Dysfunction In Aged Rats Research Articles

Polygonatum polysaccharide ameliorates D-galactose-induced cognitive dysfunction in aging rats by inhibiting ferroptosis through activation of Nrf2

ContextAging is a major risk factor for various neurodegenerative diseases, and ferroptosis has been identified as an important mode of cell death during accelerated aging. As the main component of the edible plant YuZhu in China, Polygonatum polysaccharide (POP) is an important natural compound with anti-aging properties. ObjectiveTo evaluate the anti-aging effects of POP and the underlying molecular mechanisms involved and to evaluate the overall anti-aging effects of POP on cognitive impairment due to accelerated aging. Materials and methodsA D-galactose (D-gal)-induced accelerated aging rat model was established to evaluate the anti-aging effects of POP and the underlying molecular mechanisms involved. In turn, Morris water maze and open field experiments were used to evaluate the anti-aging effects of POP on cognitive impairment due to accelerated aging. ResultsThe mechanism by which POP affects nuclear factor E2-related factor 2 (Nrf2), an essential transcription factor, was confirmed. POP significantly improved d-gal-induced cognitive dysfunction in treated model rats, which exhibited reduced pathological changes in the hippocampus, reduced latency of the water maze platform, and increased exploration time in the central area in the open field experiment compared to those of untreated model rats. Furthermore, POP intervention downregulated ferroptosis-related proteins and upregulated Nrf2 expression, and selective inhibition of Nrf2 eliminated the ability of POP to reduce ferroptosis. ConclusionsPOP is a natural ingredient with therapeutic potential due to its ability to alleviate aging by activating Nrf2, inhibiting ferroptosis, and alleviating cognitive dysfunction.

Propionic acid ameliorates cognitive function through immunomodulatory effects on Th17 cells in perioperative neurocognitive disorders

BackgroundElderly patients undergoing surgery are prone to cognitive decline known as perioperative neurocognitive disorders (PND). Several studies have shown that the microglial activation and the decrease of short-chain fatty acids (SCFAs) in gut induced by surgery may be related to the pathogenesis of PND. The purpose of this study was to determine whether microglia and short-chain fatty acids were involved in cognitive dysfunction in aged rats. MethodsMale wild-type Wistar rats aged 11–12 months were randomly divided into control group (Ctrl: Veh group), propionic acid group (Ctrl: PA group), exploratory laparotomy group (LP: Veh group) and propionic acid + exploratory laparotomy group (LP: PA group) according to whether exploratory laparotomy (LP) or PA pretreatment for 21 days was performed. The motor ability of the rats was evaluated by open field test on postoperative day 3 (POD3), and then the cognitive function was evaluated by Y-maze test and fear conditioning test. The expression of IL-1β, IL-6, RORγt and IL-17A mRNA in hippocampus was detected by RT-qPCR, the expression of IL-17A and IL-17RA in hippocampus was detected by Western blot, and the activation of microglia was detected by immunofluorescence. ResultsThe PND rat model was successfully established by laparotomy. Compared with Ctrl: Veh group, the body weight of LP: Veh group decreased, the percentage of spontaneous alternations in Y maze decreased (P < 0.001), and the percentage of freezing time in contextual fear test decreased (P < 0.001). Surgery triggers neuroinflammation, manifested as the elevated levels of the inflammatory cytokines IL-1β (P < 0.001) and IL-6 (P < 0.001), the increased expression of the transcription factor RORγt (P = 0.0181, POD1; P = 0.0073, POD5)and major inflammatory cytokines IL-17A (P = 0.0215, POD1; P = 0.0071, POD5), and the increased average fluorescence intensity of Iba1 (P < 0.001, POD1; P < 0.001, POD5). After PA preconditioning, the recovery of rats in LP: PA group was faster than that in LP: Veh group as the body weight lost on POD1 (P = 0.0148) was close to the baseline level on POD5 (P = 0.1846), and they performed better in behavioral tests. The levels of IL-1β (P < 0.001) and IL-6 (P = 0.0035) inflammatory factors in hippocampus decreased on POD1 and the average fluorescence intensity of Iba1 decreased (P = 0.0024, POD1; P < 0.001, POD5), representing the neuroinflammation was significantly improved. Besides, the levels of RORγt mRNA (P = 0.0231, POD1; P = 0.0251, POD5) and IL-17A mRNA (P = 0.0208, POD1; P = 0.0071, POD5) in hippocampus as well as the expression of IL-17A (P = 0.0057, POD1; P < 0.001, POD5) and IL-17RA (P = 0.0388) decreased. ConclusionPA pretreatment results in reduced postoperative neuroinflammation and improved cognitive function, potentially attributed to the regulatory effects of PA on Th17-mediated immune responses.

