Impaired Aged Rats Research Articles

The role of the cholinergic system in the memory-protecting effects of metformin in a model of scopolamine-induced memory impairment in aged rats

PurposeAs the elderly population grows, the prevalence of dementia is also rapidly increasing worldwide. Metformin, an antidiabetic drug, has been shown to have ameliorative effects on impaired cognitive functions in experimental models. However, studies have generally used young animals. Additionally, although it has a major role in Alzheimer's disease (AD) and memory, literature information about the effects of metformin on the cholinergic system is limited. In this study, we investigated the effects of metformin on memory in a model of scopolamine-induced memory impairment in aged rats. We also examined the effects of metformin on the cholinergic system, which is very important in cognitive functions. MethodsMetformin was administered orally to male Wistar rats (20–22 months old) at 100 mg/kg/day for three weeks. Morris water maze (MWM) tests were performed to assess spatial memory. Before the probe test of the MWM test, scopolamine was injected intraperitoneally at a dose of 1 mg/kg. After testing, animals were sacrificed, whole brains were removed, and hippocampus samples were separated for biochemical analysis. ResultsImpaired memory associated with scopolamine administration was reversed by metformin. In addition, metformin administration ameliorated scopolamine-induced changes in acetylcholine (ACh) levels, acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and choline acetyltransferase (ChAT) activity. ConclusionOur results show that metformin may have protective effects in a scopolamine-induced memory impairment model in aged animals by improving cholinergic function. Metformin shows promise in preventing dementia with its dual cholinesterase inhibition and ChAT activation effect.

Bajitianwan formula extract ameliorates bone loss induced by iron overload via activating RAGE/PI3K/AKT pathway based on network pharmacology and transcriptomic analysis.

Osteoporosis (OP) is closely related to iron overload. Bajitianwan (BJTW) is a traditional Chinese medicine formulation used for treating senile diseases such as dementia and osteoporosis. Modern pharmacological researches have found that BJTW has beneficial effect on bone loss and memory impairment in aging rats. This paper aimed to explore the role and mechanism of BJTW in ameliorating iron overload-induced bone loss. Furthermore, BJTW effectively improved the bone micro-structure of the femur in mice, and altered bone metabolism biomarkers alkaline phosphatase (ALP) and osteocalcin (OCN) in serum, as well as oxidative indexes superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR) glutathione (GSH) and malondialdehyde (MDA) in liver. As for network pharmacology, 73 components collected from BJTW regulated 99 common targets merged in the BJTW and OP. The results of RNA-seq indicated that there were 418 potential targets in BJTW low dose group (BJTW-L) and 347 potential targets in BJTW high dose group (BJTW-H). Intriguingly, both PI3K-AKT signaling pathway and the AGEs-RAGE signaling pathway were contained in the KEGG pathways enrichment results of network pharmacology and transcriptomics, which were considered as the potential mechanism. Additionally, we verified that BJTW regulated the expression of related proteins in RAGE/PI3K-AKT pathways in MC3T3-E1 cells. In summary, BJTW has potent effect on protecting against iron overload-induced OP, and its mechanism may be related to the activation of the RAGE/PI3K-AKT signaling pathways.

Involvement of Fgf2-mediated tau protein phosphorylation in cognitive deficits induced by sevoflurane in aged rats

ObjectiveAnesthetics have been linked to cognitive alterations, particularly in the elderly. The current research delineates how Fibroblast Growth Factor 2 (Fgf2) modulates tau protein phosphorylation, contributing to cognitive impairments in aged rats upon sevoflurane administration.MethodsRats aged 3, 12, and 18 months were subjected to a 2.5% sevoflurane exposure to form a neurotoxicity model. Cognitive performance was gauged, and the GEO database was employed to identify differentially expressed genes (DEGs) in the 18-month-old cohort post sevoflurane exposure. Bioinformatics tools, inclusive of STRING and GeneCards, facilitated detailed analysis. Experimental validations, both in vivo and in vitro, examined Fgf2’s effect on tau phosphorylation.ResultsSevoflurane notably altered cognitive behavior in older rats. Out of 128 DEGs discerned, Fgf2 stood out as instrumental in regulating tau protein phosphorylation. Sevoflurane exposure spiked Fgf2 expression in cortical neurons, intensifying tau phosphorylation via the PI3K/AKT/Gsk3b trajectory. Diminishing Fgf2 expression correspondingly curtailed tau phosphorylation, neurofibrillary tangles, and enhanced cognitive capacities in aged rats.ConclusionSevoflurane elicits a surge in Fgf2 expression in aging rats, directing tau protein phosphorylation through the PI3K/AKT/Gsk3b route, instigating cognitive aberrations.

