Senescence-accelerated Mouse Prone 8 Research Articles

Analysis of the Effects of Ninjin'yoeito on Physical Frailty in Mice.

Physical frailty is an aging-related clinical syndrome involving decreases in body weight, mobility, activity, and walking speed that occurs in individuals with sarcopenia and is accelerated by increased oxidative stress. Ninjin’yoeito, a traditional Japanese Kampo medicine, is used for treating conditions, including anemia and physical weakness. Here, we investigated whether ninjin’yoeito could improve physical frailty by controlling oxidative stress in the senescence-accelerated mouse prone 8 (SAMP8) model. First, SAMP8 mice were divided into two groups, ninjin’yoeito treated and untreated, with the former consuming a diet containing 3% ninjin’yoeito from 3 months of age. At 7 months of age, body weight, motor function, locomotor activity, and mean walking speed were measured. Subsequently, mice were euthanized and measured for muscle weight, 8-hydroxy-2′-deoxyguanosine levels in muscle and brain, and cleaved caspase-3 expression in brain. The results showed reductions in weight, locomotor function, locomotion, and average walking speed in the untreated group, which were significantly improved by ninjin’yoeito. Furthermore, 8-hydroxy-2′-deoxyguanosine levels were reduced in muscle and brain from ninjin’yoeito-treated mice, compared with the levels in untreated mice; cleaved caspase-3 expression was similarly reduced in brain from the treated mice, indicating reduced apoptosis. Our findings suggest that ninjin’yoeito inhibits sarcopenia-based physical frailty through its antioxidant effects.

Age-related metabolic and neurodegenerative changes in SAMP8 mice.

The most important risk factor for the development of sporadic Alzheimer’s disease (AD) is ageing. Senescence accelerated mouse prone 8 (SAMP8) is a model of sporadic AD, with senescence accelerated resistant mouse (SAMR1) as a control. In this study, we aimed to determine the onset of senescence-induced neurodegeneration and the related potential therapeutic window using behavioral experiments, immunohistochemistry and western blotting in SAMP8 and SAMR1 mice at 3, 6 and 9 months of age. The Y-maze revealed significantly impaired working spatial memory of SAMP8 mice from the 6th month. With ageing, increasing plasma concentrations of proinflammatory cytokines in SAMP8 mice were detected as well as significantly increased astrocytosis in the cortex and microgliosis in the brainstem. Moreover, from the 3rd month, SAMP8 mice displayed a decreased number of neurons and neurogenesis in the hippocampus. From the 6th month, increased pathological phosphorylation of tau protein at Thr231 and Ser214 was observed in the hippocampi of SAMP8 mice. In conclusion, changes specific for neurodegenerative processes were observed between the 3rd and 6th month of age in SAMP8 mice; thus, potential neuroprotective interventions could be applied between these ages.

Effects of Electroacupuncture on the Correlation between Serum and Central Immunity in AD Model Animals.

Objective The goal was to investigate the connection between neuroinflammation in the brain and serum inflammatory markers as Alzheimer's disease progressed. We also sought to determine whether electroacupuncture had an effect on inflammatory markers found in blood and other brain regions. Methods As an animal model for AD, we used senescence-accelerated mouse prone 8 (SAMP8) mice. To examine the effects and probable mechanism of electroacupuncture, we used HE staining, immunofluorescence staining, western blotting, and enzyme-linked immunosorbent assay. Results Electroacupuncture therapy protected neurons, significantly downregulated the Iba-1 level in the hippocampus (p value was 0.003), frontal lobe cortex (p value was 0.042), and temporal lobe cortex (p value was 0.013) of the AD animal model, all of which had significantly lower levels of IL-6 (p value was 0.001), IL-1β (p value was 0.001), and TNF-α (p value was 0.001) in their serum. Conclusion The amounts of IL-6, IL-1β, and TNF-α detected in the serum were strongly linked to the levels discovered in the hippocampus and the frontal lobes of the brain, respectively. A better understanding of the electroacupuncture process as well as the course of Alzheimer's disease and the therapeutic benefits of electroacupuncture may be gained by using biomarkers such as serum inflammatory marker biomarkers.