The effects of dexmedetomidine on postoperative cognitive dysfunction in rats with bone fractures undergoing open reduction.

To investigate the effects of dexmedetomidine on the cognitive dysfunction of aged rats after open tibia fracture surgery and the expression of inflammatory cytokines in the hippocampus. A total of 45 aged healthy male Sprague Dawley rats were divided into control group, sham group, and dexmedetomidine group. The open tibia fracture surgery rat model was established, and dexmedetomidine was intraperitoneally injected before operation. The cognitive function of aged rats was examined by Morris Water-Maze Test, open field experiment, and passive avoidance memory test. The expression levels of IL-6, IL-1β, and TNF-α in the hippocampus were examined by enzyme-linked immunosorbent assay (ELISA). The escape latency over 5 continuous days in the dexmedetomidine group was significantly shorter than that in the control group (all P<0.05). The number of swimming times and the percentage of swimming time in the dexmedetomidine group were significantly higher and longer than those in the control group (all P<0.05). Moreover, rats in the dexmedetomidine group exhibited shorter time of stay at the central square and higher number of standing times in comparison with the control group (all P<0.05). Compared with the control group, dexmedetomidine intraperitoneally injected before surgery significantly inhibited the expression levels of IL-6, IL-1β, and TNF-α in the hippocampus (all P<0.05). Dexmedetomidine could significantly relieve the postoperative cognitive dysfunction in aged rats. The mechanism may be associated with the decreased inflammatory cytokines in the hippocampus.

SESN2 attenuates sevoflurane-induced cognitive impairment and neuroinflammation in rats.

Long-term use of sevoflurane, an inhalation anesthetic, could negatively impact cognitive function. Current studies have suggested that cognitive impairment induced by sevoflurane may be associated with neuroinflammation. Sestrin2 (SESN2), which belongs to a family of stress-inducible genes, has been reported to exert neuroprotective effects against brain injury. However, its role and underlying mechanisms in sevoflurane-induced cognitive dysfunction in aged rats remain unknown. A sevoflurane-induced aging rat injury model with or without SESN2 overexpression was constructed. The learning and memory abilities of rats were evaluated by the MWM test. ELISA assay and qRT-PCR were conducted to analyze the level of pro-inflammatory factors in the hippocampus. Levels of oxidative stress markers were measured by DHE staining or kit methods. Neuronal apoptosis in the hippocampus was detected using TUNEL assay. Expression of proteins were analyzed by western blot. Sevoflurane exposure caused elevated protein level of SESN2 in hippocampus and cognitive impairment of aged rats. Importantly, overexpression of SESN2 alleviated sevoflurane-induced cognitive dysfunction and inhibited the production of pro-inflammatory factors, oxidative stress, and neuronal apoptosis in the hippocampus. Furthermore, SESN2 overexpression suppressed NLRP3 inflammasome activation induced by sevoflurane. These findings suggested that SESN2 could exert neuroprotective against sevoflurane-induced nerve injury of aged rats through anti-oxidant and anti-inflammatory effects.

Abstract 148: Differential Neuroprotective Effects of Targeted Temperature Management in Adult and Aged Rats Post-Cardiac Arrest

Background: Targeted temperature management (TTM) has been recognized as a crucial brain protective method post-cardiac arrest (CA). However, its efficacy has recently been questioned due to several clinical trials. Hypothesis: TTM may not offer significant neuroprotective benefits in older individuals post-CA. Aims: This study aims to evaluate the therapeutic efficacy of TTM on neurological dysfunction in aged rats post-CA. Methods: Fifty-six male Sprague-Dawley (SD) rats were divided into two age groups: adult group (3-4 months, n=28) and aged group (19-22 months, n=28). Each group was then randomized into four subgroups: 1) sham, 2) sham + TTM, 3) control, 4) control + TTM. Control and control + TTM groups underwent 6 minutes of asphyxiation followed by cardiopulmonary resuscitation. TTM was applied at 32-34°C for 2 hour post-return of spontaneous circulation (ROSC). Neurological outcomes were assessed five days post-CA using the Y-maze and the Open field test. Serum IL-17 and IL-6 levels were measured four hours post-CA. Results: TTM significantly enhanced the spontaneous alternation in the Y-maze (p &lt;0.05), increased moter active in Open field test (p&lt;0.05), and reduced serum IL-17 and IL-6 levels in the adult group (p &lt;0.05). Conversely, in the aged group, TTM did not exhibit any significant benefits in Y maze performance, Open field test, IL-17 or IL-6 serum levels reduction (p &gt;0.05). Conclusion(s): TTM demonstrated improvement in post-CA neurological deficits in adult rats, yet it failed to deliver similar benefits in aged rats. IL-6 and IL-17 might play a role in the differential neuroprotective effects of TTM.