Carnosol ameliorates sevoflurane induced cognitive impairment in aged rats by suppressing NLRP3 inflammasome via activation of autophagy

Purpose: To investigate the effect of carnosol on the progression of postoperative cognitive dysfunction (POCD) and to elucidate its mechanism of action.
 Methods: A cognitive impairment model rat induced by sevoflurane (SEV) was established. Dihydroethidium (DHE) assay was conducted to determine the effect of carnosol on reactive oxygen species (ROS) levels in sevoflurane-induced rats. Adenosine triphosphate (ATP) production and immunoblot assays were used to assess carnosol effect on mitochondrial damage, while water maze experiment was performed to evaluate cognitive dysfunction in the rats. The mechanism of action was investigated using immunoblot assay.
 Results: Carnosol suppressed sevoflurane-induced ROS production in the rats, and alleviated sevoflurane-induced mitochondrial damage; it also activated autophagy. Furthermore, carnosol suppressed SEV-induced NLRP3 inflammasome activation by activating autophagy and suppressing SEV-induced cognitive dysfunction via the suppression of NLRP3 inflammasome activation.
 Conclusion: Carnosol ameliorates SEV-stimulated cognitive impairment by suppressing NLRP3 inflammasome and thus, can potentially be developed serve as a therapeutic agent for the management of cognitive impairment.

Retraction: Young plasma reverses anesthesia and surgery-induced cognitive impairment in aged rats by modulating hippocampal synaptic plasticity.

[This retracts the article DOI: 10.3389/fnagi.2022.996223.].

Short-term high-fat diet consumption impairs synaptic plasticity in the aged hippocampus via IL-1 signaling

More Americans are consuming diets higher in saturated fats and refined sugars than ever before. These trends could have serious consequences for the older population because high-fat diet (HFD) consumption, known to induce neuroinflammation, has been shown to accelerate and aggravate memory declines. We have previously demonstrated that short-term HFD consumption, which does not evoke obesity-related comorbidities, produced profound impairments to hippocampal-dependent memory in aged rats. These impairments were precipitated by increases in proinflammatory cytokines, primarily interleukin-1 beta (IL-1β). Here, we explored the extent to which short-term HFD consumption disrupts hippocampal synaptic plasticity, as measured by long-term potentiation (LTP), in young adult and aged rats. We demonstrated that (1) HFD disrupted late-phase LTP in the hippocampus of aged, but not young adult rats, (2) HFD did not disrupt early-phase LTP, and (3) blockade of the IL-1 receptor rescued L-LTP in aged HFD-fed rats. These findings suggest that hippocampal memory impairments in aged rats following HFD consumption occur through the deterioration of synaptic plasticity and that IL-1β is a critical driver of that deterioration.

Faecal microbiota transplantation from young rats attenuates age-related sarcopenia revealed by multiomics analysis.

