SAMR1 Mice Research Articles

Functions of miR-9 and miR-9* during Aging in SAMP8 Mice and Their Possible Mechanisms.

To explore the functions of miR-9 and miR-9(*) in SAMP8 mice during the aging and their possible mechanisms. SAMP8 mice(4-,8-,12-month old,respectively)were selected,three age-matched SAMR1 mice were used as the control group with three mice in each group. The brains were collected and then sectioned for in situ hybridization of miR-9 and miR-9(*). Mimics or inhibitors of miR-9 and miR-9(*) were transfected into N2a cells,and the effects of overexpression or knockdown of the microRNAs on the cell cycle were detected by flow cytometry. Target genes were predicted by bioinformatic analysis and confirmed by dual luciferase assay. Expressions of miR-9 and miR-9(*) in hippocampus of SAMP8 mice were lower than those of SAMR1 mice. Knockdown of miR-9 and miR-9(*) induced a prolonged G1 phase and a shortened S phase in N2a cells;in contrast,miR-9 and miR-9(*) overexpression showed opposite effects. The predicted target genes of miR-9 were PSEN1,SCN2B,MAP3K3,and BACE1,and that of miR-9(*) was CDKn1c. Dual luciferase reporter gene assay showed that miR-9 targeted MAP3K3 while miR-9(*) targeted CDKn1c. miR-9 and miR-9(*) play an important role during aging via the target genes MAP3K3 and CDKn1c in the SAMP8 mice.

Effect of Electro-Acupuncture on Behavioral Changes,Aβ and LRP1 level in Cortex of APP/PS1 Transgenic Mice

Purpose: To observe the effects of EA on the expression of PS1protein level inhippocampusof SAMP8mice. Investigating themechanismof EA in therapeutic intervention of Alzheimer Disease (AD). Methods: Ten male SAMR1 mice as the Normal control group. Twenty male SAMP8 mice were randomly divided into Model group and EA group (n=10 in each group). EAwas stimulated at Baihui (GV20) andYintang (GV29) for 20min once a day (2V, 1mA). After 15 days, learning and memorizing abilities of mice were detected through Morris water maze. Observe the morphologic changes of PS1 and related metabolites in hippocampus through immunohistochemistry. Detecting PS1 level in hippocampus through Western blot method. Results: 1) Each group showed a significant difference in latency time in different days. 2) Compared with normal control group, Model group showed an increasing latency time and a decreasing swimming time to passing through the platform and quadrants (P < 0.05, P < 0.01), while EA group showed an obvious decreasing latency time (P<0.05, P < 0.01) and an increasing swimming time (P<0.01). 3) Immunohistochemical detection showedmice in EA group had a significant reduction in the expression of PS1 level in hippocampuswhile compared with theModel group. 4) Findings ofWestern blot revealed that compared with Model group, mice in Normal control group and EA group both had a reduction of PS1 content in hippocampus (P<0.05). Conclusion: EA could have a certain effect to improve the learning andmemorizing abilities of SAMP8mice and, to some extent, may be able to help prevent AD. However, the regulating effect of EA on PS1 level is much greater, this outcome could be seen as one of the mechanisms of treating AD. Contact: Jin Cao, jade cao@yeah.net

Effects of Electro-acupuncture (EA) on the Behavioral changes and presenilian-1 (PS1) level in hippocampus of SAMP8 mice

