I2 imidazoline receptor modulation protects aged SAMP8 mice against cognitive decline by suppressing the calcineurin pathway.
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ABSTRACT:
SUBMITTER: Vasilopoulou F
PROVIDER: S-EPMC8110656 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundPostoperative cognitive dysfunction (POCD) is a very common complication that might increase the morbidity and mortality of elderly patients after surgery. However, the mechanism of POCD remains largely unknown. The NAD-dependent deacetylase protein Sirtuin 3 (SIRT3) is located in the mitochondria and regulates mitochondrial function. SIRT3 is the only sirtuin that specifically plays a role in extending lifespan in humans and is associated with neurodegenerative diseases. Therefore, the aim of this study was to evaluate the effect of SIRT3 on anesthesia/surgery-induced cognitive impairment in aged mice.MethodsSIRT3 expression levels were decreased after surgery. For the interventional study, an adeno-associated virus (AAV)-SIRT3 vector or an empty vector was microinjected into hippocampal CA1 region before anesthesia/surgery. Western blotting, immunofluorescence staining, and enzyme-linked immune-sorbent assay (ELISA) were used to measure the oxidative stress response and downstream microglial activation and proinflammatory cytokines, and Golgi staining and long-term potentiation (LTP) recording were applied to evaluate synaptic plasticity.ResultsOverexpression of SIRT3 in the CA1 region attenuated anesthesia/surgery-induced learning and memory dysfunction as well as synaptic plasticity dysfunction and the oxidative stress response (superoxide dismutase [SOD] and malondialdehyde [MDA]) in aged mice with POCD. In addition, microglia activation (ionized calcium binding adapter molecule 1 [Iba1]) and neuroinflammatory cytokine levels (tumor necrosis factor-alpha [TNF-α], interleukin [IL]-1β and IL-6) were regulated after anesthesia/surgery in a SIRT3-dependent manner.ConclusionThe results of the current study demonstrate that SIRT3 has a critical effect in the mechanism of POCD in aged mice by suppressing hippocampal neuroinflammation and reveal that SIRT3 may be a promising therapeutic and diagnostic target for POCD.
| S-EPMC7863360 | biostudies-literature
Project description:Behavioural and psychological symptoms of dementia (BPSD), including fear-anxiety- and depressive-like behaviour, are present in Alzheimer's disease (AD), together with memory decline. I2-imidazoline receptors (I2-IRs) have been associated with neuropsychiatric and neurodegenerative disorders, further, I2-IR ligands have demonstrated a neuroprotective role in the central nervous system (CNS). In this study, we assessed the effect of the I2-IR ligand MCR5 on both cognitive and non-cognitive symptoms in the Senescence accelerated mice prone 8 (SAMP8) mouse model. Oral administration of I2-IR ligand MCR5 (5 mg/kg/day for four weeks) in 10-month SAMP8 mice ameliorated both BPSD-like phenotype and cognitive decline by attenuating depressive-like behaviour, reducing fear-anxiety-like behaviour and improving cognitive performance using different tasks. Interaction of I2-IR ligand MCR5 with serotoninergic system did not account for behavioural or cognitive improvement, although changes in molecular pathways underlying depression and anxiety phenotype were observed. MCR5 increased levels of p-AKT, phosphorylated glycogen synthase kinase 3 ? (GSK3?) at Ser9 and phosphorylated mammalian target of rapamycin complex 1 (mTORC1) levels in SAMP8 treated mice compared to SAMP8 control. Moreover, MCR5 treatment altered N-methyl-d-aspartate receptor (NMDA) 2B phosphorylation, and decreased the protein levels of phosphorylated cyclin-dependent kinase 5 (p-CDK5) and dopamine- and cyclic adenosine monophosphate (cAMP)-regulated phosphoprotein of Mr 32 kDa phosphorylated at Thr75 (p-DARPP32), with a parallel increase in protein kinase A (PKA) and p-cAMP response element-binding (pCREB) levels. Consistent with these changes MCR5 attenuated neuroinflammation by decreasing expression of pro-inflammatory markers such as Tumor necrosis factor-alpha (Tnf-?), Interleukin 1? (Il-1?), Interleukin 6 (Il-6), and promoted synaptic plasticity by increasing levels of postsynaptic density protein 95 (PSD95) as well as ameliorating tropomyosin-related kinase B (TrkB) and nerve growth factor receptor (NGFR) signalling. Collectively, these results increase the potential of highly selective I2-IR ligands as therapeutic agents in age-related BPSD and cognitive alterations.