Gut microbiota plays a key role in the development of sarcopenia via the 'gut-muscle' axis, and probiotics-based therapy might be a strategy for sarcopenia. Fecal microbiota transplantation from young donors (yFMT) has attracted much attention because of its probiotic function. However, whether or not yFMT is effective for sarcopenia in old recipients is largely unknown. Thus, we aimed to investigate the effect and mechanism of yFMT on age-related sarcopenia. The fecal microbiota of either young (12weeks) or old (88weeks) donor rats was transplanted into aged recipient rats for 8weeks. Then, muscle mass, muscle strength, muscle function, muscle atrophy, and muscle regeneration capacity were measured. Analysis of fecal 16s rRNA, serum non-targeted metabolomic, gut barrier integrity, and muscle transcriptome was conducted to elucidate the interaction between gut microbiota and skeletal muscles. As evaluated by magnetic resonance imaging examination, grip strength test (P<0.01), rotarod test (P<0.05), and exhaustive running test (P<0.05), we found that yFMT mitigated muscle mass loss, muscle strength weakness, and muscle function impairment in aged rats. yFMT also countered age-related atrophy and poor regeneration capacity in fast- and slow-switch muscles, which were manifested by the decrease in slow-switch myofibres (both P<0.01) and muscle interstitial fibrosis (both P<0.05) and the increase in the cross-section area of myofibres (both P<0.001), fast-switch myofibres (both P<0.01), and muscle satellite cells (both P<0.001). In addition, yFMT ameliorated age-related dysbiosis of gut microbiota and metabolites by promoting the production of beneficial bacteria and metabolites-Akkermansia, Lactococcus, Lactobacillus, γ-glutamyltyrosine, 3R-hydroxy-butanoic acid, and methoxyacetic acid and inhibiting the production of deleterious bacteria and metabolites-Family_XIII_AD3011_group, Collinsella, indoxyl sulfate, indole-3-carboxilic acid-O-sulphate, and trimethylamine N-oxide. Also, yFMT prevented age-related destruction of gut barrier integrity by increasing the density of goblet cells (P<0.0001) and the expression levels of mucin-2 (P<0.0001) and tight junctional proteins (all P<0.05). Meanwhile, yFMT attenuated age-related impairment of mitochondrial biogenesis and function in fast- and slow-switch muscles. Correlation analysis revealed that yFMT-induced alterations of gut microbiota and metabolites might be closely related to mitochondria-related genes and sarcopenia-related phenotypes. yFMT could reshape the dysbiosis of gut microbiota and metabolites, maintain gut barrier integrity, and improve muscle mitochondrial dysfunction, eventually alleviating sarcopenia in aged rats. yFMT might be a new therapeutic strategy for age-related sarcopenia.

C/EBPα involvement in microglial polarization via HDAC1/STAT3 pathway aggravated sevoflurane-induced cognitive impairment in aged rats.

Postoperative cognitive dysfunction (POCD) is a clinically frequent postoperative complication in the elderly, which is mainly manifested by the occurrence of cognitive dysfunction after anesthetized surgery in patients. To explore the involvement of C/EBPα in microglial polarization in sevoflurane anesthesia induced cognitive impairment in aged rats. Sprague-Dawley (SD) rats were anesthetized by inhalation of 3% sevoflurane for 6 h to establish the POCD model. The histopathological structure of hippocampus was observed by hematoxylin and eosin (HE) staining. Associative learning and memory function and spatial learning and memory function were assessed by conditioned fear test and water maze test. The concentrations of inflammatory factors in the hippocampus were measured by ELISA. The levels of microglial activation marker (Iba1) and microglial M1 (CD86) and M2 (CD206) polarization markers were determined by immunofluorescence staining and RT-qPCR, respectively. The transcriptional regulation of HDAC1 by C/EBPα was confirmed by dual luciferase reporter assay and ChIP assay. Sevoflurane-induced pathomorphological damage in the hippocampal tissue of aged rats, accompanied by elevated expression of C/EBPα. Silencing of C/EBPα alleviated hippocampal histopathological injury, inhibited M1 microglial activation and the expression of M1 marker CD86, enhanced the expression of M2 marker CD206. C/EBPα transcriptionally activated HDAC1. Knockdown of C/EBPα downregulated the expression of HDAC1 and STAT3 phosphorylated proteins, which inhibited the pro-inflammatory factors (IL-6 and TNF-α) and accelerated anti-inflammatory factors (IL-10 and TGF-β) secretion. In addition, silencing of C/EBPα caused rats to have a delayed freezing time in contextual conditioned fear, a shorter escape latency, and an increased number of platform crossings. Inhibition of C/EBPα promotes the M2 polarization of microglia and reduces the production of pro-inflammatory cytokines to alleviate the cognitive dysfunction of sevoflurane-induced elderly rats by HDAC1/STAT3 pathway.