Purpose: To observe the effects of EA on the expression of PS1protein level inhippocampusof SAMP8mice. Investigating themechanismof EA in therapeutic intervention of Alzheimer Disease (AD). Methods: Ten male SAMR1 mice as the Normal control group. Twenty male SAMP8 mice were randomly divided into Model group and EA group (n=10 in each group). EAwas stimulated at Baihui (GV20) andYintang (GV29) for 20min once a day (2V, 1mA). After 15 days, learning and memorizing abilities of mice were detected through Morris water maze. Observe the morphologic changes of PS1 and related metabolites in hippocampus through immunohistochemistry. Detecting PS1 level in hippocampus through Western blot method. Results: 1) Each group showed a significant difference in latency time in different days. 2) Compared with normal control group, Model group showed an increasing latency time and a decreasing swimming time to passing through the platform and quadrants (P < 0.05, P < 0.01), while EA group showed an obvious decreasing latency time (P<0.05, P < 0.01) and an increasing swimming time (P<0.01). 3) Immunohistochemical detection showedmice in EA group had a significant reduction in the expression of PS1 level in hippocampuswhile compared with theModel group. 4) Findings ofWestern blot revealed that compared with Model group, mice in Normal control group and EA group both had a reduction of PS1 content in hippocampus (P<0.05). Conclusion: EA could have a certain effect to improve the learning andmemorizing abilities of SAMP8mice and, to some extent, may be able to help prevent AD. However, the regulating effect of EA on PS1 level is much greater, this outcome could be seen as one of the mechanisms of treating AD. Contact: Jin Cao, jade cao@yeah.net

Dietary (‐)‐epigallocatechin‐3‐gallate (EGCG) supplementation counteracts metabolic disorders in senescence‐accelerated mouse

Senescence‐accelerated mouse (SAM) prone 8 (SAMP8) displayed aging‐related insulin resistance has been reported; however, peripheral tissues like muscle and liver involved in modulation of glucose and lipid metabolism have not been reported in SAMP8 mice. Epigallocatechin gallate (EGCG) with anti‐diabetes was postulated to delay age‐related insulin resistance. Thus, dietary (3 months) EGCG supplementation (0.32% w:w) on the metabolic defects in skeletal muscle and liver were investigated in SAMP8 (n=15) mice compared to control diet SAMP8 mice (n=15) and SAM resistant 1 (SAMR1, n=8). Higher levels of fasting glucose, insulin and free fatty acid, inhibited Akt activity, and decreased GLUT4 protein expression were observed in SAMP8 mice compared to age‐matched SAMR1 mice. EGCG treatment successfully decreased blood glucose and insulin levels via restoring Akt activity and GLUT4 expression and increasing AMPK activity. Histological examination of the liver revealed hepatocellular ballooning and increasing lipid accumulation in SAMP8 mice. Hepatic triacylglycerol and ALT activities were higher in SAMP8 mice. Decreased ATGL (the gene for triglycerides hydrolysis) and increased SREBP1c and ChREBP1 (genes involved in de novo lipogenesis) in mRNA levels were observed in SAMP8 mice in accordance with hepatic lipid accumulation. Prevented hepatic lipid accumulation was mainly attributed to inhibited SREBP1c gene expression by EGCG. Ultimately, EGCG supplementation is potential to counteract age‐related metabolic disorders.

Regulation of the p19(Arf)/p53 pathway by histone acetylation underlies neural stem cell behavior in senescence-prone SAMP8 mice.

Brain aging is associated with increased neurodegeneration and reduced neurogenesis. B1/neural stem cells (B1-NSCs) of the mouse subependymal zone (SEZ) support the ongoing production of olfactory bulb interneurons, but their neurogenic potential is progressively reduced as mice age. Although age-related changes in B1-NSCs may result from increased expression of tumor suppressor proteins, accumulation of DNA damage, metabolic alterations, and microenvironmental or systemic changes, the ultimate causes remain unclear. Senescence-accelerated-prone mice (SAMP8) relative to senescence-accelerated-resistant mice (SAMR1) exhibit signs of hastened senescence and can be used as a model for the study of aging. We have found that the B1-NSC compartment is transiently expanded in young SAMP8 relative to SAMR1 mice, resulting in disturbed cytoarchitecture of the SEZ, B1-NSC hyperproliferation, and higher yields of primary neurospheres. These unusual features are, however, accompanied by premature loss of B1-NSCs. Moreover, SAMP8 neurospheres lack self-renewal and enter p53-dependent senescence after only two passages. Interestingly, in vitro senescence of SAMP8 cells could be prevented by inhibition of histone acetyltransferases and mimicked in SAMR1 cells by inhibition of histone deacetylases (HDAC). Our data indicate that expression of the tumor suppressor p19, but not of p16, is increased in SAMP8 neurospheres, as well as in SAMR1 neurospheres upon HDAC inhibition, and suggest that the SAMP8 phenotype may, at least in part, be due to changes in chromatin status. Interestingly, acute HDAC inhibition in vivo resulted in changes in the SEZ of SAMR1 mice that resembled those found in young SAMP8 mice.

