly prevented the reduction of spatial and non-spatial memory in 5-FU-treated mice. In addition, GA not only ameliorated the damage to hippocampal neurons and mitochondrial structure, but also significantly improved abnormal protein expression of mitochondrial biogenesis related marker PGC-1α, and mitochondrial dynamics related markers MFN2, DRP1 and FIS1 in the hippocampi of 5-FU-treated mice. Moreover, GA could up-regulate the expression of neuronal survival and growth-related proteins, such as BDNF, p-ERK, p-CREB, p-Akt, p-GSK3β, Nrf2, p-mTOR, and p-S6, in the hippocampi of 5-FU-treated mice. These results suggest that GA could prevent cognitive dysfunction in mice treated with 5-FU via preventing mitochondrial impairment and enhancing neuronal survival and growth, which provide evidence for GA as a promising adjunctive therapy for chemotherapy related cognitive impairment in clinics.

Surgery Trauma Severity but not Anesthesia Length Contributes to Postoperative Cognitive Dysfunction in Mice.

Perioperative, modifiable factors contributing to perioperative neurocognitive disorders (PND) have not been clearly defined. To determine the contribution of anesthesia lengths and the degrees of surgical trauma to PND and neuroinflammation, a critical process for PND. Three-month-old C57BL/6J mice were subjected to 2 h or 6 h isoflurane anesthesia plus a 5 min or 15 min left common carotid artery exposure (surgery) in a factorial design (two factors: anesthesia with two levels and surgery with three levels). Their learning and memory were tested by Barnes maze and novel object recognition paradigms. Blood, spleen, and hippocampus were harvested for measuring interleukin (IL)-6 and IL-1β. Eighteen-month-old C57BL/6J mice (old mice) were subjected to 6 h isoflurane anesthesia or 2 h isoflurane anesthesia plus 15 min surgery and then had learning and memory tested. Three-month-old mice with 15 min surgery (long surgery) under 2 h or 6 h anesthesia performed poorly in the learning and memory tests compared with controls. Anesthesia alone or anesthesia plus 5 min surgery did not affect mouse performance in these tests. Similarly, only mice with long surgery but not mice with other experimental conditions had increased IL-6 and IL-1β in the blood, spleen, and hippocampus and decreased spleen weights. Splenocytes were found in the hippocampus after surgery. Similarly, old mice with long surgery but not the mice with isoflurane anesthesia alone had poor performance in the Barnes maze and novel object recognition tests. Surgical trauma, but not anesthesia, contributes to the development of PND and neuroinflammation. Splenocytes may modulate these processes.

Treatment with anti-interleukin-6 receptor antibody improves mechanical hypersensitivity and cognitive dysfunction in mice with neuropathic pain

Treatment with anti-interleukin-6 receptor antibody improves mechanical hypersensitivity and cognitive dysfunction in mice with neuropathic pain

The Protective Effects of Trans-Cinnamaldehyde against D-Galactose and Aluminum Chloride-Induced Cognitive Dysfunction in Mice

The increased prevalence of cognitive impairment, specifically among the aging population, has attracted attention in recent years. Trans-cinnamaldehyde (TCA), which is isolated from cinnamon, has recently drawn attention because of its potent anti-inflammatory and antioxidant properties. This study aimed to investigate the effects of TCA on learning and memory using a mouse model of cognitive impairment induced by a combination of D-galactose (D-gal) and aluminum chloride (AlCl3). TCA (10 and 30 mg/kg/day) was administered orally for 30 days after the induction of cognitive impairment. The Morris water maze (MWM) task was performed to directly evaluate the neuroprotective effects of TCA on memory and spatial learning abilities. We found that TCA treatment attenuated cognitive impairment and reduced brain damage in the D‑gal- and AlCl3-treated mice. To further investigate the mechanisms involved in the effects of TCA, we analyzed the nuclear factor erythroid 2-related factor (Nrf2) and related signaling pathways. We found that TCA upregulated AMP-activated protein kinase (AMPK), Nrf2, heme oxygenase 1 (HO-1) and NAD(P)H dehydrogenase [quinone] 1 (NQO-1); this suggests that TCA may attenuate cognitive dysfunction by reducing oxidative stress. We concluded that TCA reduced D-gal and AlCl3-induced cognitive dysfunction through activation of the AMPK-mediated Nrf2/HO-1 signaling pathway in the brain. These results suggest that TCA may be a candidate for treating age-associated cognitive impairment.