Effects of Ocimum basilicum L. Extract on Hippocampal Oxidative Stress, Inflammation, and BDNF Expression in Amnesic Aged Rats

ABSTRACT The present study was conducted to investigate the effects of Ocimum basilicum L. (OB) extract on learning and memory impairment in aged rats. Male rats were divided into the following experimental groups: Group 1 (control): including 2 months old rats, Group 2 (aged) including 2 years old rats, Groups 3–5 (aged-OB): including 2 years old rats received 50, 100, and 150 mg/kg OB for 8 weeks by oral gavage. Aging increased the delay to find the platform but, however, decreased the time spent in the target quadrant when tested by Morris water maze (MWM). Aging also reduced the latency to enter the dark chamber in the passive avoidance (PA) test compared to the control group. Moreover, interleukin-6 (IL-6) and malondialdehyde (MDA) levels were raised in the hippocampus and cortex of aged rats. In contrast, thiol levels and enzymatic activity of superoxide dismutase (SOD) and catalase (CAT) significantly reduced. In addition, aging significantly reduced BDNF expression. Finally, OB administration reversed the mentioned effects. The current research showed that OB administration improves learning/memory impairment induced by aging. It also found that this plant extract protects the brain tissues from oxidative damage and neuroinflammation.

Rapamycin Affects the Hippocampal SNARE Complex to Alleviate Cognitive Dysfunction Induced by Surgery in Aged Rats.

Delayed neurocognitive recovery (dNCR) is a common complication that occurs post-surgery, especially in elderly individuals. The soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex plays an essential role in various membrane fusion events, such as synaptic vesicle exocytosis and autophagosome-lysosome fusion. Although SNARE complex dysfunction has been observed in several neurodegenerative disorders, the causal link between SNARE-mediated membrane fusion and dNCR remains unclear. We previously demonstrated that surgical stimuli caused cognitive impairment in aged rats by inducing α-synuclein accumulation, inhibiting autophagy, and disrupting neurotransmitter release in hippocampal synaptosomes. Here, we evaluated the effects of propofol anesthesia plus surgery on learning and memory and investigated levels of SNARE proteins and chaperones in hippocampal synaptosomes. Aged rats that received propofol anesthesia and surgery exhibited learning and memory impairments in a Morris water maze test and decreased levels of synaptosome-associated protein 25, synaptobrevin/vesicle-associated membrane protein 2, and syntaxin 1. Levels of SNARE chaperones, including mammalian uncoordinated-18, complexins 1 and 2, cysteine string protein-α, and N-ethylmaleimide-sensitive factor, were all significantly decreased following anesthesia with surgical stress. However, the synaptic vesicle marker synaptophysin was unaffected. The autophagy-enhancer rapamycin attenuated structural and functional disturbances of the SNARE complex and ameliorated disrupted neurotransmitter release. Our results indicate that perturbations of SNARE proteins in hippocampal synaptosomes may underlie the occurrence of dNCR. Moreover, the protective effect of rapamycin may partially occur through recovery of SNARE structural and functional abnormalities. Our findings provide insight into the molecular mechanisms underlying dNCR.

Activation of α7nAChR by PNU282987 improves cognitive impairment through inhibiting oxidative stress and neuroinflammation in D-galactose induced aging via regulating α7nAChR/Nrf2/HO-1 signaling pathway

Aging is an important risk factor for neurodegenerative diseases. The activation of α7 nicotinic acetylcholine receptor (α7nAChR) is involved in inflammation and cognition, but the specific role it plays in aging remains unknown. This study aimed to investigate the anti-aging effect of the activation of α7nAChR on aging rats and BV2 cells induced by D-galactose, as well as its potential mechanism. D-galactose induced an increase in the SA-β-Gal positive cells, expression of p16 and p21 in vivo and in vitro. α7nAChR selective agonist PNU282987 decreased levels of pro-inflammatory factors, MDA, and Aβ, enhanced SOD activity and levels of anti-inflammatory factor (IL10) in vivo. PNU282987 enhanced the expression of Arg1, decreased the expression of iNOS, IL1β and TNFα in vitro. PNU282987 upregulated the levels of α7nAChR, Nrf2 and HO-1 in vivo and in vitro. The results of Morris water maze and novel object recognition tests showed that PNU282987 improved cognitive impairment in aging rats. Furthermore, α7nAChR selective inhibitor methyllycaconitine (MLA) results were opposite with PNU282987. PNU282987 improves cognitive impairment through inhibiting oxidative stress and neuroinflammation in D-galactose induced aging via regulating the α7nAChR/Nrf2/HO-1 signaling pathway. Therefore, targeting the α7nAChR may be a viable therapeutic approach for anti-inflammaging and neurodegenerative diseases.

