Diosgenin-induced cognitive enhancement in normal mice is mediated by 1,25D₃-MARRS.
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ABSTRACT:
SUBMITTER: Tohda C
PROVIDER: S-EPMC3844946 | biostudies-other | 2013
REPOSITORIES: biostudies-other
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Project description:Approximately 35 million people worldwide suffer from Alzheimer’s disease (AD). Existing therapeutics, while moderately effective, are currently unable to stem the widespread rise in AD prevalence. AD is associated with an increase in amyloid beta (A) oligomers and hyperphosphorylated tau, along with cognitive impairment and neurodegeneration. Several antidepressants have shown promise in improving cognition and alleviating oxidative stress in AD but have failed as long-term therapeutics. In this study, amitriptyline, an FDA-approved tricyclic antidepressant, was administered orally to aged and cognitively impaired transgenic AD mice (3xTgAD). After amitriptyline treatment, cognitive behavior testing demonstrated that there was a significant improvement in both long- and short-term memory retention. Amitriptyline treatment also caused a significant potentiation of non-toxic A monomer with a concomitant decrease in toxic oligomer A load, compared to vehicle-treated 3xTgAD controls. In addition, amitriptyline administration caused a significant increase in dentate gyrus neurogenesis as well as increases in expression of neurosynaptic marker proteins. Amitriptyline treatment resulted in increases in hippocampal brain-derived neurotrophic factor protein as well as increased tyrosine phosphorylation of its cognate receptor (TrkB). These results indicate that amitriptyline has significant beneficial actions in aged and damaged AD brains and that it shows promise as a tolerable novel therapeutic for the treatment of AD. Male 3xTgAD mice, 14 months of age, were maintained on a 12hr light dark cycle in pathogen free conditions. Animals received food and water ad libitum. The test group received 100ug/g body weight amitriptyline-hydrochloride per os in their drinking water (Sigma-Aldrich, St. Louis MO) for 4 months (n = 15), and the control group received water (n = 15). The Hippocampus and Cortex were removed from 3 replicates of each group and RNA purification was done using glass bead disruption followed by the RNEasy Mini Kit (Qiagen, Valencia, CA) according to the manufacturer's instructions. The RNA was examined for quantity and quality using an Agilent Bioanalyzer 2100 (Agilent Technologies, Palo Alto, CA). The samples were hybridized to Illumina's SentrixMouse Ref-8 v2. Expression BeadChips (Illumina, San Diego, CA).
2011-12-31 | E-GEOD-26836 | biostudies-arrayexpress
Project description:The epigenetic changes of the chromatin represent an attractive molecular substrate for adaptation to the environment. We examined here the role of CBP, a histone acetyltransferase involved in mental retardation, in the genesis and maintenance of long-lasting systemic and behavioral adaptations to environmental enrichment (EE). Morphological and behavioral analyses demonstrated that EE ameliorates deficits associated to CBP-deficiency. However, CBP-deficient mice also showed a strong defect in environment-induced neurogenesis and impaired EE-enhanced spatial navigation and patter separation ability. These defects correlated with an attenuation of the transcriptional program induced in response to EE and with deficits in histone acetylation at the promoters of EE-regulated, neurogenesis-related genes. Additional experiments in CBP restricted and inducible knockout mice indicated that environment-induced adult neurogenesis is extrinsically regulated by CBP function in mature granule cells. Overall, our experiments demonstrate that the environment alters gene expression by impinging on activities involved in modifying the epigenome and identify CBP-dependent transcriptional neuroadaptation as an important mediator of EE-induced benefits, a finding with important implications for mental retardation therapeutics. To identify those genes whose expression was altered in the hippocampus of cbp heterozygous mice both under basal conditions and after 2 weeks of exposure to environmental enrichment, we performed a gene profiling analysis of hippocampal tissue using high-density oligonucleotide microarrays. We obtained quintuplicate (standard housing) and triplicate (environmental enrichment) samples containing total RNA from the hippocampi of four 3-month old females of either genotype (in total 32 cbp+/- mice and 32 wild type littermates were used in the experiment).