Pterostilbene Alleviates Aβ1-42 -Induced Cognitive Dysfunction via Inhibition of Oxidative Stress byActivatingNrf2 Signaling Pathway.

In the present study, effect of pterostilbene on β-amyloid 1-42 (Aβ1-42 ) induced cognitive impairment in mice is investigated and explored its possible mechanism of action. The behavior results show that pterostilbene alleviated Aβ1-42 -induces cognitive dysfunction assessed using the Y-maze test, novel object recognition task, Morris water maze test, and passive avoidance test. Pterostilbene alleviates neuron loss and accumulation of reactive oxygen species in Aβ1-42 treated mouse brain. Additionally, pterostilbene promotes nuclear factor-E2 p45-related factor 2 (Nrf2) nuclear translocation and enhance the transcription and expression of antioxidant genes such as heme oxygenase-1 and superoxide dismutase both in vivo and in vitro. Nrf2 inhibitor ML385 reverses the antioxidant function of pterostilbene in SH-SY5Y cells. Nrf2 is the master regulator of oxidative homeostasis and can be activated by substrate adaptor sequestosome-1 (also named p62). Pterostilbene promotes the binding of Kelch-like ECH-associated protein 1 and p62, which enhanced activation of Nrf2. The present study reports that pterostilbene alleviated Aβ1-42 -induces cognitive dysfunction in mice. The mechanism of pterostilbene can be associated to the inhibition of oxidative stress through the Nrf2 signaling pathway.

Effect of Treadmill Exercise and Trans-Cinnamaldehyde against d-Galactose- and Aluminum Chloride-Induced Cognitive Dysfunction in Mice

Mild cognitive impairment (MCI) generally refers to impairment in cognition above that which accompanies the normal age-related cognitive decline and has attracted attention in recent years. Trans-cinnamaldehyde (TCA), which is isolated from cinnamon, has anti-inflammatory and antioxidant properties. Treadmill exercise also has diverse positive effects. The purpose of this study was to investigate the combination effects of TCA and treadmill exercise on learning and memory in a cognitive impairment mouse induced by a combination of d-galactose (d-gal) and aluminum chloride (AlCl3). We found that exercise and TCA attenuated cognitive impairment in mice with induced MCI. This effect was further increased by costimulation of exercise and TCA. To clarify the mechanisms of the positive effects of TCA and exercise, we analyzed the nuclear factor erythroid 2-related factor (Nrf2) and related signaling pathways. We found that TCA and exercise upregulated Nrf2, NAD(P)H dehydrogenase quinone 1 (NQO-1), heme oxygenase 1 (HO-1), and superoxide dismutase 1 (SOD-1); this suggests that TCA and exercise attenuate cognitive dysfunction by reducing oxidative stress. We also found that Nrf2-related signaling pathways, i.e., the AMP-activated protein kinase (AMPK)/Nrf2 and SIRT1/PGC-1a/Nrf2-ARE pathways, exerted antioxidant effects. Together, these results suggest that costimulation with TCA and exercise may be a therapeutic candidate for mild cognitive impairment.

Cognitive dysfunction in mice lacking proper glucocorticoid receptor dimerization

Cognitive dysfunction in mice lacking proper glucocorticoid receptor dimerization

Screening of potential genes and transcription factors involved in post-radiation cognitive dysfunction in mice via bioinformatics.

BackgroundThis study aimed to identify potential genes and transcription factors involved in postradiation cognitive dysfunction using bioinformatics analysis.MethodsBioinformatics tools were used to identify differentially expressed mRNAs between postradiation cognitive dysfunctional and control tissue. The GSE115735 dataset containing mRNA expression profiles was downloaded from the Gene Expression Omnibus database. The mRNA expression data corresponded to three hippocampus and three brain lateral ventricles from postradiation cognitive dysfunctional mice and controls. The differentially expressed mRNAs between the two groups were identified, and protein-protein interaction network was constructed. This was followed by functional enrichment and pathway analysis with further prediction of transcription factors that targeted differentially expressed mRNAs. Network analysis was conducted between the differentially expressed mRNAs and these potential transcription factors.ResultsA total of 134 differentially expressed mRNAs were obtained, including 64 mRNAs in the hippocampus and 84 in the posterior lateral ventricles. Fourteen mRNAs were expressed differentially in both tissues. Furthermore, genes in the network were strongly enriched in neuroactive ligand-receptor interactions, regulation of calcium ion transport, mitotic spindle associated pathway, and TGF-beta signaling pathways. Six transcription factors associated with the regulation of target genes were identified.ConclusionsMost of the genes identified were involved in transcriptional regulation, including TFAP4, RUNX1, and CUX2, which may play important roles in the development of postradiation cognitive dysfunction.