Impaired nitric oxide mechanisms underlying lower urinary tract dysfunction in aging rats.

The study aimed to investigate the bladder and urethral activity and nitric oxide (NO)-related molecular changes in aging rats. Rats were divided into two groups: Group Y (young rats; 12 wk) and Group A (aging rats; 15 mo). A 24-h voiding assay was performed, and the urodynamic parameters were evaluated using awake cystometry (CMG) and urethral perfusion pressure (UPP) recordings under urethane anesthesia. The mRNA expression levels of NO-, ischemia-, and inflammation-related markers in urethra and bladder tissues and cGMP levels in the urethra were assessed. Body weight was significantly higher in Group A than in Group Y. Voiding assay results (24 h) were insignificant. In the CMG, the number of non-voiding contractions per voiding cycle and post-void residual volume were significantly higher in Group A than in Group Y; voiding efficiency was significantly lower in Group A than in Group Y. In the UPP recordings, the urethral pressure reduction and high-frequency oscillation (HFO) amplitude were significantly lower in Group A than in Group Y. The mRNA expression levels of Hif-1α, Vegf-a, and Tgf-β1 in the bladder were significantly higher in Group A than in Group Y. The mRNA expression levels of Nos1 and Prkg1 and the cGMP concentrations in the urethra were significantly lower in Group A than in Group Y. Aging rats can be useful models for studying the natural progression of age-related lower urinary tract dysfunctions, for which impaired NO-mediated transmitter function is likely to be an important mechanism.NEW & NOTEWORTHY Aging rats can be useful models for studying the natural progression of age-related lower urinary tract dysfunctions, for which impaired nitric oxide-mediated transmitter function is likely to be an important mechanism.

Effects of electroacupuncture pretreatment on long-term postoperative cognitive dysfunction and neuron-inflammation in aged rats

To observe the effects of electroacupuncture pretreatment on postoperative cognitive dysfunction (POCD), neuronal apoptosis and neuron-inflammation in aged rats. Thirty-six male SD rats aged 20 months were randomly divided into sham operation group, model group and electroacupuncture (EA) group, with 12 rats in each group. The POCD rats model was prepared by internal fixation of left tibial fracture. Five days before modeling, EA stimulation (2 Hz/15 Hz, 1 mA, 30 min) was applied to "Zusanli" (ST36), "Hegu" (LI4) and "Neiguan" (PC6) on the unaffected side of rats in the EA group, once a day for consecutive 5 d. The learning and memory abilities of rats were evaluated by water maze test 31-35 days after operation. The apoptosis of hippocampal neurons was observed by Tunel/NeuN double staining. The expressions of high mobility group protein B1 (HMGB1) and phosphorylated (p)-nuclear factor (NF)-κB in microglia cells in hippocampal dentate gyrus were detected by immunofluorescence staining. The expression levels of interleukin (IL)-6 and IL-1β in the hippocampus were detected by Western blot. Compared with the sham operation group, the escape latency was prolonged (P<0.05); the frequency of crossing the original platform, ratio of the swimming distance and the time in the target quadrant of the Morris water maze were significantly decreased (P<0.05); the apoptosis rate of hippocampal neurons was significantly increased (P<0.05); the expressions of HMGB1 and p-NF-κB in microglia cells in the dentate gyrus and the expression levels of IL-6 and IL-1β in hippocampus were increased (P<0.05) in the model group. Compared with the model group, the results of the above indexes were all opposite (P<0.05) in the EA group. EA preconditioning can regulate hippocampal inflammatory response, alleviate neuronal apoptosis rate and long-term cognitive dysfunction in aged rats with POCD, the mechanisms may be related to the inhibition of microglia HMGB1/NF-κB pathway in hippocampal dentate gyrus.

