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Venlafaxine Attenuated the Cognitive and Memory Deficit in Mice Exposed to Isoflurane Alone.

ABSTRACT: Post-operative cognitive dysfunction (POCD) is a common complication during the post-operative period. It affects the recovery time of the patient after surgery and the stay time in hospital, which causes a great deal of burden to patients and families emotionally and financially. However, there is no specific and effective treatment available for this disorder. Recent study indicated exposure to general anesthetics contributed to POCD by triggering gamma-amino butyric acid type A (GABA_A) receptors hyperactivities that persisted even the anesthetic compounds have been eliminated. Here, we investigated the antidepressant, venlafaxine (VLX), in a mouse model of POCD and studied whether VLX attenuated the cognitive dysfunction of mice exposed to general anesthetic, isoflurane (ISO). We found that ISO significantly induced an increased surface expression of the GABA_A receptor subunit, ?5, in the hippocampus of the mice. However, VLX treatment reduced the increase in ?5 subunit expression. Meanwhile, we found the expression levels of interleukin (IL)-1?, tumor necrosis factor alpha (TNF-?), and IL-6 in the brains of mice exposed to ISO were significantly increased. However, VLX could prevent the increase in these cytokines. We also investigated the memory deficit of these mice by using a Y maze behavioral test. Mice with ISO exposure showed decreased alternation performance that could be prevented by the VLX treatment. Collectively, our results here are in line with the previous findings that ?5 subunit plays an important role of the formation of POCD, but VLX may be a promising candidate compound for the treatment of POCD.

SUBMITTER: Li L

PROVIDER: S-EPMC7940694 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Venlafaxine Attenuated the Cognitive and Memory Deficit in Mice Exposed to Isoflurane Alone.

Li Liang L Zhang Chunhai C

Frontiers in neurology 20210223

Post-operative cognitive dysfunction (POCD) is a common complication during the post-operative period. It affects the recovery time of the patient after surgery and the stay time in hospital, which causes a great deal of burden to patients and families emotionally and financially. However, there is no specific and effective treatment available for this disorder. Recent study indicated exposure to general anesthetics contributed to POCD by triggering gamma-amino butyric acid type A (GABA<sub>A</s ...[more]

PMID: 33708168

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Project description:BACKGROUND:Early life anesthesia exposure results in long-term cognitive deficits in rats. Environmental enrichment consisting of social housing, a stimulating environment, and voluntary exercise can rescue this deficit. We hypothesized that exercise alone is sufficient to rescue the cognitive deficit associated with perinatal anesthesia. METHODS:Postnatal day 7 male rats (P7) underwent isoflurane (Iso) or sham exposure and were subsequently weaned at P21. They were then singly housed in a cage with a running wheel or a fixed wheel. After 3 weeks of exercise, animals underwent behavioral testing for spatial and recognition memory assessments. Animals were killed at various time points to accomplish either bromodeoxyuridine (BrdU) labeling or quantitative real-time polymerase chain reaction (qRT-PCR) to quantify brain-derived neurotrophic factor (BDNF) messenger ribonucleic acid (mRNA) levels. RESULTS:Postweaning voluntary exercise rescued the long-term spatial memory deficit associated with perinatal Iso exposure. Iso-sedentary animals did not discriminate the goal quadrant, spending no more time than chance during the Barnes maze probe trial (1-sample t test, P = .524) while all other groups did (1-sample t test, PIso-exercise = .033; Pcontrol [Con]-sedentary = .004). We did not find a deficit in recognition memory tasks after Iso exposure as we observed previously. BrdU incorporation in the adult hippocampus of Iso-sedentary animals was decreased compared to sedentary controls (Tukey P = .005). Exercise prevented this decrease, with Iso-exercise animals having more proliferation than Iso-sedentary (Tukey P < .001). There was no effect of exercise or Iso on BDNF mRNA in either the cortex or hippocampus (cortex: FExercise[1,32] = 0.236, P = .631; FIso [1,32] = 0.038, P = .847; FInteraction [1,32] = 1.543, P = .223; and hippocampus: FExercise[1,33] = 1.186, P = .284; FIso [1,33] = 1.46, P = .236; FInteraction[1,33] = 1.78, P = .191). CONCLUSIONS:Exercise restores BrdU incorporation and rescues a spatial memory deficit after early life anesthesia exposure. This demonstrates sufficiency of exercise alone in the context of environmental enrichment to recover a behavioral phenotype after a perinatal insult.