Potential antidepressant effects of a dietary supplement from the chlorella and lion's mane mushroom complex in aged SAMP8 mice.

Since the 1990s, the prevalence of mental illnesses, such as depression, has been increasing annually and has become a major burden on society. Due to the many side effects of antidepressant drugs, the development of a complementary therapy from natural materials is an urgent need. Therefore, this study used a complex extract of chlorella and lion's mane mushroom and evaluated its antidepressant effects. Six-month-old male senescence-accelerated mice prone-8 (SAMP8) were divided into positive control; negative control; and low, medium, and high-dose groups. All groups were treated with corticosterone (CORT) at 40 mg/Kg/day for 21- days to induce depression in the animals, and the effects of different test substances on animal behavior was observed. The positive control group was intraperitoneally injected with a tricyclic antidepressant (Fluoxetine, as tricyclic antidepressant), the control group was given ddH2O, and the test substance groups were administered test samples once daily for 21 days. The open field test (OFT) and forced swimming test (FST) were applied for behavior analyses of depression animal models. The OFT results showed that the mice in the positive control and the medium-, and high-dose groups demonstrated a significantly prolonged duration in the central area and a significantly increased travel distance. In the FST, the positive control and the medium, and high-dose groups displayed significantly reduced immobility times relative to the control group. The blood analysis results showed significant decreases in triglyceride and blood urea nitrogen levels relative to the positive control and the medium- and high-dose groups. Notably, in the positive control and the medium- and high-dose groups, brain-derived neurotrophic factor (BDNF) increase by more than in the control group. In summary, medium and high dose of extract of chlorella and lion's mane mushroom could improve depression behavior in animals and have the potential to be antidepressant health care products.

Cognitive Decline and BPSD Are Concomitant with Autophagic and Synaptic Deficits Associated with G9a Alterations in Aged SAMP8 Mice.

Behavioural and psychological symptoms of dementia (BPSD) are presented in 95% of Alzheimer’s Disease (AD) patients and are also associated with neurotrophin deficits. The molecular mechanisms leading to age-related diseases are still unclear; however, emerging evidence has suggested that epigenetic modulation is a key pathophysiological basis of ageing and neurodegeneration. In particular, it has been suggested that G9a methyltransferase and its repressive histone mark (H3K9me2) are important in shaping learning and memory by modulating autophagic activity and synaptic plasticity. This work deepens our understanding of the epigenetic mechanisms underlying the loss of cognitive function and BPSD in AD. For this purpose, several tasks were performed to evaluate the parameters of sociability (three-chamber test), aggressiveness (resident intruder), anxiety (elevated plus maze and open field) and memory (novel object recognition test) in mice, followed by the evaluation of epigenetic, autophagy and synaptic plasticity markers at the molecular level. The behavioural alterations presented by senescence-accelerated mice prone 8 (SAMP8) of 12 months of age compared with their senescence-accelerated mouse resistant mice (SAMR1), the healthy control strain was accompanied by age-related cognitive deficits and alterations in epigenetic markers. Increased levels of G9a are concomitant to the dysregulation of the JNK pathway in aged SAMP8, driving a failure in autophagosome formation. Furthermore, lower expression of the genes involved in the memory-consolidation process modulated by ERK was observed in the aged male SAMP8 model, suggesting the implication of G9a. In any case, two of the most important neurotrophins, namely brain-derived neurotrophic factor (Bdnf) and neurotrophin-3 (NT3), were found to be reduced, along with a decrease in the levels of dendritic branching and spine density presented by SAMP8 mice. Thus, the present study characterizes and provides information regarding the non-cognitive and cognitive states, as well as molecular alterations, in aged SAMP8, demonstrating the AD-like symptoms presented by this model. In any case, our results indicate that higher levels of G9a are associated with autophagic deficits and alterations in synaptic plasticity, which could further explain the BPSD and cognitive decline exhibited by the model.