Maresin1 ameliorates postoperative cognitive dysfunction in aged rats by potentially regulating the NF-κB pathway to inhibit astrocyte activation

Postoperative cognitive dysfunction (POCD) is one of the most serious postoperative complications in the elderly population. Perioperative central neuroinflammation is considered to be an important pathological mechanism of POCD, with the activation of astrocytes playing a key role in central neuroinflammation. Maresin1 (MaR1) is a specific pro-resolving mediator synthesized by macrophages in the resolution stage of inflammation, and provides unique anti-inflammatory and pro-resolution effects by limiting excessive neuroinflammation and promoting postoperative recovery. However, the question remains whether MaR1 can have a positive effect on POCD. The objective of this study was to investigate the protective effect of MaR1 on POCD cognitive function in aged rats after splenectomy. Morris water maze test and IntelliCage test showed that splenectomy could cause transient cognitive dysfunction in aged rats; however, the cognitive impairment of rats was significantly mitigated when MaR1 pretreatment was administered. MaR1 significantly alleviated the fluorescence intensity and protein expression of glial fibrillary acidic protein and central nervous system specific protein in the cornu ammonis 1 region of the hippocampus. Simultaneously, the morphology of astrocytes was also severely altered. Further experiments showed that MaR1 inhibited the mRNA and protein expression of several key proinflammatory cytokines–interleukin-1β, interleukin-6, and tumor necrosis factor-α in the hippocampus of aged rats following splenectomy. The molecular mechanism underlying this process was explored by evaluating expression of components of the nuclear factor κB (NF-κB) signaling pathway. MaR1 substantially inhibited the mRNA and protein expression of NF-κB p65 and κB inhibitor kinase β. Collectively, these results suggest that MaR1 ameliorated splenectomy-induced transient cognitive impairment in elderly rats, and this neuroprotective mechanism may occur through regulating the NF-κB pathway to inhibit astrocyte activation.

Luteoloside Prevents Sevoflurane-induced Cognitive Dysfunction in Aged Rats via Maintaining Mitochondrial Function and Dynamics in Hippocampal Neurons.

Postoperative cognitive dysfunction (POCD) is characterized by impaired cognitive function, such as decreased learning and memory after anesthesia and surgery. This study aimed to explore the effect of luteoloside, a flavonoid extracted from natural herbs, on sevoflurane-induced cognitive dysfunction. Aged Sprague-Dawley male rats (20months old) were treated with luteoloside for 7days prior to sevoflurane exposure. After evaluation using an open field, novel object recognition, and Y-maze tests, it was determined that luteoloside effectively prevented sevoflurane-induced cognitive dysfunction. Sevoflurane exposure led to hippocampal neuron apoptosis in vivo (n=6) and in vitro (n=3), while this injury was prevented by luteoloside in a dose-dependent manner. Mechanistically, luteoloside maintained mitochondrial function and dynamics, as evidenced by the restored adenosine triphosphate (ATP) production and mitochondrial membrane potential as well as the upregulated levels of mitochondrial fission (optic atrophy protein 1 (Opa1) and mitofusin1 (Mfn1)) and downregulated mitochondrial fusion (mitochondrial fission 1 (Fisl) and dynamin-related protein 1 (Drp1)) factors. Notably, silencing Opa1 blocked the protective effect of luteoloside on hippocampal neurons and mitochondrial function. In summary, luteoloside prevented sevoflurane-induced cognitive dysfunction in aged rats, which may be achieved by regulating mitochondrial dynamics. Our study reveals the potential of luteoloside in preventing POCD in aged patients.

Abdominal surgery plus sevoflurane exposure induces abnormal emotional changes and cognitive dysfunction in aged rats

