Hippocampal SIRT1 Research Articles

Brain–gut photobiomodulation restores cognitive alterations in chronically stressed mice through the regulation of Sirt1 and neuroinflammation

BackgroundChronic stress is an important risk factor for the development of major depressive disorder (MDD). Recent studies have shown microbiome dysbiosis as one of the pathogenic mechanisms associated with MDD. Thus, it is important to find novel non-pharmacological therapeutic strategies that can modulate gut microbiota and brain activity. One such strategy is photobiomodulation (PBM), which involves the non-invasive use of light. Objective/hypothesisBrain-gut PBM could have a synergistic beneficial effect on the alterations induced by chronic stress. MethodsWe employed the chronic unpredictable mild stress (CUMS) protocol to induce a depressive-like state in mice. Subsequently, we administered brain-gut PBM for 6 min per day over a period of 3 weeks. Following PBM treatment, we examined behavioral, structural, molecular, and cellular alterations induced by CUMS. ResultsWe observed that the CUMS protocol induces profound behavioral alterations and an increase of sirtuin1 (Sirt1) levels in the hippocampus. We then combined the stress protocol with PBM and found that tissue-combined PBM was able to rescue cognitive alterations induced by CUMS. This rescue was accompanied by a restoration of hippocampal Sirt1 levels, prevention of spine density loss in the CA1 of the hippocampus, and the modulation of the gut microbiome. PBM was also effective in reducing neuroinflammation and modulating the morphology of Iba1-positive microglia. LimitationsThe molecular mechanisms behind the beneficial effects of tissue-combined PBM are not fully understood. ConclusionsOur results suggest that non-invasive photobiomodulation of both the brain and the gut microbiome could be beneficial in the context of stress-induced MDD.

Lipoic acid inhibits cognitive impairment induced by multiple cell phones in young male rats: role of Sirt1 and Atg7 pathway

The utilization of digital technology has grown rapidly in the past three decades. With this rapid increase, cell phones emit electromagnetic radiation; that is why electromagnetic field (EMF) has become a substantial new pollution source in modern civilization, mainly having adverse effects on the brain. While such a topic attracted many researchers’ scopes, there are still minimal discoveries made regarding chronic exposure to EMF. The extensive use of cell phones may affect children's cognition even indirectly if parents and guardians used their phones repeatedly near them. This study aims to investigate possible lipoic acid (LA) effects on cognitive functions and hippocampal structure in young male rats exposed to electromagnetic fields (EMF) emitted from multiple cell phones. Forty young male Wistar rats were randomly allocated into three groups: control, multiple cell phones-exposed and lipoic acid-treated rats. By the end of the experimental period, the Morris water maze was used as a cognitive test. The rats were sacrificed for the collection of serum and hippocampal tissue. These serum samples were then utilized for assessment of Liver function tests. The level ofglutamate, acetylcholine (Ach) and malondialdehyde (MDA) was estimated, in addition to evaluating the expression of autophagy-related protein-7 (Atg7) and Sirt1 genes. The left hippocampal specimens were used for histopathological studies. Results showed that multiple cell phone-exposed rats exhibited shorter latency time to reach the platform by the fifth day of training; additionally, there was a reduction in consolidation of spatial long-term memory. Correspondingly, there was an elevation of hippocampal Ach, glutamate, and MDA levels; accompanied by up-regulation of hippocampal Sirt1 and Atg7 gene expression. Compared to the EMF-exposed group, LA administration improved both learning and memory, this was proved by the significant decline in hippocampal MDA and Ach levels, the higher hippocampal glutamate, the downregulated hippocampal Sirt1 gene expression and the upregulated Atg7 gene expression. In conclusion, EMF exposure could enhance learning ability; however, it interfered with long-term memory consolidation shown by higher hippocampal Ach levels. Lipoic acid treatment improved both learning and memory by enhancing autophagy and hippocampal glutamate level and by the reduced Ach levels and Sirt1 gene expression.