IgA natural antibodies are produced following T-cell independent B-cell activation following stroke

Up to 30% of stroke patients experience cognitive decline within one year of their stroke. There are currently no FDA-approved drugs that can prevent post-stroke cognitive decline, in part due to a poor understanding of the mechanisms involved. We have previously demonstrated that a B-lymphocyte response to stroke, marked by IgA + cells, can cause delayed cognitive dysfunction in mice and that a similar adaptive immune response occurs in the brains of some human stroke patients that suffer from vascular dementia. The stimuli which trigger B-lymphocyte activation following stroke, and their target antigens, are still unknown. Therefore, to learn more about the mechanisms by which B-lymphocytes become activated following stroke we first characterized the temporal kinetics of the B-lymphocyte, T-lymphocyte, and plasma cell (PC) response to stroke in the brain by immunohistochemistry (IHC). We discovered that B-lymphocyte, T-lymphocyte, and plasma cell infiltration within the infarct progressively increases between 2 and 7 weeks after stroke. We then compared the B-lymphocyte response to stroke in WT, MHCII-/-, CD4-/-, and MyD88-/- mice to determine if B-lymphocytes mature into IgA + PCs through a T-lymphocyte and MyD88 dependent mechanism. Our data from a combination of IHC and flow cytometry indicate that following stroke, a population of IgA + PCs develops independently of CD4 + helper T-lymphocytes and MyD88 signaling. Subsequent sequencing of immunoglobulin genes of individual IgA + PCs present within the infarct identified a novel population of natural antibodies with few somatic mutations in complementarity-determining regions. These findings indicate that a population of IgA + PCs develops in the infarct following stroke by B-lymphocytes interacting with one or more thymus independent type 2 (TI-2) antigens, and that they produce IgA natural antibodies.

SerpinA3N deficiency deteriorates impairments of learning and memory in mice following hippocampal stab injury

Traumatic brain injury is a global leading cause of disability and death, which puts patients at high risk for developing dementia. Early intervention is believed as the key to minimize the development of brain damages that could aggravate the symptoms. Here, we report that the serine protease inhibitor SerpinA3N is upregulated in hippocampal neurons in the early stage of hippocampal stab injury (HSI), while its deficiency causes a greater degree of neuronal apoptosis and severer impairments of spatial learning and memory in mice after HSI. We further show that MMP2 is a key substrate of SerpinA3N, and MMP2 specific inhibitor (ARP100) can protect against neuronal apoptosis and cognitive dysfunction in mice after HSI. These findings demonstrate a critical role for SerpinA3N in neuroprotection, suggesting that SerpinA3N and MMP2 inhibitors might be a novel therapeutic agents for neurotrauma.

High Salt Elicits Brain Inflammation and Cognitive Dysfunction, Accompanied by Alternations in the Gut Microbiota and Decreased SCFA Production.