BackgroundCognitive impairment, which includes perioperative psychological distress and cognitive dysfunction, can be determined by preoperative and post-operative neuropsychological tests. Several mechanisms have been proposed regarding the two-way communication between the immune system and the brain after surgery. We aimed to understand the mechanisms underlying perioperative neurocognitive disorders (PND) in elderly rats using an experimental abdominal surgery model. Methods24-month-old SD rats were exposed to the abdominal surgery model (AEL) under 3% anesthesia. On day 15 and day 30 post-surgery, fractional anisotropy (FA) using diffusion kurtosis imaging (DKI) was measured. From day 25 to day 30 post-surgery, behavioral tests, including open field test (OFT), Morris water maze (MWM), novel object recognition (NOR), force swimming test (FST), and elevated plus maze (EPM), were performed. Then, the rats were euthanized to perform pathological analysis and western blot measurement. ResultsThe rats exposed to AEL surgical treatment demonstrated significantly decreased time crossing the platform in the MWM, decreased recognition index in the NOR, reduced time in the open arm in the EPM, increased immobility time in the FST, and increased number of crossings in the OFT. Aged rats, after AEL exposure, further demonstrated decreased FA in the mPFC, nucleus accumbens (NAc), and hippocampus, together with reduced MAP2 intensity, attenuation of GAD65, VGlut2, CHAT, and phosphorylated P38MAPK expression, and increased reactive astrocytes and microglia. ConclusionsIn this study, the aged rats exposed to abdominal surgery demonstrated both emotional changes and cognitive dysfunction, which may be associated with neuronal degeneration and reduced phosphorylated P38MAPK.

Chronic stress-induced apoptosis is mitigated by young mitochondria transplantation in the prefrontal cortex of aged rats.

Apoptosis is common and often comorbid with aging and stress-related mood disorders. Evidence suggests that fresh mitochondria could reverse age-related dysfunctions in organs, especially in the brain. Therefore, this study investigated the effect of young mitochondria administration on the apoptosis process in the prefrontal cortex (PFC) of aged rats exposed to chronic stress. Aged (22 months old) male rats were randomly assigned into four groups: aged control (AC), aged rats treated with young mitochondria (A+M), aged rats subjected to chronic stress for four weeks (A+St), and aged rats subjected to chronic stress and treated with young mitochondria (A+St+M). A+M and A+St+M groups received a single ICV injection (10 μl) of fresh mitochondria isolated from the brain of young rats for five minutes (2 µl/min). Finally, the levels of Malondialdehyde (MDA), Cytochrome c (Cyt c), Bax, Bcl-2, and Caspase-3 expression were investigated in the PFC. Young mitochondria administration reduced neuronal apoptosis in the PFC, associated with down-regulation of MDA, Bax, and Caspase-3 and up-regulation of Bcl-2. Moreover, fresh mitochondria partially improved the chronic stress-induced mitochondrial dysfunction in aged rats, as indicated by reduced cytochrome c (Cyt c) release from the mitochondria. These results suggest mitotherapy could reverse cell viability and mitochondrial dysfunction-induced apoptosis in the PFC tissue of aged rats subjected to stressful stimuli.

Naringin Prevents Cognitive Dysfunction in Aging Rats by Inhibiting Toll-Like Receptor 4 (TLR4)/NF-κB Pathway and Endoplasmic Reticulum Stress.

Naringin is a flavonoid derived from Chinese herbs. According to earlier studies, naringin may have the potential to alleviate aging-induced cognitive dysfunction. Therefore, this study attempted to explore the protective effect and underlying mechanism of naringin on aging rats with cognitive dysfunction. After the construction of a model of aging rats with cognitive dysfunction through subcutaneous injection of D-galactose (D-gal; 150 mg/kg), intragastric administration of naringin (100 mg/kg) was performed for treatment. Behavioral tests, including Morris water maze test (MWM), novel object recognition test (NORT), and fear conditioning test, were used to measure the cognitive function; ELISA and biochemical tests were used to determine the levels of interleukin (IL)-1β, IL-6, monocyte chemoattractant protein-1 (MCP-1), brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), malondialdehyde (MDA), and glutathione peroxidase (GSH-Px) in the hippocampus of rats in each group, respectively; H&E staining was used to observe the pathological changes in the hippocampus; Western blot was used to examine the expression of toll-like receptor 4 (TLR4)/NF-κB pathway-related proteins and endoplasmic reticulum (ER) stress-related proteins in the hippocampus. The model was successfully constructed by subcutaneous injection of D-gal (150 mg/kg). The behavioral test results showed that naringin could ameliorate the cognitive dysfunction and alleviate the histopathological damage of hippocampus. Moreover, naringin significantly improve the inflammatory response (the levels of IL-1β, IL-6, and MCP-1 were decreased), oxidative stress response (MDA level was increased while GSH-Px activity was decreased), and ER stress (the expression of glucose-regulated protein 78 (GRP78), C/-EBP homologous protein (CHOP), and transcription factor 6 (ATF6) expression was downregulated), and increased the levels of neurotrophic factors BDNF and NGF in D-gal rats. Besides, further mechanistic studies revealed the downregulation of naringin on TLR4/NF-κB pathway activity. Naringin may inhibit inflammatory response, oxidative stress, and ER stress by downregulating TLR4/NF-κB pathway activity, thereby improving cognitive dysfunction and alleviating histopathological damage of hippocampus in aging rats. Briefly, naringin is an effective drug for the treatment of cognitive dysfunction.