Downregulation of canonical Wnt signaling in hippocampus of SAMP8 mice

In the adult brain, canonical Wnt (Wnt/β-catenin) signaling modulates neuronal function, hippocampal neurogenesis, and synaptic plasticity. Indeed, growing evidence suggests that downregulation of Wnt signaling could be involved in the cognitive decline associated with aging and also with the physiopathology of Alzheimer's disease (AD). However, the molecular basis remains unknown. At present, SAMP8 is an experimental model that has been proposed for studying age-related neurodegenerative changes associated with aging and the pathogenesis of AD. Here, we examined Wnt signaling in the hippocampus of SAMP8 mice at 9 and 12 months of age, as well as in its control-strain SAMR1 mice. Our results showed increased Dickkopf-1 protein levels in SAMP8 with age, in addition to GSK-3 α/β activation and hyperphosphorylated tau. Consequently, higher β-catenin phosphorylation at Ser33,37 and Thr41, which promotes its degradation, along with a decrease in active β-catenin (ABC) in the nucleus, were observed in SAMP8, mainly at the age of 12 months. Moreover, nuclear levels of Dvl3 were lower in 9- and 12-month-old SAMP8 mice. Related to these findings, SAMP8 showed an increase in neuronal loss in the hippocampus that was associated with lower protein levels of the antiapoptotic protein and the Wnt target gene, Bcl-2, in addition to an increase in the proapototic protein Bax. Our results suggest a relationship between age-related downregulation of canonical Wnt signaling and neuronal loss observed in the hippocampus of SAMP8 mice. Thus, enhancing Wnt signaling may represent a novel neuroprotective strategy aimed at counteracting the cognitive decline that is associated not only with aging but also with AD.

Rcor2 underexpression in senescent mice: a target for inflammaging?

BackgroundAging is characterized by a low-grade systemic inflammation that contributes to the pathogenesis of neurodegenerative disorders such as Alzheimer’s disease (AD). However, little knowledge is currently available on the molecular processes leading to chronic neuroinflammation. In this context, recent studies have described the role of chromatin regulators in inflammation and longevity including the REST corepressor (Rcor)-2 factor, which seems to be involved in an inflammatory suppressive program.MethodsTo assess the impact of Rcor2 in age-related inflammation, gene expression levels were quantified in different tissues and ages of the spontaneous senescence-accelerated P8 mouse (P8) using the SAMR1 mouse (R1) as a control. Specific siRNA transfection in P8 and R1 astrocyte cultures was used to determine Rcor2 involvement in the modulation of neuroinflammation. The effect of lipopolysaccharide (LPS) treatment on Rcor2 levels and neuroinflammation was analyzed both in vivo and in vitro.ResultsP8 mice presented a dramatic decrease in Rcor2 gene expression compared with R1 controls in splenocytes, an alteration also observed in the brain cortex, hippocampus and primary astrocytes of these mice. Rcor2 reduction in astrocytes was accompanied by an increased basal expression of the interleukin (Il)-6 gene. Strikingly, intraperitoneal LPS injection in R1 mice downregulated Rcor2 in the hippocampus, with a concomitant upregulation of tumor necrosis factor (Tnf-α), Il1-β and Il6 genes. A negative correlation between Rcor2 and Il6 gene expression was also verified in LPS-treated C6 glioma cells. Knock down of Rcor2 by siRNA transfection (siRcor2) in R1 astrocytes upregulated Il6 gene expression while siRcor2 further increased Il6 expression in P8 astrocytes. Moreover, LPS activation provoked a further downregulation of Rcor2 and an amplified induction of Il6 in siRcor2-tranfected astrocytes.ConclusionsData presented here show interplay between Rcor2 downregulation and increased inflammation and suggest that Rcor2 may be a key regulator of inflammaging.