2011-08-29 | E-GEOD-30880 | biostudies-arrayexpress
Project description:The epigenetic changes of the chromatin represent an attractive molecular substrate for adaptation to the environment. We examined here the role of CBP, a histone acetyltransferase involved in mental retardation, in the genesis and maintenance of long-lasting systemic and behavioral adaptations to environmental enrichment (EE). Morphological and behavioral analyses demonstrated that EE ameliorates deficits associated to CBP-deficiency. However, CBP-deficient mice also showed a strong defect in environment-induced neurogenesis and impaired EE-enhanced spatial navigation and patter separation ability. These defects correlated with an attenuation of the transcriptional program induced in response to EE and with deficits in histone acetylation at the promoters of EE-regulated, neurogenesis-related genes. Additional experiments in CBP restricted and inducible knockout mice indicated that environment-induced adult neurogenesis is extrinsically regulated by CBP function in mature granule cells. Overall, our experiments demonstrate that the environment alters gene expression by impinging on activities involved in modifying the epigenome and identify CBP-dependent transcriptional neuroadaptation as an important mediator of EE-induced benefits, a finding with important implications for mental retardation therapeutics. To identify those genes whose expression was altered in the hippocampus of cbp heterozygous mice both under basal conditions and after 2 weeks of exposure to environmental enrichment, we performed a gene profiling analysis of hippocampal tissue using high-density oligonucleotide microarrays.
2011-08-30 | GSE30880 | GEO
Project description:Approximately 35 million people worldwide suffer from Alzheimer’s disease (AD). Existing therapeutics, while moderately effective, are currently unable to stem the widespread rise in AD prevalence. AD is associated with an increase in amyloid beta (A) oligomers and hyperphosphorylated tau, along with cognitive impairment and neurodegeneration. Several antidepressants have shown promise in improving cognition and alleviating oxidative stress in AD but have failed as long-term therapeutics. In this study, amitriptyline, an FDA-approved tricyclic antidepressant, was administered orally to aged and cognitively impaired transgenic AD mice (3xTgAD). After amitriptyline treatment, cognitive behavior testing demonstrated that there was a significant improvement in both long- and short-term memory retention. Amitriptyline treatment also caused a significant potentiation of non-toxic A monomer with a concomitant decrease in toxic oligomer A load, compared to vehicle-treated 3xTgAD controls. In addition, amitriptyline administration caused a significant increase in dentate gyrus neurogenesis as well as increases in expression of neurosynaptic marker proteins. Amitriptyline treatment resulted in increases in hippocampal brain-derived neurotrophic factor protein as well as increased tyrosine phosphorylation of its cognate receptor (TrkB). These results indicate that amitriptyline has significant beneficial actions in aged and damaged AD brains and that it shows promise as a tolerable novel therapeutic for the treatment of AD.
2011-12-31 | GSE26836 | GEO
Project description:Approximately 35 million people worldwide suffer from Alzheimer's disease (AD). Existing therapeutics, while moderately effective, are currently unable to stem the widespread rise in AD prevalence. AD is associated with an increase in amyloid beta (Aβ) oligomers and hyperphosphorylated tau, along with cognitive impairment and neurodegeneration. Several antidepressants have shown promise in improving cognition and alleviating oxidative stress in AD but have failed as long-term therapeutics. In this study, amitriptyline, an FDA-approved tricyclic antidepressant, was administered orally to aged and cognitively impaired transgenic AD mice (3×TgAD). After amitriptyline treatment, cognitive behavior testing demonstrated that there was a significant improvement in both long- and short-term memory retention. Amitriptyline treatment also caused a significant potentiation of non-toxic Aβ monomer with a concomitant decrease in cytotoxic dimer Aβ load, compared to vehicle-treated 3×TgAD controls. In addition, amitriptyline administration caused a significant increase in dentate gyrus neurogenesis as well as increases in expression of neurosynaptic marker proteins. Amitriptyline treatment resulted in increases in hippocampal brain-derived neurotrophic factor protein as well as increased tyrosine phosphorylation of its cognate receptor (TrkB). These results indicate that amitriptyline has significant beneficial actions in aged and damaged AD brains and that it shows promise as a tolerable novel therapeutic for the treatment of AD.