Stellate Ganglion Block Improves Postoperative Cognitive Dysfunction in aged rats by SIRT1-mediated White Matter Lesion Repair

Postoperative cognitive dysfunction (POCD) is a common complication of the central nervous system after surgery, especially in elderly patients. Many factors can influence POCD, one of which is white matter lesion. Nowadays, stellate ganglion block (SGB) is considered as an effective intervention for postoperative cognitive dysfunction and SIRT1 may play a role in that, but the exact mechanism remains unclear. Therefore, the underlying mechanisms that SGB improves postoperative cognitive dysfunction through SIRT1 in aged rats and its association with white matter lesion are yet to be elucidated. The role of SIRT1 in the process that stellate ganglion block improves the cognitive impairment, and its association with white matter lesion was investigated using splenectomy-induced POCD model. To investigate this result further, we performed transection of the cervical sympathetic trunk on the basis of POCD model, and the role of SIRT1 was then verified again by intraperitoneal injection of EX527 (5mg/kg) five min before surgery. Data show that SGB treatment has neuroprotective effects in POCD rats. SGB treatment can ameliorate cognitive impairment, neuroinflammation and neuronal apoptosis in white matter. Moreover, SGB treatment enhanced the expression of SIRT1 in the hippocampus and white matter, decreased NF-κB activity in the hippocampus and white matter. It also increased the levels of inflammatory factor in serum and white matter, primarily at the level of anti-inflammatory factor. These findings indicated that SIRT1-mediate white matter repair could be a new therapeutic target for neurodegenerative illnesses.

MiR-182-5p Delivered by Plasma Exosomes Promotes Sevoflurane-Induced Neuroinflammation and Cognitive Dysfunction in Aged Rats with Postoperative Cognitive Dysfunction by Targeting Brain-Derived Neurotrophic Factor and Activating NF-κB Pathway.

The objective of this study was to discuss the possible mechanism and effect of miR-182-5p delivered by plasma exosomes on sevoflurane-induced neuroinflammation and cognitive disorder in aged rats with postoperative cognitive dysfunction (POCD). Firstly, aged POCD rat models were constructed by sevoflurane anesthesia and superior mesenteric artery occlusion. Subsequently, exosomes and miR-182-5p were inhibited by injection of GW4869 and miR-182-5p-sponge, respectively. Then, exosomes were extracted from the plasma of rats in each group, followed by the determination of the morphology and diameters of exosomes as well as the expression of exosome markers CD63 and CD81 by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot. Besides, the Morris water maze (MWM) and fear conditioning test were used to evaluate the learning and memory ability of rats; Western blot to detect the expression levels of neurotrophic factors (brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF)) as well as NF-κB pathway-related proteins (p65 and p-p65) in rat hippocampal tissues or PC-12 cells; qRT-PCR to assess the expression levels of miR-182-5p and BDNF in rat plasma, plasma exosomes, hippocampal tissues, and PC-12 cells; ELISA to evaluate the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β in rat hippocampal tissues; and dual-luciferase reporter assay to verify the targeting relationship between miR-182-5p and BDNF. After examination, the results were obtained as follows. miR-182-5p expression was up-regulated in POCD rats and could be delivered by plasma exosomes. Inhibition of plasma exosomes or miR-182-5p could significantly ameliorate learning and memory disorders; decrease the levels of pro-inflammatory cytokines TNF-α, IL-6, and IL-1β; increase the expression of BDNF and NGF; and inhibit the activity of NF-κB signaling pathway in POCD rat hippocampus. In addition, miR-182-5p could also target and inhibit BDNF. All in all, miR-182-5p delivered by plasma exosomes promotes sevoflurane-induced neuroinflammation and cognitive dysfunction in aged POCD rats by targeting BDNF and activating the NF-κB pathway.

Sevoflurane exposure causes neuronal apoptosis and cognitive dysfunction by inducing ER stress via activation of the inositol 1, 4, 5-trisphosphate receptor.