Optimized N-methyl-D-aspartate receptor antagonist exhibits hippocampal proneurogenic effects in aged senescence-accelerated mouse prone 8 mice.

N-methyl-D-aspartate (NMDA) receptor antagonists mediate adult neurogenic effects. Here, the neurogenic effect of a new NMDA receptor antagonist endowed with neuroprotective effects in Alzheimer's disease mice model. Nine-month-old senescence-accelerated mouse prone 8 (SAMP8) with UB-ALT-EV were orally treated. 5-Bromo-2-deoxyuridine (BrdU) (50 mg/kg) was 3× injected I.P. every 2 h. After 28 days of treatment, SAMP8-treated group improved working memory. Moreover, the number of BrdU+ cells and DCX+ cells in the SAMP8 dentate gyrus (DG) was significantly increased. GFAP+ cells were not affected by treatment. Together, these results provided evidence that UB-ALT-EV promotes the survival and proliferation of neural progenitor cells in the aged SAMP8 hippocampus.

Astragalin alleviates cognitive deficits and neuronal damage in SAMP8 mice through upregulating estrogen receptor expression.

Senile plaques composed of β-amyloid protein (Aβ) and neurofibrillary tangles (NFTs) composed of intracellular hyper-phosphorylated tau are major causes of cognitive impairment and neuronal damage in Alzheimer disease (AD). Astragalin (AST), a naturally-occurring flavonoid compound, was reported to have neuroprotective effects in the brain, but its effects in AD remain unknown. Herein, the learning and memory deficits were alleviated and neuronal damage in the hippocampus were inhibited after the senescence-accelerated mouse prone 8 (SAMP8) mouse were given AST (5mg/kg or 10mg/kg) daily by gavage for 2 months. Furthermore, AST reduced Aβ1-40 and Aβ1-42 deposition, decreased β-carboxyl-terminal fragment (β-CTF) protein level and tau hyper-phosphorylation, but increased α-CTF protein level and glycogen synthase kinase-3beta (GSK-3β) phosphorylation in hippocampus of SAMP8 mice. Meanwhile, the effects of AST on AD were also explored in vitro by treating primary neurons with amyloid-β1-42 oligomers (Aβ1-42O). Consistently, AST also alleviated amyloid-β1-42 oligomers (Aβ1-42O)-induced neuronal damage, amyloid plaques, and tau phosphorylation in vitro model. Of note, estrogen receptor (ER)α and ERβ expression in the hippocampus of SAMP8 mice and Aβ1-42O-treated neurons was significantly decreased but their levels were increased by AST. Moreover, in vivo and in vitro experiments revealed that ER antagonist, Fulvestrant, reversed the effects caused by AST. Altogether, our investigation indicates that AST may ameliorate cognitive deficits and AD-type pathologies in SAMP8 mice and Aβ1-42O-treated neurons through upregulating ERα and ERβ expression. Our findings indicate the value of AST as a potential reagent for AD treatment.

Sulforaphane Increase Mitochondrial Biogenesis-Related Gene Expression in the Hippocampus and Suppresses Age-Related Cognitive Decline in Mice.

Sulforaphane (SFN) is a potent activator of the transcriptional factor, Nuclear Factor Erythroid 2 (NF-E2)-Related factor 2 (NRF2). SFN and its precursor, glucoraphanin (sulforaphane glucosinolate, SGS), have been shown to ameliorate cognitive function in clinical trials and in vivo studies. However, the effects of SGS on age-related cognitive decline in Senescence-Accelerated Mouse Prone 8 (SAMP8) is unknown. In this study, we determined the preventive potential of SGS on age-related cognitive decline. One-month old SAMP8 mice or control SAM resistance 1 (SAMR1) mice were fed an ad libitum diet with or without SGS-containing broccoli sprout powder (0.3% w/w SGS in diet) until 13 months of age. SGS significantly improved long-term memory in SAMP8 at 12 months of age. Interestingly, SGS increased hippocampal mRNA and protein levels of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC1α) and mitochondrial transcription factor A (TFAM), which are master regulators of mitochondrial biogenesis, both in SAMR1 and SAMP8 at 13 months of age. Furthermore, mRNAs for nuclear respiratory factor-1 (NRF-1) and mitochondrial DNA-encoded respiratory complex enzymes, but not mitochondrial DNA itself, were increased by SGS in SAMP8 mice. These results suggest that SGS prevents age-related cognitive decline by maintaining mitochondrial function in senescence-accelerated mice.