Resveratrol ameliorates the behavioural and molecular changes in rats exposed to uninephrectomy: role of hippocampal SIRT1, BDNF and AChE

Subtle memory and cognitive changes may occur in uninephrectomized (Unix) patients long before the development of chronic kidney disease, such changes may be unnoticed. The dietary polyphenol, Resveratrol, displayed various neuroprotective effects, its role in chronic kidney disease is an area of intense studies. This work was designed to investigate the behavioural and molecular changes that may occur following 7 months of Unix in rats, and to determine whether Resveratrol intake can improve such pathology. Male Wistar rats were divided into three groups: sham operated, Unix and Unix group treated with Resveratrol (20 mg/kg/day). Rats were subjected to series of behavioural testing, different biochemical parameters along with RT-PCR and immunohistochemistry of the hippocampal tissue to track the development of functional or structural brain changes. Anxiety behaviour and reduced spatial memory performance were observed in rats 7 months post-nephrectomy; these deficits were remarkably reversed with Resveratrol. Among the species typical behaviour, burrowing was assessed; it showed significant impairment post-nephrectomy. Resveratrol intake was almost able to increase the burrowing behaviour. Decreased SIRT1 in immune-stained sections, oxidative stress, inflammatory changes, and increased AChE activity in hippocampal homogenates were found in Unix rats, and Resveratrol once more was capable to reverse such pathological changes. This work has investigated the occurrence of behavioural and structural brain changes 7 months following Unix and underlined the importance of Resveratrol to counterbalance the behavioural impairment, biochemical and brain pathological changes after uninephrectomy. These findings may raise the possible protective effects of Resveratrol intake in decreased kidney function.

Sirt1 protects against hippocampal atrophy and its induced cognitive impairment in middle-aged mice

BackgroundSirtuin 1 (Sirt1) is a recognized longevity gene and has been shown to be associated with aging and its related diseases. Hippocampal volume is considered to be the most sensitive brain imaging phenotype for cognition, but the effect of Sirt1 on hippocampal morphology during aging has not been reported.ResultsHerein, we investigated the effect of conditional Sirt1 knockdown on hippocampal volume in middle-aged mice, as well as its cognitive function and the underlying molecular mechanisms. Brain structural magnetic resonance imaging (MRI) showed that adeno-associated virus (AAV) mediated hippocampal Sirt1 knockdown caused hippocampal atrophy in 8-month-old mice. Open field test (OFT) and Morris Water Maze (MWM) test revealed that hippocampal Sirt1 knockdown significantly weakened spatial learning and memory of mice without effect on anxiety and exploratory behavior. Western blotting analysis showed that P-tau levels at serine 396 epitope were significantly increased with slightly decreased T-tau levels, while PSD95 and NMDAR2B levels were obviously reduced, indicating that hippocampal Sirt1 knockdown could activate tau hyperphosphorylation and synaptic damage.ConclusionsThis work revealed that Sirt1 is an important protective gene against hippocampal atrophy and its induced cognitive impairment during aging, providing potential therapeutic targets for the prevention and intervention of aging-related neuropsychic diseases.

Effects of Jiaotai Pills on CUMS-induced depression model in mice based on changes of SIRT1 expression in hippocampus