| S-EPMC3124550 | biostudies-literature
Project description:Obesity is one of the most serious health problems in the world, increasing the risk of other chronic diseases. Alterations in fatty acid synthesis related genes are crucially involved in obesity progression. Diosgenin (DG) was one of the phytosterols compounds with vital activity against lipid disorders. Therefore, this study was intended to evaluate the protective effect of DG on lipogenesis in the high-fat diet (HFD)-induced obesity in mice, via investigating the expression of two of the fatty acid synthesis-involved genes; sterol regulatory element-binding protein (SREBP-1c) and fatty acid synthase (FASN) genes. Thirty adult male mice were divided into 3 groups. Control group, fed with normal diet; HFD group, mice fed with a high-fat diet and HFD + DG group, mice fed with a high-fat diet and supplemented in parallel with DG for 6 consecutive weeks. The effect of DG on Body weights, liver enzymes, lipid profile, were evaluated. Histopathological fatty changes as well as SREBP-1c and FASN gene expression were also investigated. DG significantly alleviated body weight gain, adjusted liver enzymes, and improved lipid profile. Additionally, DG ameliorated the histopathological changes by reducing the lipid vacuoles and hence the hepatosteatosis. Accordingly, DG significantly downregulated the two-fold increase in the SREBP-1c and FASN gene expression observed in the HFD group. In conclusion, DG possesses a beneficial impact against diet-induced obesity in mice, which makes it a good candidate for NAFLD and obesity prevention.
| S-EPMC7783812 | biostudies-literature
Project description:The epigenetic changes of the chromatin represent an attractive molecular substrate for adaptation to the environment. We examined here the role of CREB-binding protein (CBP), a histone acetyltransferase involved in mental retardation, in the genesis and maintenance of long-lasting systemic and behavioural adaptations to environmental enrichment (EE). Morphological and behavioural analyses demonstrated that EE ameliorates deficits associated to CBP deficiency. However, CBP-deficient mice also showed a strong defect in environment-induced neurogenesis and impaired EE-mediated enhancement of spatial navigation and pattern separation ability. These defects correlated with an attenuation of the transcriptional programme induced in response to EE and with deficits in histone acetylation at the promoters of EE-regulated, neurogenesis-related genes. Additional experiments in CBP restricted and inducible knockout mice indicated that environment-induced adult neurogenesis is extrinsically regulated by CBP function in mature granule cells. Overall, our experiments demonstrate that the environment alters gene expression by impinging on activities involved in modifying the epigenome and identify CBP-dependent transcriptional neuroadaptation as an important mediator of EE-induced benefits, a finding with important implications for mental retardation therapeutics.