Excessive salt intake is considered as an important risk factor for cognitive impairment, which might be the consequence of imbalanced intestinal homeostasis. To investigate the effects of dietary salt on the gut microbiota and cognitive performance and the underlying mechanisms. Adult female C57BL/6 mice were maintained on either normal chow (control group, CON) or sodium-rich chow containing 8% NaCl (high-salt diet, HSD) for 8 weeks. Spatial learning and memory ability, short-chain fatty acids (SCFAs) concentrations, gut bacterial flora composition, blood-brain barrier permeability, and proinflammatory cytokine levels and apoptosis in the brain were evaluated. The mice fed a HSD for 8 weeks displayed impaired learning and memory abilities. HSD significantly reduced the proportions of Bacteroidetes (S24-7 and Alloprevotella) and Proteobacteria and increased that of Firmicutes (Lachnospiraceae and Ruminococcaceae). SCFA concentrations decreased in the absolute concentrations of acetate, propionate, and butyrate in the fecal samples from the HSD-fed mice. The HSD induced both BBB dysfunction and microglial activation in the mouse brain, and increased the IL-1β, IL-6, and TNF-α expression levels in the cortex. More importantly, the degree of apoptosis was higher in the cortex and hippocampus region of mice fed the HSD, and this effect was accompanied by significantly higher expression of cleaved caspase-3, caspase-3, and caspase-1. The HSD directly causes cognitive dysfunction in mice by eliciting an inflammatory environment and triggering apoptosis in the brain, and these effects are accompanied by gut dysbiosis, particularly reduced SCFA production.

Dopamine D1 receptor agonist A-68930 ameliorates Aβ1-42-induced cognitive impairment and neuroinflammation in mice

Alzheimer's disease (AD) is an irreversible neurodegenerative disease characterized by progressive cognitive dysfunction and memory impairment. Dopamine is an important catecholaminergic neurotransmitter that controls movement, reward, motivation, and cognition. Recently, dopamine receptors were reported to regulate immune system in both periphery and central nervous system. However, whether dopamine D1 receptor (DRD1) activation could improve neuroinflammation in AD conditions remains unknown. The present study aimed to investigate the therapeutic effects and underlying mechanisms of a potent and selective DRD1 agonist A-68930 on Aβ1-42-induced mice. Here we showed that intraperitoneal injection of A-68930 significantly ameliorated Aβ1–42-induced cognitive dysfunction in mice. Moreover, both in vivo and in vitro data showed that A-68930-induced DRD1 activation significantly inhibited NLRP3 inflammasome-dependent neuroinflammation induced by Aβ1–42, and this effect may be mediated by the activation of AMPK/autophagy signaling pathway, which enhanced NLRP3 inflammasome degradation and thus decreased the secretion of IL-1β and IL-18. The present study suggests that A-68930-induced DRD1 signaling efficiently alleviates Aβ1–42-induced cognitive impairment and neuroinflammation in mice and BV2 cells, and DRD1 may become a promising therapeutic target for AD.

Effects of the excitation or inhibition of basal forebrain cholinergic neurons on cognitive ability in mice exposed to chronic intermittent hypoxia

Cognitive impairment of obstructive sleep apnea syndrome (OSAS) patients is related to the basal forebrain (BF) cholinergic neurons. To further investigate the effect of the excitation or inhibition of BF cholinergic neurons on cognitive ability, we employed a chronic intermittent hypoxia (CIH) mice model and implanted microinjection cannulas in the BFs for targeted intervention, finally performed the behavioral experiments and examined immunohistochemistry and biochemical changes in the BFs. The results showed that (1) CIH induced cognitive decline in mice. (2) The excitation of BF cholinergic neurons attenuated cognitive decline, while the inhibition of these neurons aggravated cognitive impairment. (3) Microinjection of adenosine into the BF aggravated cognitive decline, while caffeine improved cognitive ability. (4) CIH induced BF cholinergic neuron injury in mice. (5) The excitation of BF cholinergic neurons alleviated cholinergic neuron injury, while the inhibition of these neurons aggravated this injury. (6) Microinjection of adenosine into the BF aggravated cholinergic neuron injury, while caffeine alleviated this injury. (7) CIH induced endoplasmic reticulum stress, oxidative stress and inflammatory responses in the BFs of mice. (8) The excitation of BF cholinergic neurons mitigated endoplasmic reticulum stress, oxidative stress and inflammatory responses in the BF in mice, while the inhibition of BF cholinergic neurons worsened these responses in the BF. (9) Microinjection of adenosine into the BF aggravated endoplasmic reticulum stress, oxidative stress and the inflammatory response, while caffeine alleviated these responses. This work indicates that CIH induces BF cholinergic neuron injury through multiple pathways, including endoplasmic reticulum stress, oxidative stress and the inflammatory response, thereby leading to cognitive dysfunction in mice. BF cholinergic neurons play a vital role in these pathways, thus reducing cholinergic neuron injury and restoring cognitive function in mice. Adenosine, which is an upstream modifier of acetylcholine, also plays an important role in altering cognitive ability.