A Combined Chronic Low-Dose Soluble Epoxide Hydrolase and Acetylcholinesterase Pharmacological Inhibition Promotes Memory Reinstatement in Alzheimer’s Disease Mice Models

Alzheimer’s disease (AD) is a progressive neurological disorder with multifactorial and heterogeneous causes. AD involves several etiopathogenic mechanisms such as aberrant protein accumulation, neurotransmitter deficits, synaptic dysfunction and neuroinflammation, which lead to cognitive decline. Unfortunately, the currently available anti-AD drugs only alleviate the symptoms temporarily and provide a limited therapeutic effect. Thus, new therapeutic strategies, including multitarget approaches, are urgently needed. It has been demonstrated that a co-treatment of acetylcholinesterase (AChE) inhibitor with other neuroprotective agents has beneficial effects on cognition. Here, we have assessed the neuroprotective effects of chronic dual treatment with a soluble epoxide hydrolase (sEH) inhibitor (TPPU) and an AChE inhibitor (6-chlorotacrine or rivastigmine) in in vivo studies. Interestingly, we have found beneficial effects after chronic low-dose co-treatment with TPPU and 6-chlorotacrine in the senescence-accelerated mouse prone 8 (SAMP8) mouse model as well as with TPPU and rivastigmine co-treatment in the 5XFAD mouse model, in comparison with the corresponding monotherapy treatments. In the SAMP8 model, no substantial improvements in synaptic plasticity markers were found, but the co-treatment of TPPU and 6-chlorotacrine led to a significantly reduced gene expression of neuroinflammatory markers, such as interleukin 6 (Il-6), triggering receptor expressed on myeloid cell 2 (Trem2) and glial fibrillary acidic protein (Gfap). In 5XFAD mice, chronic low-dose co-treatment of TPPU and rivastigmine led to enhanced protein levels of synaptic plasticity markers, such as the phospho-cAMP response element-binding protein (p-CREB) ratio, brain-derived neurotrophic factor (BDNF) and postsynaptic density protein 95 (PSD95), and also to a reduction in neuroinflammatory gene expression. Collectively, these results support the neuroprotectant role of chronic low-dose co-treatment strategy with sEH and AChE inhibitors in AD mouse models, opening new avenues for effective AD treatment.

The role of substance P on maintaining ligament homeostasis by inhibiting endochondral ossification during osteoarthritis progression

ABSTRACT Purpose Osteoarthritis (OA) is characterized by the degeneration of various tissues, including ligaments. However, pathological changes such as chondrogenesis and ossification in ligaments during OA are still unclear. Substance P (SP), a neuropeptide, has various functions including bone metabolism. This study aimed to analyze the expression and function of SP in OA ligaments, and the therapeutic potential of SP agonists in OA mice. Materials and methods Expressions of SP, SOX9, and MMP13 were histologically analyzed in the posterior cruciate ligament (PCL) in humans with OA and Senescence-accelerated mouse-prone 8 (SAMP8) mice as a spontaneous OA model. The effect of SP agonists on chondrogenesis was evaluated using human ligament cells. Finally, SP agonists were administered intraperitoneally to destabilized medial meniscus (DMM) mice, and the PCL was histologically evaluated. Results In PCL of humans and mice, the expression of SP, SOX9, and MMP13 was upregulated as OA progressed, but their expression was downregulated in severe degeneration. SP and SOX9 were co-expressed in chondrocyte-like cells. In ligament cells, SP agonists downregulated SOX9, RUNX2, and COL10A1. On evaluating chondrogenesis in ligament cells, pellet diameter was reduced in those treated with the SP agonists compared to those untreated. Administration of SP agonists ameliorated PCL degeneration in DMM mice. The Osteoarthritis Research Society and ligament scores in mice with SP agonists were significantly lower than those without SP agonists. Conclusions SP plays an important role in maintaining ligament homeostasis by inhibiting endochondral ossification during OA progression. Targeting SP has therapeutic potential for preventing ligament degeneration.