The present study investigated the effects and mechanisms of Jiaotai Pills on depressed mice induced by chronic unpredictable mild stress(CUMS). The CUMS-induced depression model mice were established and the depression behaviors of mice were evaluated by sucrose preference test, open field test, tail suspension test, and forced swimming test. Molecular docking was employed to simulate the interaction of six main active ingredients in Jiaotai Pills with SIRT1. Immunohistochemical staining was used to detect the level of SIRT1 in the hippocampus of mice. Western blot was used to detect the protein expression levels of SIRT1, p-NF-κB p65, NF-κB p65, and FoxO1 in the hippocampus of mice. Enzyme-linked immunosorbent assay(ELISA) kits were used to detect the levels of interleukin(IL)-1β, IL-6, tumor necrosis factor-α(TNF-α), and brain-derived neurotrophic factor(BDNF) in the hippocampus and serum of mice. Biochemical kits were used to detect superoxide dismutase(SOD) activity and malondialdehyde(MDA) and glutathione(GSH) levels in the hippocampus and serum of mice. Liquid chromatography-tandem mass spectrometry(LC-MS/MS) was used to detect the levels of dopamine(DA), 5-hydroxytryptamine(5-HT), and norepinephrine(NE) in the hippocampus and serum of mice. The results showed that the sucrose preference rate, movement distance, and the number of crossing centers were reduced in the model group(P<0.01), and the tail suspension time and swimming immobility time were increased(P<0.01). Molecular docking results indicated good binding of six main active ingredients in Jiaotai Pills to SIRT1. In the hippocampus, the expression level of SIRT1 was reduced(P<0.01), and the levels of p-NF-κB p65/NF-κB p65 and FoxO1 were increased(P<0.01). In the hippocampus and serum, the levels of IL-1β, IL-6, TNF-α, and MDA were increased(P<0.01), and the activity of SOD and the levels of GSH, DA, 5-HT, NE, and BDNF were reduced(P<0.01). The treatment with high-dose Jiaotai Pills increased the sucrose preference rate, movement distance, and the number of crossing centers(P<0.05), reduced tail suspension time and swimming immobility time(P<0.01), elevated hippocampal SIRT1 expression level(P<0.01), decreased hippocampal and serum IL-1β, IL-6, TNF-α, and MDA levels(P<0.01), potentiated SOD activity, and up-regulated GSH, DA, 5-HT, NE, and BDNF levels in the hippocampus and serum(P<0.05, P<0.01) in model mice. In conclusion, the results showed that Jiaotai Pills could improve the depression behaviors of model mice with CUMS-induced depression, and the underlying mechanism was related to the up-regulation of SIRT1 in the hippocampus of mice to exert anti-inflammatory and anti-oxidative stress effects.

Fat mass and obesity-associated protein regulates RNA methylation associated with depression-like behavior in mice

Post-transcriptional modifications of RNA, such as RNA methylation, can epigenetically regulate behavior, for instance learning and memory. However, it is unclear whether RNA methylation plays a critical role in the pathophysiology of major depression disorder (MDD). Here, we report that expression of the fat mass and obesity associated gene (FTO), an RNA demethylase, is downregulated in the hippocampus of patients with MDD and mouse models of depression. Suppressing Fto expression in the mouse hippocampus results in depression-like behaviors in adult mice, whereas overexpression of FTO expression leads to rescue of the depression-like phenotype. Epitranscriptomic profiling of N6-methyladenosine (m6A) RNA methylation in the hippocampus of Fto knockdown (KD), Fto knockout (cKO), and FTO-overexpressing (OE) mice allows us to identify adrenoceptor beta 2 (Adrb2) mRNA as a target of FTO. ADRB2 stimulation rescues the depression-like behaviors in mice and spine loss induced by hippocampal Fto deficiency, possibly via the modulation of hippocampal SIRT1 expression by c-MYC. Our findings suggest that FTO is a regulator of a mechanism underlying depression-like behavior in mice.

Hydrogen sulfide antagonizes sleep deprivation-induced depression- and anxiety-like behaviors by inhibiting neuroinflammation in a hippocampal Sirt1-dependent manner

Increasing evidence confirms that sleep deprivation (SD), which induces hippocampal neuroinflammation, is a risk factor for depression. Hydrogen sulfide (H2S) is a novel neuromodulator that plays antidepressant-like role. Silent mating type information regulation 2 homolog 1 (Sirt1) is well-characterized as a regulator of mood disorder. Furthermore, we have previously reported that H2S upregulates Sirt1 expression in the hippocampus of SD-exposed rats. Here, we explored whether H2S ameliorates depression- and anxiety-like behaviors as well as hippocampal neuroinflammatory in SD-exposed rats and whether Sirt1 mediates these protective roles of H2S. In the present work, we showed that NaHS (a donor of H2S) significantly alleviated depression- and anxiety-like behaviors in the SD-exposed rats tested by novelty-suppressed feeding test (NST), forced swim test (FST), tail suspension test (TST), and elevated plus maze test (EPMT) and that NaHS attenuates neuroinflammatory in the hippocampus of SD-exposed rats, as evidenced by reducing the levels of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) and chemokine CCL2, as well as increasing the levels of anti-inflammatory cytokines (IL-4 and IL-10) in the hippocampus. However, Sirt1 inhibitor reversed the protective effects of H2S against SD-induced depression- and anxiety-like behaviors as well as hippocampal neuroinflammatory. In conclusion, H2S antagonizes SD-induced depression- and anxiety-like behaviors and neuroinflammation, which is required hippocampal Sirt1. These findings suggested that H2S is a novel approach to prevent SD-induced depression and anxiety.