Activation of autophagy inhibits the activation of NLRP3 inflammasome and alleviates sevoflurane-induced cognitive dysfunction in elderly rats

Aims/introductionAs a common complication in elderly patients after surgery/anesthesia, postoperative cognitive dysfunction (POCD) is mainly characterized by memory, attention, motor, and intellectual retardation. Neuroinflammation is one of the most uncontroversial views in POCD. The sevoflurane-induced neurotoxicity has attracted widespread attention in recent years. However, its mechanism has not been determined. This study aimed to observe the effects of sevoflurane on cognitive function and the changes in inflammatory indices and autophagy protein expression in the prefrontal cortex in aged rats.MethodBefore the experiment, D-galactose was diluted with normal saline into a liquid with a concentration of 125 mg/kg and injected subcutaneously into the neck and back of rats for 42 days to establish the aging rat model. Morris water maze experiments were performed, including positioning navigation (5 days) and space exploration (1 day). The POCD model was established by 3.2% sevoflurane inhalation. The rats were treated with or without MCC950, a potent and selective nucleotide‐binding oligomerization domain‐like receptor protein 3 (NLRP3) inhibitor, followed by autophagy agonists and autophagy inhibitors. The expression levels of inflammasome-related protein NLRP3 and autophagy-related proteins LC3B and P62 were detected to test the behavior of rats with a water maze.ResultsWe found that sevoflurane exposure affected learning and working memory ability in aged rats. We also observed microglia activation in the prefrontal cortex. NLRP3 protein expression was significantly upregulated after sevoflurane inhalation. NLRP3 inflammasome activation induced increased expression and mRNA expression of cleaved Caspase-1 and inflammatory cytokines IL-1β and IL-18, and increased secretion of peripheral proinflammatory cytokines. The inhibitor MCC950 was used to improve cognitive ability and inflammation in rats and inhibit the secretion of cytokines. In addition, we demonstrated that significant inhibition of autophagy (decreased LC3-II/I and increased P62) was accompanied by increased activation of NLRP3 inflammasomes and more severe neural cell damage. However, autophagy inhibitor rapamycin administration to activate autophagy resulted in the inhibition of NLRP3 inflammasomes, ultimately attenuating neuronal injury.ConclusionsThe activation of autophagy suppressed the formation of NLRP3 inflammasomes. It also alleviated cognitive impairment in aged rats.

The TgF344-AD rat: behavioral and proteomic changes associated with aging and protein expression in a transgenic rat model of Alzheimer's disease

Animal models of Alzheimer's Disease (AD) are attractive tools for preclinical, prodromal drug testing. The TgF344-AD (Tg) rat exhibits cognitive deficits and 5 major hallmarks of AD. Here we show that spatial water maze (WMZ) memory deficits and proteomic differences in dorsal CA1 were present in young Tg rats. Aged learning-unimpaired (AU) and aged learning-impaired (AI) proteome associated changes were identified and differed by sex. Levels of phosphorylated tau, reactive astrocytes and microglia were significantly increased in aged Tg rats and correlated with the WMZ learning index (LI); in contrast, no significant correlation was present between amyloid plaques or insoluble Aβ levels and LI. Neuroinflammatory markers were also significantly correlated with LI and increased in female Tg rats. The anti-inflammatory marker, triggering receptor expressed on myeloid cells-2 (TREM2), was significantly reduced in aged impaired Tg rats and correlated with LI. Identifying and understanding mechanisms that allow for healthy aging by overcoming genetic drivers for AD, and/or promoting drivers for successful aging, are important for developing successful therapeutics against AD.