Cyanidin-3-O-galactoside and Blueberry Extracts Supplementation Improves Spatial Memory and Regulates Hippocampal ERK Expression in Senescence-accelerated Mice

ObjectiveTo investigate whether the antioxidation and the regulation on the Extracellular Regulated Protein Kinases (ERK) signaling pathway are involved in the protective effects of blueberry on central nervous system. Methods30 Senescence-accelerated mice prone 8 (SAMP8) mice were divided into three groups and treated with normal diet, blueberry extracts (200 mg/kg·bw/day) and cyaniding-3-O-galactoside (Cy-3-GAL) (50 mg/kg·bw/day) from blueberry for 8 weeks. 10 SAMR1 mice were set as control group. The capacity of spatial memory was assessed by Passive avoidance task and Morris water maze. Histological analyses on hippocampus were completed. Malondialdehyde (MDA) levels, Superoxide Dismutase (SOD) activity and the expression of ERK were detected. ResultsBoth Cy-3-GAL and blueberry extracts were shown effective functions to relieve cellular injury, improve hippocampal neurons survival and inhibit the pyramidal cell layer damage. Cy-3-GAL and blueberry extracts also increased SOD activity and reduced MDA content in brain tissues and plasma, and increased hippocampal phosphorylated ERK (p-ERK) expression in SAMP8 mice. Further more, the passive avoidance task test showed that both the latency time and the number of errors were improved by Cy-3-GAL treatment, and the Morris Water Maze test showed significant decreases of latency were detected by Cy-3-GAL and blueberry extracts treatment on day 4. ConclusionBlueberry extracts may reverse the declines of cognitive and behavioral function in the ageing process through several pathways, including enhancing the capacity of antioxidation, altering stress signaling. Cy-3-GAL may be an important active ingredient for these biological effects.

Differences in saccharin preference and genetic alterations of the Tas1r3 gene among senescence-accelerated mouse strains and their parental AKR/J strain

The senescence-accelerated mouse (SAM) is used as an animal model of senescence acceleration and age-associated disorders. SAM is derived from unexpected crosses between the AKR/J and unknown mouse strains. There are nine senescence-prone (SAMP) strains and three senescence-resistant (SAMR) strains. Although SAMP strains exhibit strain-specific and age-related pathological changes, the genes responsible for the pathologic changes in SAMP strains have not been comprehensively identified. In the present study, we evaluated sweet taste perception using the two-bottle test. We compared genotypes of the taste related gene, Tas1r3, using SAM strains and the parental AKR/J strain. The two-bottle test revealed that SAMR1 (R1), SAMP6 (P6), SAMP8 (P8), and SAMP10 (P10) mice were saccharin-preferring strains, whereas AKR/J did not prefer saccharin. All genotypes of the R1, P6, P8, and P10 strains at the polymorphic sites in Tas1r3, which is known to influence saccharin preference, were identical to those of C57BL6/J, a well-known saccharin-preferring strain, and were completely different from those of the parental AKR/J strain. These genetic alterations in SAM strains appear to arise from an unknown strain that is thought to have been crossed with AKR/J initially.