| S-EPMC3199387 | biostudies-literature
Project description:Elevated brain activation, or hyperexcitability, induces cognitive impairment and confers an increased risk of Alzheimer's disease (AD). Blocking the overexcitation of the neural network may be a promising new strategy to prevent, halt, and even reverse this condition. Physical exercise has been shown to be an effective cognitive enhancer that reduces the risk of AD in elderly individuals, but the underlying mechanisms are far from being fully understood. We explored whether long-term treadmill exercise attenuates amyloid precursor protein (APP)/presenilin-1 (PS1) mutation-induced aberrant network activity and thus improves cognition by altering the numbers and/or distribution of voltage-gated sodium channels (Nav) in transgenic mice. APP/PS1 mice aged 2, 3.5, 5, 6.5, 8, and 9 months underwent treadmill exercise with different durations or at different stages of AD. The alterations in memory, electroencephalogram (EEG) recordings, and expression levels and distributions of Nav functional members (Nav1.1α, Nav1.2, Nav1.6, and Navβ2) were evaluated. The results revealed that treadmill exercise with 12- and 24-week durations 1) induced significant improvement in novel object recognition (NOR) memory and Morris water maze (MWM) spatial memory; 2) partially reduced abnormal spike activity; and 3) redressed the disturbed cellular distribution of Nav1.1α, aberrant Navβ2 cleavage augmentation, and Nav1.6 upregulation. Additionally, APP/PS1 mice in the 24-week exercise group showed better performance in the NOR task and a large decrease in Nav1.6 expression, which was close to the wild-type level. This study suggests that exercise improves cognition and neural activity by altering the numbers and distribution of hippocampal Nav in APP/PS1 mice. Long-term treadmill exercise, for about 24 weeks, starting in the preclinical stage, is a promising therapeutic strategy for preventing AD and halting its progress.
| S-EPMC7103997 | biostudies-literature
Project description:A rodent model of diet-induced obesity revealed that obesity significantly altered hematopoietic and lymphopoietic functions in the bone marrow and thymus. C57BL/6 mice were fed a mixed high-fat diet (HFD) of 45% fat or 10% fat diet (lean controls) for 180 d. A sustained increase in the numbers of cells found in bone marrow and thymus of HFD mice occurred from day 90 to day 180. However, with the exception of a 10-18% increase in the proportion of lymphocytes, the composition of monocytes, granulocytes, erythrocytes, and mixed progenitor lineages remained normal in the marrow. Likewise, thymuses of HFD mice increased 30-50% in size compared with controls, with analogous increases in thymocyte numbers. The overall thymus cellular composition remained normal. Although increased blood and lymphatic volume in obese mice would play a role in increased hematopoiesis, there were large and disproportionate increases in blood leukocytes of HFD mice, indicating that homeostasis was not maintained. Leptin, which promotes lymphopoiesis and myelopoiesis, reached 100 ng/mL in sera from HFD mice. Moreover, a three- to sixfold increase in adipocytes in marrow resulted in spiked leptin mRNA expression in bones of HFD mice compared with lean controls. Other cytokines and growth factors did not show any increases in obese marrow. The substantial increase in lymphopoietic and hematopoietic processes in HFD mice indicates that the primary tissues are another facet of the immune system dysregulated by obesity, which was perhaps fostered by higher amounts of leptin in marrow and serum.
| S-EPMC3356670 | biostudies-literature
Project description:The effects of the oligosaccharides from the endophytic fungus Fusarium oxysporum Dzf17 as elicitors on diosgenin production in cell suspension cultures of its host Dioscorea zingiberensis were investigated. Three oligosaccharides, DP4, DP7 and DP10, were purified from the oligosaccharide fractions DP2-5, DP5-8 and DP8-12, respectively, which were prepared from the water-extracted mycelial polysaccharide of the endophytic fungus F. oxysporum Dzf17. When the cell cultures were treated with fraction DP5-8 at 20 mg/L on day 26 and harvested on day 32, the maximum diosgenin yield (2.187 mg/L) was achieved, which was 5.65-fold of control (0.387 mg/L). When oligosaccharides DP4, DP7 and DP10 were individually added to 26-day-old D. zingiberensis cell cultures at concentrations of 2, 4, 6, 8 and 10 mg/L in medium, DP7 at 6 mg/L was found to significantly enhance diosgenin production, with a yield of 3.202 mg/L, which was 8.27-fold of control. When the cell cultures were treated with DP7 twice on days 24 and 26, and harvested on day 30, both diosgenin content and yield were significantly increased and reached the maximums of 1.159 mg/g dw and 4.843 mg/L, both of which were higher than those of single elicitation, and were 9.19- and 12.38-fold of control, respectively.
| S-EPMC6264283 | biostudies-literature