The role of the inositol 1, 4, 5-trisphosphate receptor (IP3R) in hippocampal neuronal apoptosis and cognitive dysfunction induced by sevoflurane is currently unclear. Therefore, in this study, we investigated the role of the IP3R in endoplasmic reticulum (ER) stress and hippocampal neuronal apoptosis induced by sevoflurane in aged rats and isolated hippocampal neurons using both in vivo and in vitro experiments, including bioinformatics, functional enrichment analysis, gene set enrichment analysis, hematoxylin, and eosin staining, TUNEL assay, flow cytometry, western blot analysis and transmission electron microscopy. Furthermore, behavioral assessment was performed with the Morris water maze test. We identified 232 differentially expressed genes induced by sevoflurane exposure, including 126 upregulated genes and 106 downregulated genes. Sevoflurane exposure caused cognitive impairment and neuronal injury, and increased p-IP3R levels and ER stress. An IP3R inhibitor, 2-APB, suppressed these changes, while an IP3R agonist, FK-506, aggravated these changes. Together, these findings suggest that sevoflurane exposure causes marked cognitive dysfunction in aged rats and neuronal injury in isolated hippocampal neurons by activating the IP3R and inducing cytoplasmic calcium overload, thereby resulting in ER stress and hippocampal neuronal apoptosis. GRAPHICAL ABSTRACT.

Suppression of phosphodiesterase IV enzyme by roflumilast ameliorates cognitive dysfunction in aged rats after sevoflurane anaesthesia via PKA-CREB and MEK/ERK pathways.

Postoperative cognitive dysfunction (POCD) is a prevalent disorder after anaesthesia in the elderly patients. Roflumilast (RF), a phosphodiesterase 4 (PDE-4) inhibitor, could improve cognition with no side effects. Here, we sought to explore the efficacy of RF in the improvement of cognitive dysfunction caused by sevoflurane (Sev). Sprague-Dawley rats were anaesthetized, and the hippocampal neurons were treated with Sev to develop in vivo and in vitro POCD models, followed by RF administration. The mechanism of the PKA-CREB and MEK/ERK pathways in the pathogenesis of POCD was explored. Sev impaired the cognitive functions of rats, significantly reduced cyclic adenosine monophosphate (cAMP) concentrations and blocked the PKA-CREB and MEK/ERK pathways. Moreover, the Sev-treated rats and neurons exhibited enhanced apoptosis and reactive oxygen species (ROS). After treatment with RF, rats had better learning and memory function, and the activity of neurons in hippocampus and cortex was improved. Loss-of-function assay indicated that PKA-CREB and MEK/ERK signalling impairment reduced cAMP levels and promoted apoptosis and ROS in rat hippocampus and neurons. Generally, RF promotes neuronal activity in rats after Sev treatment by maintaining cAMP levels and sustaining the activation of PKA-CREB and MEK/ERK pathways. This might offer novel sights for POCD therapy.

Glycoproteins of Capsosiphon fulvescens modulate synaptic clustering of PSD95 and prevent social isolation-induced cognitive decline in aged male rats

Social isolation and loneliness inducing cognitive decline are serious health problems in the elderly. Although the hydrophilic glycoproteins of Capsosiphon fulvescens (Cf-hGP) prevent aging-induced cognitive impairment, its effects on social isolation-induced cognitive dysfunction are unclear. This study investigated the efficacy of Cf-hGP against cognitive dysfunction in aged rats and delineated its underlying mechanisms. The oral administration of Cf-hGP (15 mg/kg/d, 4 weeks) reversed the social isolation-induced decreases in phosphorylation of extracellular signal‑regulated protein kinase 1/2 (ERK1/2), postsynaptic density protein 95, and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor subunit 1 and increased expression of metabotropic glutamate receptor 5 in the synaptosome of the dorsal hippocampus. Furthermore, Cf-hGP prevented social isolation-induced spatial memory impairment, and its effects were attenuated by inhibition of ERK1/2 or deglycosylation of Cf-hGP. Cf-hGP-induced clustering of ERK1/2-mediated postsynaptic density protein 95 in the dorsal hippocampus improves memory formation in socially isolated aged rats, and protein glycosylation contributes to enhancing the Cf-hGP effect.

Effects of Atipamezole Preconditioning on Cognitive Function and Protein Expression in Related Brain Regions of Aged Rats after General Anesthesia.