Purification, structural characterization, and cognitive improvement activity of a polysaccharides from Schisandra chinensis

The present study aimed to evaluate structural characteristics of a polysaccharides, SCP2-1, isolated from Schisandra chinensis (Turcz.) Baill (S. chinensis) and to assess its improvement on cognitive dysfunction caused by excessive neuroinflammation. Structural characterization indicated that SCP2-1 was composed of glucose and galactose in a molar ratio of 8.78:1.23 with molecular weight of 5.388 kDa. The main linkages of the glycosidic bonds of SCP2-1were 1,4-linked-Glcp, 1,4-linked-Galp, 1-linked-Galp and 1,4,6-linked-Galp. The evaluation of behavioral pharmacology and the detection of biochemical markers exhibited that SCP2-1 could improve LPS-induced cognitive dysfunction in mice, ameliorate excessive inflammatory response. The results showed that SCP2-1 could ameliorated the animals' exploration time of novel arm in Y maze test, shortened the escape latency of mice in MWM test, and increased the exploration time of new object in NOR test. What's more, mice could improve histopathological changes induced by LPS, suppress the over-activation of glial cells, decrease the expression of proinflammatory cytokines, increase the levels of anti-inflammatory cytokines, reduce the levels of NLRP3, M-caspaes-1, which may further induce the decrease of excessive deposition of Aβ. Furthermore, SCP2-1 could inhibit the over-activation of NF-κB and the hyperphosphorylation of P38 MAPK pathway.

Casticin ameliorates scopolamine-induced cognitive dysfunction in mice

Ethnopharmacological relevanceThe fruit of Vitex rotundifolia L. (Verbenaceae) has been used in traditional medicine as sedative or analgesic agent for headache. Recent population-based cohort studies have shown that headache including migraines is a risk factor for dementia. Thus, the fruit of V. rotundifolia may be useful for treating cognitive dysfunction observed in dementia. Aim of the studyWe had previously found that the ethanolic extract of the fruit of V. rotundifolia ameliorated cognitive dysfunction and isolated casticin as an active compound. In the present study, we studied the effect of casticin on a mouse model of cognitive impairment induced by scopolamine. Materials and methodsMice were treated with the ethanolic extract of the fruit of V. rotundifolia (EEVR; 30, 100 or 300 mg/kg, p.o.) or casticin (0.3, 1 or 3 mg/kg, p.o.). We examined the effect of casticin or EEVR using the passive avoidance test, the Morris water maze test and the novel object recognition test. Scopolamine (1 mg/kg, i.p.) was used to induce cognitive impairment by blocking cholinergic neurotransmitter system. We investigated the effects of casticin on acetylcholinesterase (AchE) activity and the phosphorylation levels of extracellular signal-regulated kinase (ERK), cAMP response element binding protein (CREB), and the expression levels of brain-derived neurotrophic factor (BDNF). ResultsEEVR (100 and 300 mg/kg, p.o.) significantly ameliorated the latency in the passive avoidance test, and casticin (1 and 3 mg/kg, p.o.) also significantly improved the latency in the passive avoidance test, novel object preference in the novel object recognition test, and swimming time in the target quadrant of the Morris water maze test. Casticin also decreased AChE activity in ex vivo analysis and increased the phosphorylation levels of memory-related signaling molecules, such as ERK, CREB and BDNF in the cortex. ConclusionThese results suggest that casticin ameliorates cholinergic blockade-induced cognitive impairment, in part, through the inhibition of AChE and the activation of the ERK-CREB-BDNF signaling pathway. Taken together, the results suggest that casticin may be useful for treating the cognitive dysfunction observed during cholinergic impairment.