Dihydrotestosterone treatment delays the conversion from mild cognitive impairment to Alzheimer's disease in SAMP8 mice

The senescence-accelerated-prone mouse 8 (SAMP8) has been proposed as a suitable, naturally derived animal model for Alzheimer's disease (AD). In the current study, we focus on the problem whether SAMP8 mice show abnormal behavioral and neuropathological signs before they present the characteristic of AD. Our results demonstrated that given the presence of the senescent, behavioral and neuropathological characteristics, the “middle-aged” SAMP8 mice appear to be a suitable and naturally derived animal model for MCI basic research. There is relatively less evidence that androgen may be involved in the pathogenesis of AD. We determined testosterone (T) levels of SAMR1 and SAMP8 mice and found that the marked age-related decrease in serum androgen levels may be one of the risk factors for Alzheimer's dementia. We also evaluated the interventional effect on MCI phase by dihydrotestosterone (DHT) in male SAMP8 mice and found that timely and appropriate androgen intervention can postpone the onset and improve the symptoms of dementia.

Epigenetic alterations in hippocampus of SAMP8 senescent mice and modulation by voluntary physical exercise

The senescence-accelerated SAMP8 mouse model displays features of cognitive decline and Alzheimer's disease. With the purpose of identifying potential epigenetic markers involved in aging and neurodegeneration, here we analyzed the expression of 84 mature miRNAs, the expression of histone-acetylation regulatory genes and the global histone acetylation in the hippocampus of 8-month-old SAMP8 mice, using SAMR1 mice as control. We also examined the modulation of these parameters by 8 weeks of voluntary exercise. Twenty-one miRNAs were differentially expressed between sedentary SAMP8 and SAMR1 mice and seven miRNAs were responsive to exercise in both strains. SAMP8 mice showed alterations in genes involved in protein acetylation homeostasis such as Sirt1 and Hdac6 and modulation of Hdac3 and Hdac5 gene expression by exercise. Global histone H3 acetylation levels were reduced in SAMP8 compared with SAMR1 mice and reached control levels in response to exercise. In sum, data presented here provide new candidate epigenetic markers for aging and neurodegeneration and suggest that exercise training may prevent or delay some epigenetic alterations associated with accelerated aging.

Increase in tetrahydrobiopterin concentration with aging in the cerebral cortex of the senescence-accelerated mouse prone 10 strain caused by abnormal regulation of tetrahydrobiopterin biosynthesis

6R-L-Erythro-5,6,7,8-tetrahydrobiopterin (BH4) is an essential cofactor for tyrosine hydroxylase (TH) activity and is a risk factor for cognitive decline and brain atrophy. Previous studies have shown that the decline in TH activity in the cerebral cortex of senescence-accelerated mouse prone 10 (SAMP10) mice is caused, at least in part, by a decrease in Fe, ferritin, and TH phosphorylation. We determined the concentrations of BH4 and the enzymes GTP cyclohydrolase-1,6-pyruvoyltetrahydropterin synthase and sepiapterin reductase (SPR) in the de novo pathway of BH4 biosynthesis. Dihydrofolate reductase (DHFR), which converts BH2 to BH4 in the salvage pathway of BH4 synthesis was also determined in the cerebral cortex of SAM mice at 3 and 12months of age. The BH4 concentration was measured by HPLC, and the protein levels of enzymes involved in BH4 synthesis were measured by western blot analysis. At 12months of age, BH4 concentration in the cerebral cortex of SAMP10 mice showed significantly higher values as compared to that of control mice. Further, the protein level of SPR in SAMP10 mice was significantly higher than that in SAMR1 mice at 3 and 12months of age. In contrast to SPR, the protein level of DHFR in SAMP10 mice was significantly lower than that in SAMR1 mice. These results indicate that abnormal regulation of BH4 metabolism occurs in the cerebral cortex of SAMP10 where the dysfunction of the salvage pathway of BH4 synthesis may cause overproduction of BH4 through the de novo pathway, which is considered characteristic in the cerebral cortex of SAMP10 with aging. Therefore, there is a possibility that the excess amounts of BH4 lead to age-related brain dysfunction in the cerebral cortex of SAMP10.