H2S Attenuates Sleep Deprivation-Induced Cognitive Impairment by Reducing Excessive Autophagy via Hippocampal Sirt-1 in WISTAR RATS.

Sleep deprivation (SD) is widespread in society causing serious damage to cognitive function. Hydrogen sulfide (H2S), the third gas signal molecule, plays important regulatory role in learning and memory functions. Inhibition of excessive autophagy and upregulation of silent information regulator 1 (Sirt-1) havebeen reported to prevent cognitive dysfunction. Therefore, this present work was to address whether H2S attenuates the cognitive impairment induced by SD in Wistar rats and whether the underlying mechanisms involve in inhibition of excessive autophagy and upregulation of Sirt-1. After treatment with SD for 72h, the cognitive function of Wistar rats was evaluated by Y-maze, new object recognition, object location, and Morris water maze tests. The results shown that SD-caused cognitive impairment was reversed by treatment with NaHS (a donor of H2S). NaHS also prevented SD-induced hippocampal excessive autophagy, as evidenced by the decrease in autophagosomes, the down-regulation of Beclin1, and the up-regulation of p62 in the hippocampus of SD-exposed Wistar rats. Furthermore, Sirtinol, an inhibitor of Sirt-1, reversed the inhibitory roles of NaHS in SD-induced cognitive impairment and excessive hippocampal autophagy in Wistar rats. Taken together, our results suggested that H2S improves the cognitive function of SD-exposed rats by inhibiting excessive hippocampal autophagy in a hippocampal Sirt-1-dependent way.

Cognitive and Neurochemical Changes Following Polyphenol-Enriched Diet in Rats.

Dietary recommendations are frequently developed based on nutrient deficiency or prevention of disease, but less attention has been paid to the dietary guidelines to promote brain health. Active and healthy aging is a prerequisite for improving quality of life as people age, and evidence is establishing a relationship between diet and brain health. This work studied the effect of a diet based on foods rich in antioxidants, especially polyphenols, in rats, three days a week for 20 months starting at 14 months. Behavioral analysis testing working memory, spatial and episodic memory, as well as brain monoaminergic neurotransmitters involved in these processes but also in general brain health were analyzed. In addition, hippocampal SIRT1 protein which has an important role in regulating normal brain function was evaluated. The results show that long-term intake of polyphenol-enriched diet improves memory and learning, correlating with restoration of brain monoaminergic neurotransmitters and hippocampal SIRT1 levels in aged rats. These results agree with reports revealing a neuroprotective effect of different polyphenolic compounds on age-related brain decline, based on its antioxidant and anti-inflammatory properties; and demonstrate that consumption of antioxidant-rich foods, a few days a week, gives good long-term results in terms of brain health.

SIRT1 activation by resveratrol reverses atrophy of apical dendrites of hippocampal CA1 pyramidal neurons and neurobehavioral impairments in moderate grade hepatic encephalopathy rats

A preliminary observation about resveratrol (RSV) dependent normalization of inflammatory and apoptotic factors in the cortex of hyperammonemic rat model of moderate grade hepatic encephalopathy (MoHE) led us to evaluate whether RSV is ultimately able to confer neuroprotection against MoHE pathogenesis and that it does so by activating its bonafide molecular target SIRT1. The present study compared the profile of relevant neurobehavioral pattern vs neuromorphometry of hippocampal CA1 neurons and SIRT1 activity in the hippocampus of the chronic liver failure (CLF) model of moderate grade HE (MoHE) rats induced by administration of 100 mg/kg body weight of thioacetamide i.p. for 10 days and in the CLF/MoHE rats treated with 10 mg/kg body weight RSV i.p. for 7 days. As compared to the control group rats, the MoHE rats showed significantly deranged pattern of memory and motor functions on MWM and rota rod tests, respectively. These behavioural deficits were associated with a significant reduction in apical dendrite length and number of branching points in the CA1 pyramidal neurons. Interestingly, all these parameters were found to be recovered back to their normal levels in the MoHE rats treated with RSV. Concordantly, MoHE associated declined SIRT1 activity in the hippocampus could be normalized back due to RSV treatment to those MoHE rats. Our findings suggest that RSV is able to normalize MoHE associated memory impairments and motor deficits vis a vis reversal of CA1 dendritic atrophy via SIRT1 activation.