Polysaccharide from Schisandra chinensis acts via LRP-1 to reverse microglia activation through suppression of the NF-κB and MAPK signaling

Ethnopharmacological relevanceSchisandra chinensis (Turcz.) Baill (S. Chinensis), a traditional Chinese medicine frequently used in the traditional treatment of dementia, its polysaccharide component has been widely reported. Aim of the studyIn this paper, we studied whether SCP2-1, a natural product of homogeneous polysaccharide from S. Chinensis, could improve M1 and M2 polarization and inhibit neuroinflammation through lipoprotein receptor-related protein-1 (LRP-1), and futher exerted anti-inflammatory and neuroprotective effects. Materials and methodsSCP2-1 was obtained from crude polysaccharide of S. Chinensis, BV2 microglia cells and mice stimulated by LPS were served to detect the positive role of SCP2-1 in M1/M2 polarization. The concentration of cytokine expression, IL-1β, TNF-α, IL-12 and IL-6 for M1 polarization and TGF-β, IL-10, IL-4 and Arg-1 for M2 polarization, in the BV2 and hippocampus were tested by ELISA kits. CD86 and CD206, as surface markers of M1 and M2, were tested by flow cytometry. We examined the expression of LRP-1 in BV2 cells and mouse hippocampus. The addition of siRNA for LRP-1 demonstrated the important role of LRP-1 in the neuroprotection of SCP2-1. Western blot was used to detect the activation of various mitogen-activated protein kinase (MAPKs) pathway, i.e. the phosphorylation of JNK and ERK proteins, and nuclear translocation of nuclear factor κB (NF-κB). H.E. staining was used to observe Histopathological changes. ResultsSCP2-1 could reverse M1/M2 polarization in vitro culture and suppressed M1 polarization in the hippocampus of mice stimulated with LPS. After LPS stimulation, poor levels of LRP-1, hyperactivation of the JNK and NF-κB was appeared, which could improve by SCP2-1. The addition of siRNA for LRP-1 suppressed the protection of SCP2-1 in BV2 microglial cells. More importantly, SCP2-1 could improve LPS-induced cognitive dysfunction in mice in Y-maze and NOR test. ConclusionsSCP2-1 could improve M1/M2 polarization, especially inhibit M1 polarization, and ameliorate the cognition of mice in Y-maze and NOR test. SCP2-1 play a neuroprotective role through LRP-1 to reverse activation of microglia via suppressing the overactive NF-κB and JNK pathway.

Oral Administration of Alpha Linoleic Acid Rescues Aβ-Induced Glia-Mediated Neuroinflammation and Cognitive Dysfunction in C57BL/6N Mice.

In this work, we evaluated the effects of alpha linoleic acid (ALA), an omega-3 polyunsaturated fatty acid, on amyloid-beta-induced glial-cell-mediated neuroinflammation, amyloidogenesis, and cognitive dysfunction in mice. After an infusion of Aβ1–42 (Aβ1–42, 5 μL/5 min/mouse, intracerebroventricular injection (i.c.v), and respective treatments of ALA (60 mg/kg per oral for six weeks), neuroinflammation, apoptotic markers, and synaptic markers were evaluated by Western blot and immunofluorescence analyses. According to our findings, the infusion of Aβ1–42 activated Toll-like receptor 4 (TLR4), glial fibrillary acidic protein (GFAP), and ionized calcium adaptor molecule 1 (Iba-1) in the frontal cortices and hippocampi of the Aβ1–42-injected mice to a greater extent than the Aβ1–42 + ALA-cotreated mice. Similarly, there was an elevated expression of phospho-c-Jun-N-terminal kinase (p-JNK), phospho-nuclear factor-kB p65 (p-NF-kB p65 (Ser536)), and tissue necrosis factor (TNF) in the Aβ1–42 infused mouse brains; interestingly, these markers were significantly reduced in the Aβ + ALA-cotreated group. The elevated expression of pro-apoptotic markers was observed during apoptotic cell death in the Aβ1–42-treated mouse brains, whereas these markers were markedly reduced in the Aβ + ALA-cotreated group. Moreover, Aβ1–42 infusion significantly increased amyloidogenesis, as assessed by the enhanced expression of the amyloid precursor proteins (APP) beta-amyloid cleaving enzyme-1 (BACE-1) and amyloid-beta (Aβ1–42) in the mouse brains, whereas these proteins were markedly reduced in the Aβ + ALA-cotreated group. We also checked the effects of ALA against Aβ-triggered synaptic dysfunction and memory dysfunction, showing that ALA significantly improved memory and synaptic functions in Aβ-treated mouse brains. These results indicated that ALA could be an applicable intervention in neuroinflammation, apoptotic cell loss, amyloidogenesis, and memory dysfunction via the inhibition of TLR4 and its downstream targets in Aβ + ALA-cotreated mouse brains.