The Establishment of a Mouse Model for Degenerative Kyphoscoliosis Based on Senescence-Accelerated Mouse Prone 8.

Objective Degenerative kyphoscoliosis (DKS) is a complex spinal deformity associated with degeneration of bones, muscles, discs, and facet joints. The aim of this study was to establish an animal model of degenerative scoliosis that recapitulates key pathological features of DKS and to validate the degenerative changes in senescence-accelerated mouse prone 8 (SAMP8) mice. Methods Thirty male mice were divided into 2 groups: 10 bipedal C57BL/6J mice were used as the control group, and 20 bipedal SAMP8 mice were used as the experimental group. Mice were bipedalized under general anesthesia. The incidence of scoliosis and bone quality was determined using radiographs and in vivo micro-CT images 4, 8, and 12 weeks after surgery, respectively. Histomorphological studies of muscle samples were performed after sacrifice at 12 weeks after surgery. Results On the 12th week, the incidence rates of kyphosis in C57BL/6J and SAMP8 groups were 50% and 100%, respectively. Overall, the incidence and angle of kyphosis were significantly higher in the bipedal SAMP8 group compared to the C57BL/6J group (44.7°± 6.2° vs. 84.3°± 10.3°, P<0.001). Based on 3D reconstruction of the entire spine, degeneration of the intervertebral disc was observed in bipedal SAMP8 mice, including the reduction of disc height and the formation of vertebral osteophytes. The bone volume ratio (BV/TV) was significantly suppressed in the bipedal SAMP8 group compared with the bipedal C57BL/6J group. In addition, HE staining and Mason staining of the paraspinal muscle tissue showed chronic inflammation and fibrosis in the muscles of the bipedal SAMP8 group. Conclusions The SAMP8 mouse model can be taken as a clinically relevant model of DKS, and accelerated aging of the musculoskeletal system promotes the development of kyphosis.

Social isolation reinforces aging-related behavioral inflexibility by promoting neuronal necroptosis in basolateral amygdala.

Aging is characterized with a progressive decline in many cognitive functions, including behavioral flexibility, an important ability to respond appropriately to changing environmental contingencies. However, the underlying mechanisms of impaired behavioral flexibility in aging are not clear. In this study, we reported that necroptosis-induced reduction of neuronal activity in the basolateral amygdala (BLA) plays an important role in behavioral inflexibility in 5-month-old mice of the senescence-accelerated mice prone-8 (SAMP8) line, a well-established model with age-related phenotypes. Application of Nec-1s, a specific inhibitor of necroptosis, reversed the impairment of behavioral flexibility in SAMP8 mice. We further observed that the loss of glycogen synthase kinase 3α (GSK-3α) was strongly correlated with necroptosis in the BLA of aged mice and the amygdala of aged cynomolgus monkeys (Macaca fascicularis). Moreover, genetic deletion or knockdown of GSK-3α led to the activation of necroptosis and impaired behavioral flexibility in wild-type mice, while the restoration of GSK-3α expression in the BLA arrested necroptosis and behavioral inflexibility in aged mice. We further observed that GSK-3α loss resulted in the activation of mTORC1 signaling to promote RIPK3-dependent necroptosis. Importantly, we discovered that social isolation, a prevalent phenomenon in aged people, facilitated necroptosis and behavioral inflexibility in 4-month-old SAMP8 mice. Overall, our study not only revealed the molecular mechanisms of the dysfunction of behavioral flexibility in aged people but also identified a critical lifestyle risk factor and a possible intervention strategy.

Exogenous Nucleotides Improved the Oxidative Stress and Sirt-1 Protein Level of Brown Adipose Tissue on Senescence-Accelerated Mouse Prone-8 (SAMP8) Mice.