| S-EPMC7285228 | biostudies-literature
Project description:As populations increase their life expectancy, age-related neurodegenerative disorders such as Alzheimer's disease have become more common. I2-Imidazoline receptors (I2-IR) are widely distributed in the central nervous system, and dysregulation of I2-IR in patients with neurodegenerative diseases has been reported, suggesting their implication in cognitive impairment. This evidence indicates that high-affinity selective I2-IR ligands potentially contribute to the delay of neurodegeneration. In vivo studies in the female senescence accelerated mouse-prone 8 mice have shown that treatment with I2-IR ligands, MCR5 and MCR9, produce beneficial effects in behavior and cognition. Changes in molecular pathways implicated in oxidative stress, inflammation, synaptic plasticity, and apoptotic cell death were also studied. Furthermore, treatments with these I2-IR ligands diminished the amyloid precursor protein processing pathway and increased A? degrading enzymes in the hippocampus of SAMP8 mice. These results collectively demonstrate the neuroprotective role of these new I2-IR ligands in a mouse model of brain aging through specific pathways and suggest their potential as therapeutic agents in brain disorders and age-related neurodegenerative diseases.
| S-EPMC6554384 | biostudies-literature
Project description:Age-related biological alterations in brain function increase the risk of mild cognitive impairment and dementia, a global problem exacerbated by aging populations in developed nations. Limited pharmacological therapies have resulted in attention turning to the promising role of medicinal plants and dietary supplements in the treatment and prevention of dementia. Sugarcane (Saccharum officinarum L.) top, largely considered as a by-product because of its low sugar content, in fact contains the most abundant amounts of antioxidant polyphenols relative to the rest of the plant. Given the numerous epidemiological studies on the effects of polyphenols on cognitive function, in this study, we analyzed polyphenolic constituents of sugarcane top and examined the effect of sugarcane top ethanolic extract (STEE) on a range of central nervous system functions in vitro and in vivo. Orally administrated STEE rescued spatial learning and memory deficit in the senescence-accelerated mouse prone 8 (SAMP8) mice, a non-transgenic strain that spontaneously develops a multisystemic aging phenotype including pathological features of Alzheimer's disease. This could be correlated with an increased number of hippocampal newborn neurons and restoration of cortical monoamine levels in STEE-fed SAMP8 mice. Global genomic analysis by microarray in cerebral cortices showed multiple potential mechanisms for the cognitive improvement. Gene set enrichment analysis (GSEA) revealed biological processes such as neurogenesis, neuron differentiation, and neuron development were significantly enriched in STEE-fed mice brain compared to non-treated SAMP8 mice. Furthermore, STEE treatment significantly regulated genes involved in neurotrophin signaling, glucose metabolism, and neural development in mice brain. Our in vitro results suggest that STEE treatment enhances the metabolic activity of neuronal cells promoting glucose metabolism with significant upregulation of genes, namely PGK1, PGAM1, PKM, and PC. STEE also stimulated proliferation of human neural stem cells (hNSCs), regulated bHLH factor expression and induced neuronal differentiation and astrocytic process lengthening. Altogether, our findings suggest the potential of STEE as a dietary intervention, with promising implications as a novel nutraceutical for cognitive health.
| S-EPMC7573230 | biostudies-literature
Project description:BackgroundAlthough dementia is associated with both global and regional cerebral blood flow (CBF) changes, little is known about cerebral perfusion in the early pre-clinical stages of cognitive decline preceding overt cognitive dysfunction. The aim of this study was to investigate the association of early sub-clinical cognitive decline with CBF.Materials and methodsThe study participants were recruited from a cohort of Danish men born in 1953. Based on a regression model we selected men who performed better (Group A, n = 94) and poorer (Group B, n = 95) on cognitive testing at age 57 than expected from testing at age 20. Participants underwent supplementary cognitive testing, blood sampling and MRI including measurements of regional and global CBF.ResultsRegional CBF was lower in group B than in group A in the posterior cingulate gyrus and the precuneus. The associations were attenuated when corrected for global atrophy, but remained significant in regions of interest based analysis adjusting for regional gray matter volume and vascular risk factors. No influence of group on global CBF was observed.ConclusionsWe conclude that early sub-clinical cognitive decline is associated with reduced perfusion in the precuneus and posterior cingulate gyrus independently of regional atrophy and vascular risk factors, but cannot be statistically separated from an association with global atrophy.