To explore the possible mechanism of atipamezole in improving cognitive function after general anesthesia in aged rats, forty-five aged SD rats were separated into control, model, and atipamezole groups. Rats in the model group were anesthetized by intraperitoneal injection of 75 mg/kg ketamine plus 5 mg/kg midazolam. Results showed that the escape incubation period of the atipamezole group versus model group on the 2nd, 3rd, and 4th days was shortened, residence time of platform quadrant was prolonged on the 5th day, and number of times of crossing platform quadrant was increased. Compared with the control group, the residence time in the central region of the model group was shortened on the 1st, 2nd, and 3rd days. Atipamezole group's central residence time was prolonged on the 1st, 2nd, and 3rd days compared to the model group. Concentrations of IL-1, IL-6, and TNF-α in the hippocampus of the atipamezole group decreased significantly compared to the model group. The expressions of p-CREB and c-fos proteins in the prefrontal cortex and nucleus accumbens of rats in the atimezazole group were higher than those in the model group. In conclusion, atipamezole preconditioning can reduce cognitive dysfunction in aged rats after general anesthesia, and its mechanism may be related to inhibiting hippocampal inflammatory reaction and improving protein expression levels of p-CREB and c-fos in related brain regions of aged rats.

Neuroprotective effect of AGGF1 against isoflurane-induced cognitive dysfunction in aged rats through activating the PI3K/AKT signaling pathways.

This study aimed to evaluate and identify the value and explore the mechanisms of Angiogenic Factor with G-patch and FHA domains 1 (AGGF1) in postoperative cognitive dysfunction (POCD). Rats were separated into four different groups, namely sham, isoflurane, isoflurane + recombinant human Aggf1 (rh-Aggf1) (5 μg kg-1), and isoflurane + rh-Aggf1 (10 μg kg-1). qPCR and western blot assays were applied to detect the correlation between the expression of AGGF1 and isoflurane administration. Then, the Morris water maze (MWM) test was applied to evaluate the effect of AGGF1 on improving the POCD rats. Subsequently, TUNEL assay was applied and the cell apoptosis-related proteins were tested to reveal the anti-apoptotic effect of AGGF1 in POCD rats. Furthermore, the mRNA and protein levels of TNF-α, IL-6, and IL-1β were also detected by qPCR and ELISA to verify the anti-inflammatory effects of AGGF1 on POCD rats. Besides, the protein expression levels of PI3K, Akt, and NF-κB in each group were examined by western blot. In this study, the results revealed that isoflurane induced a decrease in AGGF1 expression in the hippocampus of aged rats. In addition, exogenous AGGF1 attenuated POCD in aged rats. Meanwhile, exogenous AGGF1 had anti-apoptotic and anti-inflammatory effects in POCD rats. Further research indicated that AGGF1 activated the PI3K/Akt pathway. AGGF1 has neuroprotective effect against isoflurane-induced cognitive dysfunction in aged rats via activating the PI3K/AKT signaling pathways.

Study on the Effect of Dexmedetomidine on Postoperative Cognitive Dysfunction and Inflammation in Aged Rats.

Objective The aim of this study is to investigate the effect of dexmedetomidine on cognitive dysfunction and inflammatory cytokines in the hippocampus after surgery in aged rats. Methods A total of 30 healthy male Sprague Dawley rats were divided into control group, sham group, and dexmedetomidine group. A splenectomy rat model was established and dexmedetomidine was intraperitoneally injected before operation. The cognitive function of rats was examined by Morris Water-Maze Test, open field experiment, and passive avoidance memory test. And the expression levels of IL-6, IL-1β, and TNF-α in the hippocampus were examined by ELISA. Results The escape latency for 5 continuous days in dexmedetomidine group was significantly decreased comparing with control group (all P < 0.05). The number of times of swimming and the percentage of swimming time in dexmedetomidine group were significantly more than those in control group (all P < 0.05). What is more, rats in dexmedetomidine group had the decreased time of stay in the central square and the increased number of standing times in comparison with the control group, and the statistical differences were found (all P < 0.05). Compared with the control group, dexmedetomidine intraperitoneally injected before surgery could significantly inhibit the expression levels of IL-6, IL-1β, and TNF-α in the hippocampus, and there were statistical differences (all P < 0.05). Conclusion Dexmedetomidine could significantly relieve the postoperative cognitive dysfunction in aged rats. The mechanism may be associated with the decreased inflammatory cytokines in the hippocampus.