Brown adipose tissue (BAT) is of great importance in rodents for maintaining their core temperature via non-shivering thermogenesis in the mitochondria. BAT′s thermogenic function has been shown to decline with age. The activation of adenosine 5′-monophosphate (AMP)-activated protein kinase/sirtuin-1 (AMPK/Sirt-1) is effective in regulating mitochondrial function. Exogenous nucleotides (NTs) are regulatory factors in many biological processes. Nicotinamide mononucleotide (NMN), which is a derivative of NTs, is widely known as a Sirt-1 activator in liver and muscle, but the effect of NMN and NTs on aging BAT has not been studied before. The purpose of this study was to investigate the effect of NTs on aging senescence-accelerated mouse prone-8 (SAMP8) mice. Senescence-accelerated mouse resistant 1 (SAMR1) mice were set as the model control group and NMN was used as the positive control. Male, 3 month old SAMP8 mice were divided into the SAMP8-normal chow (SAMP8-NC), SAMP8-young-normal chow (SAMP8-young-NC), NMN, NTs-free, NTs-low, NTs-medium, and NTs-high groups for long-term feeding. After 9 months of intervention, interscapular BAT was collected for experiments. Compared to the SAMP8-NC, the body weight and BAT mass were significantly improved in the NT-treated aging SAMP8 mice. NT supplementation had effects on oxidative stress in BAT. The concentration of malondialdehyde (MDA) was reduced and that of superoxide dismutase (SOD) increased significantly. Meanwhile, the expression of the brown adipocyte markers uncoupling protein-1 (UCP-1), peroxisome proliferator-activated receptor-γ coactlvator-1α (PGC-1α), and PR domain zinc finger protein 16 (PRDM16) were upregulated. The upregulated proteins may be activated via the Sirt-1 pathway. Thus, NT supplementation may be helpful to improve the thermogenesis of BAT by reducing oxidative stress and activating the Sirt-1 pathway.

Anthocyanin-rich blackcurrant extract improves long-term memory impairment and emotional abnormality in senescence-accelerated mice.

Alzheimer's disease (AD) is associated with a progressive worsening in cognitive function, which is often accompanied by emotional disturbance. Recent studies revealed that anthocyanin-rich blackcurrant extract (BCE) can impart health benefits, but it is not known whether BCE is useful in the prevention and/or treatment of AD. Here, we examined the effects of BCE using a senescence-accelerated mouse prone 8 (SAMP8) model. Dietary BCE supplementation for 9 weeks was found to both improve the diminished long-term recognition memory and normalize the anxiety levels of SAMP8 mice. RNA sequencing demonstrated that dietary supplementation with anthocyanin-rich BCE significantly altered the gene expression profile in the hippocampus. According to enrichment analysis, genes regulated by BCE were related to cellular component terms such as "smooth endoplasmic reticulum," "axon," and "glutamatergic synapse." Real-time PCR verified alterations in the expression of AD-related genes. These findings indicate that anthocyanin-rich BCE may be valuable for the prevention and/or treatment of AD. PRACTICAL APPLICATIONS: Blackcurrant contains an abundance of polyphenols, especially anthocyanins. This study demonstrated that anthocyanin-rich BCE improves the long-term recognition memory impairment and emotional abnormality of SAMP8 mice, a mouse model characterized by several pathological features of AD. These findings indicate that anthocyanin-rich BCE may be a useful food supplement or ingredient for the prevention of AD.

A potassium channel agonist protects hearing function and promotes outer hair cell survival in a mouse model for age-related hearing loss

Age-related hearing loss (ARHL) is the most common sensory impairment mainly caused by degeneration of sensory hair cells in the cochlea with no causal medical treatment available. Auditory function and sensory hair cell survival critically depend on the Kv7.4 (KCNQ4) channel, a voltage-gated potassium channel expressed in outer hair cells (OHCs), with its impaired function or reduced activity previously associated with ARHL. Here, we investigated the effect of a potent small-molecule Kv7.4 agonist on ARHL in the senescence-accelerated mouse prone 8 (SAMP8) model. For the first time in vivo, we show that Kv7.4 activation can significantly reduce age-related threshold shifts of auditory brainstem responses as well as OHC loss in the SAMP8 model. Pharmacological activation of Kv7.4 thus holds great potential as a therapeutic approach for ARHL as well as other hearing impairments related to Kv7.4 function.