MiR-138 Increases Depressive-Like Behaviors by Targeting SIRT1 in Hippocampus.

BackgroundMajor depressive disorder (MDD) is a serious and common mood disorder with unknown etiology. Emerging evidence has demonstrated the critical roles of SIRT1 and microRNAs (miRNAs) in the progression of MDD. However, the underlying molecular mechanisms remain to be fully understood.MethodsIn the present study, the expression level of miR-138 and SIRT1 were analyzed by RT-PCR or Western blotting in a chronic unpredictable mild stress (CUMS) model. The depressive-like behaviors were analyzed by forced swimming test (FST) and sucrose preference test (SPT) in mice injected with miR-138 and SIRT1 overexpression lentivirus. The luciferase reporter assay was used to assess the direct regulation of miR-138 on SIRT1 expression.ResultsThe upregulation of miR-138 was found in the hippocampus of the CUMS mice and correlated with decreased SIRT1 expression. C57BL/6J mice treated with SIRT1- and miR-138-expressing (miR-138) lentivirus showed increased depressive-like behaviors. In contrast, SIRT1 or si-miR-138 lentivirus treated C57BL/6J mice showed decreased depressive-like behaviors. Moreover, the Sirt1/PGC-1α/FNDC5/BDNF pathway was downregulated following miR-138 overexpression and increased upon miR-138 knockdown in hippocampus in CUMS mice and cultured primary neuronal cells. Mechanistically, luciferase reporter assay demonstrated that SIRT1 gene was a downstream transcriptional target of miR-138.ConclusionOur data demonstrated the regulation role of miR-138 on SIRT1 gene expression, miR-138 increased depressive-like behaviors by regulating SIRT1 expression in hippocampus.

Hydrogen Sulfide Prevents Sleep Deprivation-Induced Hippocampal Damage by Upregulation of Sirt1 in the Hippocampus.

Sleep deprivation (SD) induces hippocampal damage. Hydrogen sulfide (H2S) is a neuronal protective factor. Silence information regulating factor 1 (Sirt1) plays an important role in neuroprotection. Therefore, this study was aimed at exploring whether H2S meliorates SD-induced hippocampal damage and whether Sirt1 mediates this protective role of H2S. We found that sodium hydrosulfide (NaHS, a donor of H2S) alleviated SD-generated hippocampal oxidative stress, including increases in the activation of SOD and the level of GSH as well as a decrease in the level of MDA. Meanwhile, we found that NaHS reduced SD-exerted hippocampal endoplasmic reticulum (ER) Stress, including downregulations of GRP78, CHOP, and cleaved-caspase-12 expression. Moreover, NaHS reduced the apoptosis in the SD-exposed hippocampus, and this included decreases in the number of apoptotic cells and the activation of caspase-3, downregulation of Bax expression, and upregulation of Bcl-2 expression. NaHS upregulated the expression of Sirt1 in the hippocampus of SD-exposed rats. Furthermore, Sirtinol, the inhibitor of Sirt1, abrogated the protection of NaHS against SD-exerted hippocampal oxidative stress, ER stress, and apoptosis. These results suggested that H2S alleviates SD-induced hippocampal damage by upregulation of hippocampal Sirt1.

Dihydromyricetin ameliorates chronic social defeat stress induced cognitive and affective disorder in mice

To investigated the effects of dihydromyricetin on cognitive and affective disorders induced by chronic social defeat stress and its possible mechanism in mice. C57BL/6J mice were randomly divided into control group (Control), chronic social defeat stress group (CSDS) and chronic social defeat stress + DHM group (CSDS+DHM) (14 mice in each group). The mice received chronic social defeat stress and were injected with DHM or vehicle intraperitoneally. A part of mice were subjected to (10 mice of each group) novel object recognition test (NOR), Y maze test, open field test (OFT), social interaction test (SIT), forced swimming test (FST) and tail suspension test (TST). The other mice (4 mice of each group) were decapitated and the expression levels of SIRT1 in hippocampus were detected by Western blot. Compared with the control group, the learning and memory of the CSDS group were reduced significantly, the anxiety level was increased significantly, the immobility time in TST and FST was increased significantly, and the SIRT1 protein level in hippocampus was reduced significantly (P＜ 0.05 or P＜ 0.01); Compared with the CSDS group, the learning and memory of the CSDS + DHM group were improved significantly, the anxiety level of the mice was reduced significantly, and the immobility time in TST and FST was reduced significantly. The protein level of SIRT1 in hippocampus was increased significantly (P＜ 0.05 or P＜ 0.01). DHM ameliorates the cognitive impairment, anxiety like behavior and depression like behavior of mice induced by CSDS and up-regulates the expression of SIRT1 protein.