| S-EPMC5241142 | biostudies-literature
Project description:The reverse transcriptase inhibitors such as lamivudine (3TC) play important roles in anti-ageing, but their effects on neurodegenerative diseases caused by ageing are not clear, especially on the functions of the nervous system such as cognition. In this study, we administered 3TC to senescence-accelerated mouse prone 8 (SAMP8) mice by gastric perfusion (100 mg/kg) for 4 weeks. Our results showed that 3TC significantly improved the ageing status of SAMP8 mice, especially the decline of cognitive ability evaluated by the Morris water maze test. To further investigate the molecular mechanisms of improving the ageing status of SAMP8 mice by 3TC, the qPCR and tissue staining methods were used to study the brain tissues (i.e., hippocampus and cortex) of mice, while the network pharmacology analysis was applied to investigate the potential targets of 3TC. The results showed that the mRNA levels of genes related to long interspersed element-1, type 1 interferon response, the senescence-associated secretion phenotype and the Alzheimer's disease in the hippocampus and cortex of SAMP8 mice were increased due to senescence, but this trend was reversed partially by 3TC. Results of histological studies showed that 3TC reduced the death of hippocampal neurons, while the results of network pharmacology analysis indicated that 3TC may exert its influence through multiple pathways, including the oestrogen signalling and the PI3K/Akt and neuroactive ligand-receptor interaction signalling pathways, which we have verified through in vitro experiments. These findings provide evidence for the therapeutic potential of 3TC in the treatment of neurodegenerative diseases.
| S-EPMC8419189 | biostudies-literature
Project description:Isoflurane is a broadly used inhalation anesthetic that causes cognitive impairment in rodent models as well as humans. Although previous studies suggested an association between isoflurane exposure and neuro-inflammation, apoptosis and mitochondrial dysfunction, the pathogenesis of isoflurane-induced cognitive decline remains elusive. In the present study, 22-month-old male Sprague-Dawley male rats (n=96) were divided into three groups: Control (Cont), isoflurane (ISO) and MS-275 pre-treated groups. The rats were sacrificed following exposure to isoflurane and a cognitive test. The hippocampus of each animal was harvested for quantitative PCR, TUNEL staining and western blot analysis. Histone deacetylases (HDAC)-1, -2 and -3 exhibited a significant increase at the gene and protein expression levels, whereas negligible mRNA expressions were observed for genes HDAC 4-11 (P>0.05; compared with Cont). Pre-treatment with the HDAC inhibitor MS-275 significantly inhibited the increase in TUNEL-positive cells induced by isoflurane exposure (70.72% decrease; P<0.001; compared with ISO). Furthermore, MS-275 significantly decreased caspase-3 and Bax expression levels while increasing Bcl-2 protein expression. The isoflurane-induced changes in the MAPK pathway signaling proteins ERK1/2, JNK and p38 were also reversed with MS-275 pre-treatment. Finally, in a Morris water maze test, the time to find a hidden platform was reduced in MS-275 pre-treated rats, compared with the ISO group. Therefore, the present study provided insight into the effect of isoflurane exposure on neuronal apoptosis pathways, as well as cognitive decline via epigenetic programming of MAPK signaling in aged rats.