Young plasma reverses anesthesia and surgery-induced cognitive impairment in aged rats by modulating hippocampal synaptic plasticity.

We investigated the protective effect of young plasma on anesthesia- and surgery-induced cognitive impairment and the potential underlying mechanism using bioinformatics, functional enrichment analysis, gene set enrichment analysis, Golgi-Cox staining, dendritic spine analysis, immunofluorescence assay, western blot analysis, and transmission electron microscopy. Furthermore, we performed behavioral assessments using the open field test, the novel object recognition test, and the Morris water maze test. We identified 1969 differentially expressed genes induced by young plasma treatment, including 800 upregulated genes and 1169 downregulated genes, highlighting several enriched biological processes (signal release from synapse, postsynaptic density and neuron to neuron synapse). Anesthesia- and surgery-induced cognitive impairment in aged rats was comparatively less severe following young plasma preinfusion. In addition, the decreased levels of synapse-related and tyrosine kinase B/extracellular signal-regulated protein kinase/cyclic adenosine monophosphate response element-binding protein (TrkB/ERK/CREB) signaling pathway-related proteins, dendritic and spine deficits, and ultrastructural changes were ameliorated in aged mice following young plasma preinfusion. Together, these findings suggest that young plasma reverses anesthesia- and surgery-induced cognitive impairment in aged rats and that the mechanism is associated with the activation of the TrkB/ERK/CREB signaling pathway and improvement in hippocampal synaptic plasticity.

Effects Of Aerobic Exercise On Synaptic Plasticity And PKA Expression In Hippocampus Of Aging Rats

PURPOSE: To investigate the Effects of aerobic exercise on synaptic plasticity and PKA expression in hippocampus of aging rats. METHODS: Sixty male SD rats were divided into 3 group at random: saline control group(SC), aging model group(S), aerobic exercise intervention on aging group(SE). Aging model was established by injecting low galactose via peritoneal, 100 mg / kg, once a day for 6 weeks in S and SE. And S were injected the same dosage of saline. D-gal were injected in S and SE and were simultaneously administered for a 6-week swimming exercise intervention, 6 days a week for 1 hour a day. And the general state of rats was observed weekly. At the end of modeling and swimming, Morris water maze was used to evaluate the spatial learning and memory ability. HE staining was used to observe Morphological changes of Hippocampus. The expression of PKA was tested by western blotting. The expression of BDNF and SYN in Hippocampus was tested by immunofluorescence. The experimental data was reported as mean ± SE. level of significance was set at α = 0.05. RESULTS: 1) Compared with SC and SE, S showed obvious signs of aging, such as loss of weight, decrease of activity, loss hair and neurons significantly reducing, the cell morphology was incomplete and the chromatin was unevenly colored. 2) The Morris water maze test was showed that: Compared with SC, the escape latency of S was significantly increased (P < 0.01); the number of crossing the platform was significantly reduced (P < 0.01). Compared with S, the escape latency of SE was significantly decreased (P < 0.05), and the number of crossing the platform was significantly increased (P < 0.01). 3) Compared with S, the expression of PKA was significantly increased in SC and SE (1.30 ± 0.03 vs. 0.77 ± 0.07, P < 0.01; 1.22 ± 0.11 vs. 0.77 ± 0.07, P < 0.05). 4) Compared to S, the immunofluorescence density values of BDNF and SYN significantly increasing was observed in SC and SE (25.52 ± 1.34 vs. 16.83 ± 1.30, P < 0.01; 23.15 ± 1.26 vs. 16.83 ± 1.30, P < 0.05); (53.85 ± 6.14 vs. 25.68 ± 1.36, P < 0.01; 51.18 ± 1.26 vs. 25.68 ± 1.36, P < 0.01). CONCLUSIONS: 6 weeks of aerobic exercise effectively reverses brain injury and learning and memory impairment in aging rats. The mechanism may be related to significantly up-regulate the expression of PKA in hippocampus to promote synaptic plasticity and improve learning and memory ability.