Inhibition of SIRT1 in hippocampal CA1 ameliorates PTSD-like behaviors in mice by protections of neuronal plasticity and serotonin homeostasis via NHLH2/MAO-A pathway

Hippocampal SIRT1 dysfunction and gene variation have previously been found potentially involved in depressive and anxiety disorders. However, the exact role of SIRT1 in post-traumatic stress disorder (PTSD) is not well understood. Here, we employed multiple genetic and pharmacological approaches targeting SIRT1 to verify the effects of SIRT1 on SPS-induced PTSD-like behaviors and its potential cellular and molecular mechanisms. We first demonstrated that Sirt1 knockout mice showed milder PTSD-like behavior after single prolonged stress (SPS) induction than wild type mice. Moreover, the expression of SIRT1 in the ventral CA1 (vCA1) region of hippocampus showed no significant changes following SPS induction, but the activity of SIRT1 enzyme was significantly increased post-SPS. Osmotic administration of EX527 in vCA1, a SIRT1 inhibitor, was shown to normalize the SIRT1 activity in SPS mice. Mechanically, EX527 rescued the acetylation of helix-loop-helix transcription factor 2 (NHLH2) and transcriptionally inhibited the increase of MAO-A expression in the vCA1, which thus suppressed the decomposition of the neurotransmitter serotonin into 5-hydroxydoleacetic acid (5-HIAA). Morphologically, Golgi staining showed that EX527 treatment improved the abnormal neuronal structure plasticity in the vCA1 region after SPS, including reversing the atrophic dendrites and the decreased dendritic spines. Finally, SIRT1 inhibitor effectively alleviated fear conditioning responses and anxiety-like behaviors. Our study first demonstrated that the development of PTSD-like behaviors was causatively related to the abnormal increase of SIRT1 activity in the ventral hippocampal CA1 region. And we also provided evidence that SIRT1 inhibition might exert therapeutic effects on PTSD by maintaining serotonin homeostasis through transcriptional inhibition of MAO-A, and thereby remodeled synaptic plasticity in the vCA1 region.

Centella asiatica Prevents Increase of Hippocampal Tumor Necrosis Factor-α Independently of Its Effect on Brain-Derived Neurotrophic Factor in Rat Model of Chronic Stress.

Centella asiatica ameliorates memory impairment and induces expression of hippocampal brain-derived neurotropic factor (BDNF) in chronically stressed rats. The relationship between the anti-inflammatory effect of Centella asiatica on hippocampal BDNF and the involvement of sirtuin-1, a BDNF expression regulator, in neuroprotective mechanisms of Centella asiatica warrants an investigation. We investigated the effect of Centella asiatica ethanolic extracts (CA) on TNF-α, IL-10, and SIRT1 levels and whether these predicted BDNF expression in rat hippocampus after chronic stress. For the experiments, thirty male rats (Sprague Dawley) were divided into six groups: nonstressed-control, stressed-control, nonstressed +CA 300mg/kg/d, stressed +CA 150 mg/kg/d, stressed +CA 300 mg/kg/d, and stressed +CA 600 mg/kg/d. On day 28, rats were sacrificed and hippocampus was dissected out. Hippocampal TNF-α, IL-10, SIRT1, and BDNF were measured by enzyme-linked immunosorbent assay. Hippocampal TNF-α level was significantly higher in the stressed-control compared to nonstressed-control groups. Across all stress conditions, rats receiving the highest dose of CA had the lowest mean TNF-α and highest mean BDNF. There were no significant differences in IL-10 and SIRT1 levels between groups. Hippocampal TNF-α did not predict hippocampal BDNF in a regression analysis. In conclusion, lower TNF-α and higher BDNF in the hippocampus support the hypothesis that these factors independently contribute to Centella asiatica's neuroprotective effect in chronically stressed rats.