Buckwheat Flour and Its Starch Prevent Age-Related Cognitive Decline by Increasing Hippocampal BDNF Production in Senescence-Accelerated Mouse Prone 8 Mice.

Buckwheat is an important pseudo-cereal crop worldwide. This study investigated whether long-term administration of buckwheat can suppress age-related cognitive decline in senescence-accelerated mouse prone 8 (SAMP8) mice. For 26 weeks, 18-week-old male SAMP8 mice were fed a standard diet containing 5% (w/w) buckwheat, Tartary buckwheat, wheat, or rice flour. In the Barnes maze and passive avoidance tests, mice fed buckwheat whole flour (BWF) showed improved cognitive performance compared to those fed a control diet, while no improvement was noticed in case of the other diets. Analysis of the gut microbiota showed that BWF and buckwheat outer flour administration increased the abundance of Lactococcus and Ruminiclostridium, respectively, at the genus level. The expression levels of brain-derived neurotrophic factor (BDNF), postsynaptic Arc and PSD95, and the mature neuronal marker NeuN in the hippocampus were increased after BWF administration, which was induced by the activation of the ERK/CREB signaling pathway and histone H3 acetylation. A similar increase in cognitive performance-related hippocampal BDNF expression in SAMP8 mice was observed after the oral administration of starch prepared from BWF. Therefore, the long-term administration of BWF suppresses cognitive decline by increasing hippocampal BDNF production in SAMP8 mice.

Impacts of psychological stress on high dose-rate radiation acute effects in a mouse experimental model

Psychological stress affects health. Radiation workers in the medical field or astronauts living in space have possible risks of exposure to radiation, and psychological stress is considered to be easily induced in them due to activities performed in small areas or stress conditions. The impact of psychological stress on the effects of radiation was evaluated in senescence-accelerated mouse prone 10 (SAMP10) mice and ddY mice using a confrontational housing model, which makes dominant and subordinate mice in a cage live together without severe quarrel. Mice of ddY and SAMP10 have been previously demonstrated to be influenced in terms of acute and late effects, respectively, under psychological stress by this model. In SAMP10 mice, irradiation with 4 Gy induced the death of irradiated mice under psychological stress. In ddY mice, irradiation with 5 Gy X-rays alone had almost no effect on the mouse survival, but irradiation in conditions of psychological stress promoted acute death of irradiated mice. In addition, hypocellular bone marrow was also observed histopathologically in irradiated ddY mice under stress. Psychological stress may promote damage caused by radiation through modulation of radio-sensitivity in bone marrow in mice. This model would be useful for evaluation of modulation of radiation-induced various effects by psychological stress.

Human umbilical cord-derived mesenchymal stromal cells ameliorate aging-associated skeletal muscle atrophy and dysfunction by modulating apoptosis and mitochondrial damage in SAMP10 mice