Dexmedetomidine suppresses the isoflurane-induced neurological damage by upregulating Heme Oxygenase-1 via activation of the mitogen-activated protein kinase kinase 1/extracellular regulated protein kinases 1/nuclear factor erythroid 2-related factor 2 axis in aged rats

Dexmedetomidine (DEX) displays a neuroprotective role in aged rats with isoflurane (ISO)-induced cognitive impairment through antioxidant, and anti-inflammatory, and anti-apoptotic effects. Therefore, the present study was performed to define the molecular mechanism of DEX on ISO-induced neurological impairment in aged rats in relation to the MEK1/ERK1/Nrf2/HO-1 axis. The study enrolled elderly patients undergoing ISO anesthesia. Patient cognitive function following treatment with DEX was evaluated using mini-mental state examination (MMSE). The results revealed that DEX supplementation of anesthesia contributed to higher MMSE scores in patients one week post treatment. Rat model of neurological impairment was also induced in 18-month-age Wistar rats by ISO, followed by DEX treatment. Based on the results of Morris water maze experiment, ELISA, and TUNEL and hematoxylin-eosin staining, in vivo experiments confirmed that DEX could reduce the oxidative stress and neurological damage induced by ISO in rats. DEX activated the nuclear factor erythroid 2-related factor (Nrf2)/Heme Oxygenase 1 (HO-1) pathway. DEX upregulated the expression of Nrf2 and HO-1 by activating the MEK1/ERK1 pathway, whereby attenuating the ISO-caused oxidative stress and neurological damage in rats. Collectively, DEX suppresses the ISO-induced neurological impairment in the aged rats by promoting HO-1 through activation of the MEK1/ERK1/Nrf2 axis.

5-HT5A Receptor Antagonist ASP5736 Ameliorates Several Abnormal Behaviors in an Fmr1-Targeted Transgenic Male Rat Model of Fragile X Syndrome

BackgroundFragile X syndrome (FXS) is a genetic condition that causes a range of developmental problems, including intellectual disability, aggressive behavior, anxiety, abnormal sensory processing, and cognitive impairment. Despite intensive preclinical research in Fmr1-targeted transgenic mice, an effective treatment for FXS has yet to be developed. We previously demonstrated that ASP5736, a 5-Hydroxytryptamine (serotonin) receptor 5A receptor antagonist, ameliorated scopolamine-induced working memory deficits in mice, reference memory impairment in aged rats, and methamphetamine-induced positive symptoms and phencyclidine-induced cognitive impairment in animal models of schizophrenia. We hypothesized that ASP5736 may be effective for ameliorating similar behavior deficits in male Fmr1-targeted transgenic rats as a preclinical model of FXS.MethodsWe evaluated the effect of acute oral administration of ASP5736 on the abnormal behavior of hyperactivity (0.01, 0.1 mg/kg), prepulse inhibition (0.01, 0.03, 0.1 mg/kg), and the novel object recognition task (0.1 mg/kg) in Frmr1-knockout (KO) rats.Results Fmr1-KO rats showed body weight gain, hyperactivity, abnormal sensory motor gating, and cognitive impairment. ASP5736 (0.1 mg/kg) reversed the hyperactivity and ameliorated the sensory motor gating deficits (0.03–0.1 mg/kg). ASP5736 (0.01 mg/kg) also improved cognitive impairment.ConclusionsASP5736 is a potential drug candidate for FXS. Further studies are needed to confirm its clinical efficacy.

Molecular species of oxidized phospholipids in brain differentiate between learning- and memory impaired and unimpaired aged rats