Project description:Isoflurane and sevoflurane are both inhalation anesthetics, but in clinical application, sevoflurane has been considered to be less suitable for long-term anesthesia because of its catabolic compounds and potential nephrotoxicity. Nevertheless, recent studies have shown that these two inhalation anesthetics are similar in hepatorenal toxicity, cost, and long-term anesthetic effect. Moreover, sevoflurane possibly has less cognitive impact on young mice. In this study, C57BL/6 mice aged 8-10 weeks were exposed to 1.2% isoflurane or 2.4% sevoflurane for 6 hours. Cognitive function and memory were examined in young mice using the novel object recognition, contextual fear conditioning, and cued-fear extinction tests. Western blot assay was performed to detect expression levels of D1 dopamine receptor, catechol-O-methyltransferase, phospho-glycogen synthase kinase-3?, and total glycogen synthase kinase-3? in the hippocampus. Our results show that impaired performance was not detected in mice exposed to sevoflurane during the novel object recognition test. Contextual memory impairment in the fear conditioning test was shorter in the sevoflurane group than the isoflurane group. Long-term sevoflurane exposure did not affect memory consolidation, while isoflurane led to memory consolidation and reduced retention. Downregulation of hippocampal D1 dopamine receptors and phosphorylated glycogen synthase kinase-3?/total glycogen synthase kinase-3? and upregulation of catechol-O-methyltransferase may be associated with differing memory performance after exposure to isoflurane or sevoflurane. These results confirm that sevoflurane has less effect on cognitive impairment than isoflurane, which may be related to expression of D1 dopamine receptors and catechol-O-methyltransferase and phosphorylation of glycogen synthase kinase-3? in the hippocampus. This study was approved by the Institutional Animal Care and Use Committee, Nanjing University, China on November 20, 2017 (approval No. 20171102).

Project description:BackgroundPostoperative cognitive dysfunction (POCD) is a common complication following anesthesia and surgery. General anesthetic isoflurane has potential neurotoxicity and induces cognitive impairments, but the exact mechanism remains unclear. Astrocytes form interconnected networks in the adult brain through gap junctions (GJs), which primarily comprise connexin 43 (Cx43), and play important roles in brain homeostasis and functions such as memory. However, the role of the GJ-Cx43-mediated astrocytic network in isoflurane-induced cognitive dysfunction has not been defined.Methods4-month-old male C57BL/6 mice were exposure to long-term isoflurane to induce cognitive impairment. To simulate an in vitro isoflurane-induced cognitive dysfunction-like condition, primary mouse astrocytes were subjected to long-term isoflurane exposure. Cognitive function was assessed by Y-maze and fear conditioning tests. Western blot was used to determine the expression levels of different functional configurations of Cx43. The morphology of the GJs-Cx43 was evaluated by immunofluorescence staining. Levels of IL-1β and IL-6 were examined by ELISA. The ability of GJs-Cx43-mediated intercellular communication was examined by lucifer yellow dye transfer assay. Ethidium bromide uptake assays were used to measure the activity of Cx43 hemichannels. The ultrastructural morphology of astrocyte gap junctions and tripartite synapse were observed by transmission electron microscopy.ResultsAfter long-term isoflurane anesthesia, the GJs formed by Cx43 in the mouse hippocampus and primary mouse astrocytes were significantly reduced, GJs function was impaired, hemichannel activity was enhanced, the levels of IL-1β and IL-6 were increased, and mice showed significant cognitive impairment. After treatment with the novel GJ-Cx43 enhancer ZP1609, GJ-Cx43-mediated astrocytic network function was enhanced, neuroinflammation was alleviated, and ameliorated cognition dysfunction induced by long-term isoflurane exposure. However, ZP1609 enhances the astrocytic network by promoting Cx43 to form GJs without affecting hemichannel activity. Additionally, our data showed that long-term isoflurane exposure does not alter the structure of tripartite synapse.ConclusionOur results reveal a novel mechanism of the GJ-Cx43-mediated astrocytic network involved in isoflurane-induced neuroinflammation and cognitive impairments, which provides new mechanistic insight into the pathogenesis of POCD and identifies potential targets for its treatment.