Obesity caused by a high-fat diet regulates the Sirt1/PGC-1α/FNDC5/BDNF pathway to exacerbate isoflurane-induced postoperative cognitive dysfunction in older mice

ABSTRACT Objectives: To investigate the effects of obesity caused by high-fat diet (HFD) on postoperative cognitive dysfunction (POCD) and expression of the Sirt1/PGC-1α/FNDC5/BDNF pathway in the hippocampus of older mice. Methods: Fifty-six 15-month-old male C57BL/6 mice were randomly divided into eight groups – ad libitum control (ALC), ad libitum surgery (ALS), ad libitum surgery with PBS (ALS + PBS), ad libitum surgery with resveratrol (ALS + Res), HFD control (HFC), HFD surgery (HFS), HFD surgery with PBS (HFS + PBS), HFD surgery with resveratrol (HFS + Res). Surgery group mice were exposed to isoflurane before tibial fracture internal fixation. Open field tests and fear conditioning were performed to test motor ability and memory. The levels of expression of Sirt1, PGC-1α, FNDC5, and BDNF were detected using western blot and immunofluorescence. Results: The results of the open field tests indicated there were no between-group differences in motor ability and anxiety. The results of the fear conditioning indicated that the memory of the HFC group and HFS group mice were significantly worse compared with the ALC group and ALS group mice, respectively. There were parallel decreases in expression of the Sirt1/PGC-1α/FNDC5/BDNF pathway in the hippocampi of the HFC and HFS group mice. Resveratrol treatment attenuated the memory loss by increasing hippocampal Sirt1 expression. Expression of the PGC-1α/FNDC5/ BDNF pathway in the CA1 area of the hippocampus was upregulated after resveratrol treatment. Conclusion: An HFD exacerbates POCD in older mice. This change was related to HFD inhibition of expression of the Sirt1/PGC-1α/FNDC5/BDNF pathway in the hippocampus. Resveratrol pretreatment reversed the memory loss via upregulation of this pathway.

Woohwangcheongsimwon Prevents High-Fat Diet-Induced Memory Deficits and Induces SIRT1 in Mice.

Woohwangcheongsimwon (WHC) is a mixture of herbal medicines that is widely prescribed in Korean traditional medicine. SIRT1 is known for its regulatory roles in energy metabolism, oxidative stress, and circadian rhythms. This study was designed to determine whether WHC can increase and mimic the biological reactions of SIRT1 activation. Ten-month-old male mice were divided into four groups: nontreated normal diet (ND), nontreated high-fat diet (HFD), WHC-treated ND, and WHC-treated HFD. Body weight and cognitive functions were evaluated after treatment. The hippocampal expressions of SIRT1 and PGC-1α were also measured. The components of WHC were identified by liquid chromatography. High-fat diet-fed mice gained more weight and demonstrated greater deficits in short-term and long-term cognitive functions. WHC suppressed the deleterious effects of a HFD on weight gain and cognitive decline, but showed no prominent effects on animals fed NDs. The herbal treatment also increased the expression of SIRT1 and PGC-1α in the hippocampus. Despite the induction of hippocampal SIRT1 expression by WHC, resveratrol was not present among the natural compounds identified. This expression might have contributed to the suppression of high-fat diet-induced memory deficits in mice treated with the herbal mixture.

Role of silent information regulator 1 in the protective effect of hydrogen sulfide on homocysteine-induced cognitive dysfunction: Involving reduction of hippocampal ER stress