The senescence-accelerated mouse prone-8 (SAM-P8) oxidative stress is associated with upregulation of renal NADPH oxidase system

Herein, we investigate whether the NADPH oxidase might be playing a key role in the degree of oxidative stress in the senescence-accelerated mouse prone-8 (SAM-P8). To this end, the activity and expression of the NADPH oxidase, the ratio of glutathione and glutathione disulfides (GSH/GSSG), and the levels of malonyl dialdehyde (MDA) and nitrotyrosine (NT) were determined in renal tissue from SAM-P8 mice at the age of 1 and 6 months. The senescence-accelerated-resistant mouse (SAM-R1) was used as control. At the age of 1 month, NADPH oxidase activity and Nox2 protein expression were higher in SAM-P8 than in SAM-R1 mice. However, we found no differences in the GSH/GSSG ratio, MDA, NT, and Nox4 levels between both groups of animals. At the age of 6 months, SAM-R1 mice in comparison to SAM-P8 mice showed an increase in NADPH oxidase activity, which is associated with higher levels of NT and increased Nox4 and Nox2 expression levels. Furthermore, we found oxidative stress hallmarks including depletion in GSH/GSSG ratio and increase in MDA levels in the kidney of SAM-P8 mice. Finally, NADPH oxidase activity positively correlated with Nox2 expression in all the animals (r = 0.382, P < 0.05). Taken together, our data allow us to suggest that an increase in NADPH oxidase activity might be an early hallmark to predict future oxidative stress in renal tissue during the aging process that takes place in SAM-P8 mice.

The content of polyamines in the brains of 10-day-old and adult SAMP1/SAMR1 mice, which are characterized by different rates of aging

The contents of polyamines in the brains of SAMP1/SAMR1 mice (senescence accelerated mice prone/resistance) of two different age groups (10-day-old and 8-month-old) were investigated. The SAMP1 mice line is a unique model object with a genetically determined mechanism of aging, which is related to a deficiency of the antioxidant body status. We found that the contents of the studied polyamines (spermine, spermidine, and putrescine) in the brains of adult mice of both strains are much lower than in the brains of 10-day animals, although rapidly aging SAMP1 mice had a significantly higher putrescine and significantly lower spermidine level in comparison with SAMR1 mice. The level of spermine in 10-day-old SAMP1 brains was lower by 57% than in the brains of SAMR1 mice (“control”). Our results confirm that polyamine exchange in the brains of rapidly aging mice is already disturbed at early ontogenesis stages (10 days of life) and it can negatively affect the development of animals.

Assessment of social interaction and anxiety-like behavior in senescence-accelerated-prone and -resistant mice

Two members of the senescence-accelerated mouse group, SAMP8 and SAMP10, are characterized by learning and memory deficits, while the SAMR1 strain is not. In this study, we used two behavioral tests, social approach and object recognition and compared the results observed for the SAMP strains with those seen in the control strain, SAMR1. In social approach experiments, the 2 SAMP strains showed decreased sociability compared to SAMR1 as shown by their reluctance to spend time near a stranger mouse and increased immobility. In object recognition experiments, SAMP strains spent more time in the thigmotaxis zone and less time in the more exposed central zone than SAMR1 mice. From a behavioral standpoint, SAMP mice were less interactive and showed increased anxiety-like behavior compared to SAMR1.

RETRACTED: Beneficial effects of asiaticoside on cognitive deficits in senescence-accelerated mice