| S-EPMC7480129 | biostudies-literature
Project description:The age-dependent declines of skeletal muscle and cognitive functions often coexist in elderly subjects. The underlying pathophysiological mechanisms share common features of mitochondrial dysfunction, which plays a central role in the development of overt sarcopenia and/or dementia. Dietary supplementation with formulations of essential and branched-chain amino acids (EAA-BCAA) is a promising preventive strategy because it can preserve mitochondrial biogenesis and function. The senescence-accelerated mouse prone 8 (SAMP8) is considered an accurate model of age-related muscular and cognitive alterations. Hence, we aimed to investigate the progression of mitochondrial dysfunctions during muscular and cognitive aging of SAMP8 mice and to study the effects of a novel EAA-BCAA-based metabolic modulator on these changes. We evaluated body condition, motor endurance, and working memory of SAMP8 mice at 5, 9, 12, and 15 months of age. Parallel changes in protein levels of mitochondrial respiratory chain subunits, regulators of mitochondrial biogenesis and dynamics, and the antioxidant response, as well as respiratory complex activities, were measured in the quadriceps femoris and the hippocampus. The same variables were assessed in 12-month-old SAMP8 mice that had received dietary supplementation with the novel EAA-BCAA formulation, containing tricarboxylic acid cycle intermediates and co-factors (PD-0E7, 1.5 mg/kg/body weight/day in drinking water) for 3 months. Contrary to untreated mice, which had a significant molecular and phenotypic impairment, PD-0E7-treated mice showed preserved healthy body condition, muscle weight to body weight ratio, motor endurance, and working memory at 12 months of age. The PD-0E7 mixture increased the protein levels and the enzymatic activities of mitochondrial complex I, II, and IV and the expression of proliferator-activated receptor ? coactivator-1?, optic atrophy protein 1, and nuclear factor, erythroid 2 like 2 in muscles and hippocampi. The mitochondrial amyloid-?-degrading pitrilysin metallopeptidase 1 was upregulated, while amyloid precursor protein was reduced in the hippocampi of PD-0E7 treated mice. In conclusion, we show that a dietary supplement tailored to boost mitochondrial respiration preserves skeletal muscle and hippocampal mitochondrial quality control and health. When administered at the early onset of age-related physical and cognitive decline, this novel metabolic inducer counteracts the deleterious effects of precocious aging in both domains.
| S-EPMC7411305 | biostudies-literature
Project description:The aged systemic milieu promotes cellular and cognitive impairments in the hippocampus. Here, we report that aging of the hematopoietic system directly contributes to the pro-aging effects of old blood on cognition. Using a heterochronic hematopoietic stem cell (HSC) transplantation model (in which the blood of young mice is reconstituted with old HSCs), we find that exposure to an old hematopoietic system inhibits hippocampal neurogenesis, decreases synaptic marker expression, and impairs cognition. We identify a number of factors elevated in the blood of young mice reconstituted with old HSCs, of which cyclophilin A (CyPA) acts as a pro-aging factor. Increased systemic levels of CyPA impair cognition in young mice, while inhibition of CyPA in aged mice improves cognition. Together, these data identify age-related changes in the hematopoietic system as drivers of hippocampal aging.
| S-EPMC7431826 | biostudies-literature
Project description:Since first introduced more than two decades ago, the research in imidazoline I2 receptors has been steadily increasing. This review provides an update on the current status of I2 receptor pharmacology. Imidazoline I2 receptors or I2 binding sites refer to several (at least four) different proteins that bind to [3H]-idazoxan and [3H]-2-BFI with high affinity. The molecular identities of the proteins remain elusive. One of the proteins (45kD) seems to be consistent with the identity of brain creatine kinase. The biological functions of I2 receptors have been primarily unveiled by the studies of selective I2 receptor ligands. Accumulating evidence suggests that I2 receptor ligands are effective analgesics for persistent and chronic painful conditions such as inflammatory, neuropathic and postoperative pain. One selective I2 receptor ligand, CR4056, has been advanced to phase II clinical trial with the therapeutic indication of chronic inflammatory pain (osteoarthritis). The expansion to the treatment of other chronic pain conditions should be expected if CR4056 could eventually be approved as a new drug. I2 receptor ligands also demonstrate robust discriminative stimulus activity and induce a characteristic discriminative cue in animals. Biochemical and preclinical in vivo investigations also suggest that I2 receptor ligands have neuroprotective activity and modulate body temperature. The emerging discrepancies of a range of purported selective I2 receptor ligands suggest different pharmacological effects mediated by discrete I2 receptor components which likely attribute to the I2 receptor-related proteins. It is proposed that the I2 receptors represent an emerging drug target for the treatment of neurological disorders such as pain and stroke, and deserve more research attention to translate preclinical findings to pharmacotherapies.
| S-EPMC5600648 | biostudies-literature