Project description:Previous studies have shown that exposure to inhaled anesthetics can cause cognitive dysfunction, suggesting that general anesthesia might be a risk factor for the development of Alzheimer disease. However, the underlying mechanisms remain to be elucidated. In the present study, we tested our hypothesis that enhanced tau protein phosphorylation in hippocampus contributes to isoflurane-induced cognitive dysfunction in a mouse model of Alzheimer disease.Fifty-four male wild-type (WT) mice (12 months old) and 54 male amyloid precursor protein 695 (APP695) mice (12 months old) were either anesthetized for 4 hours with 1.0 minimum alveolar concentration isoflurane or sham-anesthetized (control). Learning and memory behaviors were measured using the Morris Water Maze test for mice. Phosphorylation of hippocampal tau protein at Ser262 site was analyzed with quantitative Western blotting.In the Morris Water Maze test, both WT and transgenic APP695 mice showed decreased latency times during a 4-day training period. Isoflurane exposure significantly increased the latency times on days 2 and 3 in WT mice as well as on days 3 and 4 in APP695 mice (WT: P = 0.005 for day 2 and P = 0.002 for day 3; APP695: P = 0.001 for day 3 and P < 0.0001 for day 4) and reduced platform quadrant times (WT: P < 0.0001; APP695: P < 0.0001) in both types of mice. Compared with WT mice, transgenic APP695 mice displayed worse learning and memory behaviors after isoflurane exposure (P = 0.0005 for escape latency testing on day 4 training; P = 0.009 for platform probe testing). Western blot analysis showed that the levels of phosphorylation of hippocampal tau protein at Ser262 site (tau[pS262]) in the transgenic APP695 mice were higher than those in WT mice (P < 0.0001) and that isoflurane exposure time dependently enhanced the hippocampal tau[pS262] levels in both types of mice, but this effect was much more significant in the transgenic APP695 mice (P < 0.0001). Our data also showed that isoflurane exposure had no effect on the expression of total tau protein in the hippocampi of all mice (P ? 0.54).Isoflurane may induce cognitive dysfunction by enhancing phosphorylation of hippocampal tau protein at Ser262 site, and this effect is more significant in transgenic APP695 mice.

Project description:General anesthetics can induce cognitive impairments and increase the risk of Alzheimer's disease (AD). However, the underlying mechanisms are still unknown. Our previous studies shown that long-term isoflurane exposure induced peripheral and central insulin resistance (IR) in adult mice and aggravated IR in type 2 diabetes mellitus (T2DM) mice. Clinical and preclinical studies revealed an association between impaired insulin signaling and tau pathology in AD and other tauopathies. We investigated if alleviation of hippocampal IR by the antidiabetic agent metformin could reduce tau hyperphosphorylation and cognitive decline induced by isoflurane in mice. The effects of prolonged (6 h) isoflurane anesthesia on hippocampal IR, hippocampal tau hyperphosphorylation, and hippocampus-dependent cognitive function were evaluated in wild type (WT) adult mice and the high-fat diet plus streptozotocin (HFD/STZ) mouse model of T2DM. Here we shown that isoflurane and HFD/STZ dramatically and synergistically induced hippocampal IR and fear memory impairment. Metformin pretreatment strongly ameliorated hippocampal IR and cognitive dysfunction caused by isoflurane in WT mice, but was less effective in T2DM mice. Isoflurane also induced hippocampal tau hyperphosphorylation and metformin reversed this effect. In addition, isoflurane significantly increased blood glucose levels in both adult and T2DM mice, and metformin reversed this effect as well. Administration of 25% glucose to metformin-pretreated mice induced hyperglycemia, but surprisingly did not reverse the benefits of metformin on hippocampal insulin signaling and fear memory following isoflurane anesthesia. Our findings show hippocampal IR and tau hyperphosphorylation contribute to acute isoflurane-induced cognitive dysfunction. Brief metformin treatment can mitigate these effects through a mechanism independent of glycemic control. Future studies are needed to investigate whether long-term metformin treatment can also prevent T2DM-induced hippocampal IR and cognitive decline.

Dataset Information

Venlafaxine Attenuated the Cognitive and Memory Deficit in Mice Exposed to Isoflurane Alone.

Publications

Venlafaxine Attenuated the Cognitive and Memory Deficit in Mice Exposed to Isoflurane Alone.

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