Loss of cognitive function is a typical consequence of aging in humans and rodents. The extent of decline in spatial memory performance of rats, assessed by a hole-board test, reaches from unimpaired and comparable to young individuals to severely memory impaired. Recently, proteomics identified peroxiredoxin 6, an enzyme important for detoxification of oxidized phospholipids, as one of several synaptosomal proteins discriminating between aged impaired and aged unimpaired rats. In this study, we investigated several components of the epilipidome (modifications of phospholipids) of the prefrontal cortex of young, aged memory impaired (AI) and aged unimpaired (AU) rats. We observed an age-related increase in phospholipid hydroperoxides and products of phospholipid peroxidation, including reactive aldehydophospholipids. This increase went in hand with cortical lipofuscin autofluorescence. The memory impairment, however, was paralleled by additional specific changes in the aged rat brain epilipidome. There was a profound increase in phosphocholine hydroxides, and a significant decrease in phosphocholine-esterified azelaic acid. As phospholipid-esterified fatty acid hydroxides, and especially those deriving from arachidonic acid are both markers and effectors of inflammation, the findings suggest that in addition to age-related reactive oxygen species (ROS) accumulation, age-related impairment of spatial memory performance has an additional and distinct (neuro-) inflammatory component.

The major anthocyanin of Lycium ruthenicum Murr. relieves cognitive deficits, oxidative stress, neuroinflammation, and hippocampal metabolome alterations in aging rats

• Pn3G5G is the most abundant anthocyanin in LRF. • Long term administration of Pn3G5G improved cognitive impairment of aging rats. • Pn3G5G reduced hippocampal pathologic changes, oxidative stress, and inflammation. • Pn3G5G effectively restored the abnormal hippocampal metabolites in aging rats. Lycium ruthenicum Murr. fruit (LRF) is a functional food that abundant in anthocyanins. In this study, the neuroprotection of the major anthocyanin in LRF, namely petunidin-3,5-O-diglucosides (Pn3G5G), was investigated in D-galactose-induced aging rats. Our results showed that administration of Pn3G5G by oral gavage (100 mg/kg·bw) for 7 weeks did not influence the body weight and motor function of rats. More importantly, Pn3G5G could relieve cognitive deficits, mitigate cortical and hippocampal neuron loss, reduce the levels of aging-related markers (AGEs and MDA), increase the ratio of GSH/GSSG, and suppress neuroinflammation in the hippocampus. LC-MS-based metabolomics revealed that Pn3G5G could restore the altered hippocampal metabolic profile. In total, 39 differential metabolites and 47 pathways were involved. Particularly, Pn3G5G corrected amino acid metabolic problems by restoring the levels of L-cystine, L-histidine, L-serine, S-sulfo-L-cysteine, L-asparagine, glutathione (reduced form), L-saccharopine, N-acetyl-L-leucine, 5-oxoproline (pyroglutamic acid), 3-N-methyl-L-histidine and N-methyl-L-glutamate to protect neurons from oxidative stress and inflammatory damage. Besides, Pn3G5G also regulate ABC transporters, protein digestion and absorption, and biosynthesis of cofactors to prevent abnormal energy metabolism of neurons. In conclusion, Pn3G5G likely enhance antioxidant and anti-inflammatory defenses, as well as maintain normal function of hippocampus through influencing these metabolic pathways, thereby alleviating cognitive impairment in aging rats.

Hypercholesterolemia aggravates sevoflurane-induced cognitive impairment in aged rats by inducing neurological inflammation and apoptosis.

We aimed to explore the effects of hypercholesterolemia on sevoflurane-induced cognitive impairment in aged rats and the underlying mechanism(s). Aged rats were administrated with high-fat diet, sevoflurane, or both. Thereafter, the plasma levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) were evaluated. The Morris water maze task was performed to evaluate the spatial learning and memory ability of rats. Moreover, Nissl and Evans blue staining were conducted to test nerve damage and detect the blood-brain barrier permeability, respectively. The percentage of apoptotic cells was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling assay. The messenger RNA expression of inflammatory factors and protein expression of microglial activation markers and apoptosis-related proteins were tested by real-time polymerase chain reaction, enzyme-linked immunosorbent assay, or western blot analysis, respectively. High-fat diet induced high levels of TC, TG, and LDL but decreased levels of HDL. However, sevoflurane had no effects on these levels. In contrast, sevoflurane significantly induced the impairment of learning and memory, nerve damage, neuroinflammatory damage, and neuronal apoptosis. Hypercholesterolemia exacerbated the sevoflurane-induced impairment in aged rats. These results suggested that hypercholesterolemia aggravates sevoflurane-induced cognitive impairment in aged rats, possibly by inducing neurological inflammation and apoptosis.