BackgroundSkeletal muscle mass and function losses in aging individuals are associated with quality of life deterioration and disability. Mesenchymal stromal cells exert immunomodulatory and anti-inflammatory effects and could yield beneficial effects in aging-related degenerative disease.Methods and resultsWe investigated the efficacy of umbilical cord-derived mesenchymal stromal cells (UC-MSCs) on sarcopenia-related skeletal muscle atrophy and dysfunction in senescence-accelerated mouse prone 10 (SAMP10) mice. We randomly assigned 24-week-old male SAMP10 mice to a UC-MSC treatment group and control group. At 12 weeks post-injection, the UC-MSC treatment had ameliorated sarcopenia-related muscle changes in performance, morphological structures, and mitochondria biogenesis, and it enhanced the amounts of proteins or mRNAs for myosin heavy chain, phospho-AMP-activated protein kinase, phospho-mammalian target of rapamycin, phospho-extracellular signal-regulated kinase1/2, peroxisome proliferator-activated receptor-γ coactivator, GLUT-4, COX-IV, and hepatocyte growth factor in both gastrocnemius and soleus muscles, and it reduced the levels of proteins or mRNAs for cathepsin K, cleaved caspase-3/-8, tumor necrosis factor-α, monocyte chemoattractant protein-1, and gp91phox mRNAs. The UC-MSC treatment retarded mitochondria damage, cell apoptosis, and macrophage infiltrations, and it enhanced desmin/laminin expression and proliferating and CD34+/Integrin α7+ cells in both types of skeletal muscle of the SAMP10 mice. In vitro, we observed increased levels of HGF, PAX-7, and MoyD mRNAs at the 4th passage of UC-MSCs.ConclusionsOur results suggest that UC-MSCs can improve sarcopenia-related skeletal muscle atrophy and dysfunction via anti-apoptosis, anti-inflammatory, and mitochondrial biogenesis mechanisms that might be mediated by an AMPK-PGC1-α axis, indicating that UC-MSCs may provide a promising treatment for sarcopenia/muscle diseases.

Candesartan Effectively Preserves Cognition in Senescence Accelerated Mouse Prone 8 (SAMP8) mice.

Background:Alzheimer’s disease (AD) has become a worldwide crisis with no effective therapeutic options. The medications currently available for AD are only palliative; their effect is temporary, and they are associated with unfavorable side effects. Even the newest medication aducanumab, granted accelerated FDA approval in 2021, failed to show cognitive benefits in clinical trials and continued approval requires verification in subsequent clinical trials. There is an urgent need for safe and effective therapies to preserve cognition and effectively manage AD. Generally, a new drug product takes several years for FDA approval and exceeds 2.5 billion dollars in research and development, with most new drug products never even reaching the market. This has led to a recent shift for repurposing/repositioning existing FDA-approved medications, to new therapeutic indications.Objective:To investigate the effects of long-term treatment with candesartan, an FDA-approved angiotensin-II type-1 receptor blocker (ARB), on the development of cognitive impairment associated with premature aging.Methods:Candesartan was given at a dose of 1 mg/kg/d in an AD model of senescence-accelerated mouse prone-8 (SAMP8) and senescence-accelerated mouse resistant (SAMR1) mice. Oral treatment with candesartan or vehicle was started, in 2-month-old mice and administered continuously for 4-months.Results:Low-dose candesartan prevented the development of cognitive impairment, otherwise associated with accelerated aging, in SAMP8 mice, by reducing inflammation and nitro-oxidative stress. Candesartan did not affect the cognitive function of control SAMR1 mice.Conclusion:Early ARB treatment might be beneficial in preventing age-related cognitive deficits in AD-prone individuals.

Myricetin improves cognitive function in SAMP8 mice and upregulates brain-derived neurotrophic factor and nerve growth factor

IntroductionConsidering that neurodegeneration is an irreversible process, an efficient, low-burden approach to prevent dementia is strongly needed. Here, we show that the daily intake of myricetin normalised cognitive dysfunction in senescence-accelerated mouse prone 8 (SAMP8) mice. MethodsSAMP8 mice were fed a diet supplemented with myricetin and novel object recognition tests and Y-maze tests were performed. Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in brains of SAMP8 mice were measured. The phosphorylation level of cAMP-response-element-binding protein (CREB) level in brains of SAMP8 mice were evaluated. Also, SH-SY5Y cells were treated with myricetin and cAMP levels were measured. ResultsIn SAMP8 mice, neurotrophins, including BDNF and NGF, were downregulated relative to levels in their normal counterparts. In addition, myricetin intake upregulated the phosphorylation of CREB, the major transcription factor for BDNF and NGF. Also, myricetin induced cAMP upregulation, and CREB phosphorylation via a cAMP-dependent protein kinase-dependent manner in SH-SY5Y cells. ConclusionTaken together, myricetin improves cognitive function in SAMP8 mice and upregulates BDNF and NGF.