The effect of asiaticoside isolated from Hydrocotyle sibthorpioides (AHS) on the promotion of cognition in senescence-accelerated mice (SAMP) was evaluated. Six-month old male SAMP8 mice were orally administered 20, 40 or 80mg/kg AHS daily for three months. SAMR1 mice were used as a “normal aging” control. The results showed that treatment with AHS significantly improved learning and memory abilities in behavioral tests. AHS-treated mice showed higher antioxidant enzyme activity and lower lipid oxidation in serum compared with untreated SAMP8 mice. Mechanistically, studies showed that AHS markedly reduced the content and deposition of β-amyloid peptide (Aβ) by inhibiting the expression of mRNA for amyloid protein precursor, β-site amyloid cleaving enzyme-1 and cathepsin B and promoting the expression of mRNA for neprilysin and insulin degrading enzyme. In addition, AHS significantly increased the expression of plasticity-related proteins including postsynaptic density-95, phosphor-N-methyl-d-aspartate receptor 1, phospho-calcium–calmodulin dependent kinase II, phospho-protein kinase A Catalyticβ subunit, protein kinase Cγ subunit, phospho-CREB and brain derived neurotrophic factor. Furthermore, AHS increased the levels of acetylcholine (Ach), but decreased cholinesterase (AchE) activity. These results demonstrated that AHS administration may prevent spatial learning and memory decline by scavenging free radicals, up-regulating the activity of antioxidant enzymes, decreasing the level of Aβ, ameliorating dysfunction in synaptic plasticity, and reversing abnormal changes in Ach level and AchE activity. Thus, AHS should be developed as a new drug to prevent age-related cognitive deficits.

Depression-like behavior is dependent on age in male SAMP8 mice

Aging is associated with an increased risk of depression in humans. To elucidate the underlying mechanisms of depression and its dependence on aging, here we study signs of depression in male SAMP8 mice. For this purpose, we used the forced swimming test (FST). The total floating time in the FST was greater in SAMP8 than in SAMR1 mice at 9months of age; however, this difference was not observed in 12-month-old mice, when both strains are considered elderly. Of the two strains, only the SAMP8 animals responded to imipramine treatment. We also applied the dexamethasone suppression test (DST) and studied changes in the dopamine and serotonin (5-HT) uptake systems, the 5-HT2a/2c receptor density in the cortex, and levels of TPH2. The DST showed a significant difference between SAMR1 and SAMP8 mice at old age. SAMP8 exhibits an increase in 5-HT transporter density, with slight changes in 5-HT2a/2c receptor density. In conclusion, SAMP8 mice presented depression-like behavior that is dependent on senescence process, because it differs from SAMR1, senescence resistant strain.

Implication of JNK pathway on tau pathology and cognitive decline in a senescence-accelerated mouse model

The senescence accelerated mouse-prone 8 (SAMP8) strain of mice is an experimental model of accelerated senescence that also shares several pathological features with Alzheimer's disease. Among them, cognitive impairments and abnormal hyperphosphorylation of tau are ameliorated by the phosphodiesterase 5 inhibitor sildenafil, possibly through the modulation of Cdk5/p25 and Akt/GSK-3β pathways. Here we studied the implication of protein phosphatase 2A (PP2A) and c-Jun N-terminal kinase (JNK) in the therapeutic effects of sildenafil. Results demonstrated that there were no differences in hippocampal PP2A protein levels or activity (measured by its inactive isoform phopho-PP2A Y307) when we compared 6-month old SAMP8 mice and age-matched control, SAMR1 mice, treated with saline or sildenafil (7.5mg/kg i.p. for 4weeks). However, this same treatment of sildenafil, that had been shown to reverse the cognitive impairment and tau hyperphosphorylation in this animal model, also reversed the increased levels of activated JNK (p-JNK) found in the hippocampus of SAMP8 mice. Moreover, the administration of the JNK inhibitor, D-JNKI-1 (0.2mg/kg i.p. for 3weeks) also ameliorated the cognitive deficits shown by SAMP8 mice in the Morris water maze and decreased hippocampal levels of phospho-c-Jun(Ser73). When phosphorylated tau (AT8 epitope) was analyzed a significant reduction was observed in the hippocampus of D-JNKI-1 treated SAMP8 mice, providing a plausible explanation for the attenuation of cognitive decline shown by these animals. These findings suggest the involvement of the JNK pathway on tau pathology and cognitive deficits shown by 6-month old SAMP8 mice. They also point to the modulation of this kinase to be among the mechanisms responsible for the beneficial effects shown by sildenafil.