Homocysteine (Hcy) causes cognitive deficits and hippocampal endoplasmic reticulum (ER) stress. Our previous study has confirmed that Hydrogen sulfide (H2S) attenuates Hcy-induced cognitive dysfunction and hippocampal ER stress. Silent information regulator 1 (Sirt-1) is indispensable in the formation of learning and memory. Therefore, the aim of this study was to explore the role of Sirt-1 in the protective effect of H2S against Hcy-induced cognitive dysfunction. We found that NaHS (a donor of H2S) markedly up-regulated the expression of Sirt-1 in the hippocampus of Hcy-exposed rats. Sirtinol, a specific inhibitor of Sirt-1, reversed the improving role of NaHS in the cognitive function of Hcy-exposed rats, as evidenced by that sirtinol increased the escape latency and the swim distance in the acquisition trial of morris water maze (MWM) test, decreased the times crossed through and the time spent in the target quadrant in the probe trail of MWM test, and reduced the discrimination index in the novel object recognition test (NORT) in the rats cotreated with NaHS and Hcy. We also found that sirtinol reversed the protection of NaHS against Hcy-induced hippocampal ER-stress, as evidenced by up-regulating the expressions of GRP78, CHOP, and cleaved caspase-12 in the hippocampus of rats cotreated with NaHS and Hcy. These results suggested the contribution of upregulation of hippocampal Sirt-1 to the improving role of H2S in the cognitive function of Hcy-exposed rats, which involves suppression of hippocampal ER stress. Our finding provides a new insight into the mechanism underlying the inhibitory role of H2S in Hcy-induced cognitive dysfunction.

Hydrogen sulfide attenuates chronic restrain stress-induced cognitive impairment by upreglulation of Sirt1 in hippocampus.

Chronic restraint stress (CRS) has detrimental effects on cognitive function. Hydrogen sulfide (H2S), as a neuromodulator, regulates learning and memory. Hippocampus is a key structure in learning and memory. Sirt1 (silence signal regulating factor 1) plays an important role in modulating cognitive function. Therefore, our present work was to investigate whether H2S meliorates CRS-induced damage in hippocampus and impairment in cognition, and further to explore whether the underlying mechanism is via upreglulating Sirt1. In our present work, the behavior experiments [Y-maze test, Novel object recognition (NOR) test, Morris water maze (MWM) test] showed that sodium hydrosulfide (NaHS, a donor of H2S) blocked CRS-induced cognitive impairments in rats. NaHS inhibited CRS-induced hippocampal oxidative stress as evidenced by decrease in MDA level as well as increases in GSH content and SOD activity. NaHS rescued CRS-generated ER stress as evidenced by downregulations of CPR78, CHOP, and cleaved caspase-12. NaHS reduced CRS-exerted apoptosis as evidenced by decreases in the number of TUNEL-positive cells and Bax expression as well as increase in Bcl-2 expression. NaHS upregulated the expression of Sirt1 in the hippocampus of CRS-exposed rats. Furthermore, inhibited Sirt1 by Sirtinol reversed the protective effects of NaHS against CRS-produced cognitive dysfunction and oxidative stress, ER stress as well as apoptosis in hippocampus. Together, these results suggest that H2S meliorates CRS-induced hippocampal damage and cognitive impairment by upregulation of hippocampal Sirt1.

Chronic Silymarin, Quercetin and Naringenin Treatments Increase Monoamines Synthesis and Hippocampal Sirt1 Levels Improving Cognition in Aged Rats.

Polyphenols have beneficial neurological effects delaying cognitive and motor decline in aging due to their antioxidant, antiinflammatory and neuroprotective properties. These effects could be related to SIRT1 activation (implicated in synaptic plasticity, memory and inflammation) and monoaminergic synthesis modulation. In this work, we studied in old male rats, the in vivo effects of long-term administration of different polyphenols (silymarin, quercetin and naringenin; 20mg/kg/day i.p, 4weeks) (Sprague-Dawley, 18months) on cognition and motor coordination. We also analyzed in different brain regions: tryptophan hydroxylase (TPH) and tyrosine hydroxylase (TH) activities, which mediate central monoaminergic neurotransmitters synthesis; and immunoreactivities of SIRT1 and NF-κB (total and acetylated forms). Results indicated that chronic polyphenolic treatments showed restorative effects on cognition and motor coordination consistently with the biochemical and molecular results. Polyphenols reversed the age-induced deficits in monoaminergic neurotransmitters (serotonin, noradrenaline, and dopamine), increasing TPH and TH activity. In addition, polyphenolic treatments increased SIRT1 levels and decreased NF-κB levels in hippocampus. These results confirm polyphenolic treatments as a valuable potential therapeutic strategy for attenuating inflamm-aging and brain function decline.