Rhein lysinate increases the median survival time of SAMP10 mice: protective role in the kidney

To investigate the protective effects of rhein lysinate (RHL), a major bioactive constituent of the rhizome of rhubarb (Rheum palmatum Linn or Rheum tanguticum Maxim), against kidney impairment in senescence-prone inbred strain 10 (SAMP10) mice. SAMP10 mice were orally administered RHL (25 or 50 mg/kg) daily until 50% of the mice died. Senescence-resistant inbred strain 1 (SAMR1) mice administered no drug were taken as control. The kidneys were harvested after animal death, and examined morphologically and with immunochemical assays. The levels of MAD, SOD and GSH-px in the kidneys were measured with a photometric method. The expression of inflammatory factors and related proteins in the kidneys was analyzed using Western blotting. Treatment of SAMP10 mice with RHL had no effect on the body weight or phenotype. However, RHL significantly prolonged the median survival time of SAMP10 mice by approximately 25%, as compared to untreated SAMP10 mice. Compared SAMR1 mice, SAMP10 mice had a significantly lower level of SOD in the kidneys, but had no significant difference in the MDA or GSH-px levels. Treatment of SAMP10 mice with RHL significantly reduced the MAD level, and increased the SOD and GSH-px levels in the kidneys. Glomerulonephritis was observed in SAMP10 mice but not in SAMR1 mice. RHL decreased the incidence of glomerulonephritis, and significantly decreased the levels of TNF-α, IL-6, NF-κB, collagen types I and III in the kidneys. Accelerated senescence is associated with glomerulonephritis in SAMP10 mice, and RHL prolongs their median survival time by reducing the severity of glomerulonephritis.

Neurobiological and pharmacological validity of curcumin in ameliorating memory performance of senescence-accelerated mice

The senescence-accelerated mouse prone 8 (SAMP8 mice) is known as a neurodegenerative model and may show age-related deficits of cognition. Curcumin, a major active component of spic turmeric, could increase the capacity of learning and memory in the aged rat. However, it is not known whether curcumin could improve cognitive deficits in SAMP8 mice. The present study was undertaken to evaluate the effect of curcumin on the learning and memory of SAMP8 mice and its possible mechanisms. Subjects were randomly divided into four groups: SAMR1 mice, SAMP8 mice and two SAMP8 mice groups treated, intragastrically, with curcumin at the dose of 20 and 50mg/kg per day, respectively. After 25days, spatial memory, superoxide dismutase (SOD) activity, malondialdehyde (MDA) content, p-calcium/calmodulin-dependent kinase II (p-CaMKII) and p-N-methyl-d-aspartate receptor subunit 1 (p-NMDAR1) expression in the hippocampus of mice were examined by using the Morris water maze, biochemical analysis, immunohistochemistry and Western blot. Compared with SAMR1 mice, SAMP8 mice had longer escape latency, higher MDA content, lower SOD activity in the hippocampus, and lower intensity of p-CaMKII in the stratum lucidum of hippocampal CA3 and p-NMDAR1 expression in the hippocampal membrane fraction. Both 20 and 50mg/kg curcumin administration significantly shortened the escape latencies and decreased the hippocampal MDA content in the SAMP8 mice. 50mg/kg curcumin administration significantly ameliorated the hippocampal SOD activity, and increased the intensity of p-CaMKII in the stratum lucidum of hippocampal CA3 and p-NMDAR1 expression in the hippocampal membrane fraction of the SAMP8 mice. The present study demonstrated that curcumin treatment could attenuate cognitive deficits of SAMP8 mice in a dose-dependent manner by decreasing the oxidative stress and improving the expression of p-CaMKII and p-NMDAR1 in the hippocampus. Thus treatment with curcumin may have a potential therapeutic agent for aging-related cognitive dysfunctions.