Sevoflurane exposure in 7-day-old rats affects neurogenesis, neurodegeneration and neurocognitive function.
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ABSTRACT:
SUBMITTER: Fang F
PROVIDER: S-EPMC5561912 | biostudies-other | 2012 Oct
REPOSITORIES: biostudies-other
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Project description:IntroductionWe tested the hypothesis that poor sense of smell is associated with lower cognitive function and higher mild cognitive impairment (MCI) prevalence.MethodsOlfaction, measured by the Sniffin' Sticks test, was categorized as olfactory impairment (OI) (score ≤6) or no OI (score >6). MCI was adjudicated based on review of a neuropsychological examination. Linear regression estimated the mean difference in cognitive factor scores, and log-binomial regression quantified MCI prevalence among participants with versus without OI.ResultsParticipants with OI had lower mean factor scores (memory: -0.27 standard deviation [SD], 95% confidence interval [CI]: -0.35 to -0.19; language: -0.24 SD, 95% CI: -0.30 to -0.17; executive function/processing speed: -0.09 SD, 95% CI: -0.12 to -0.06; and general cognitive performance: -0.25 SD, 95% CI: -0.30 to -0.20). OI was also associated with MCI (n = 204; prevalence ratio = 1.56, 95% CI: 1.37, 1.78).DiscussionAn impaired sense of smell may serve as a readily accessible early marker of neurodegeneration and improve upon the prevailing delayed diagnoses and underascertainment of MCI/dementia.
| S-EPMC6097922 | biostudies-literature
Project description:BackgroundMultiple human studies have shown no significant long-term results of anesthesia exposure during early childhood compared to the general population; however, reports on short-term neurodevelopmental assessment before and after anesthesia exposure are limited. This study aimed to evaluate the short-term characteristics of neurocognitive function post-anesthesia in noncardiac surgery compared with baseline.MethodsThis prospective case-control pilot study recruited healthy participants in the control group and hospitalized children in the anesthesia group. Children aged 1-36 months without previous anesthesia were included. Neurocognitive function was assessed at baseline and seven days after anesthesia administration using a cognitive scale of the Bayley Scales of Infant and Toddler Development, third edition. The control group received only a baseline assessment. The cognitive composite score had a mean of 100 and a standard deviation (SD) of 15, with a difference of score >1/3 SD (5 points) defined as clinically significant.ResultsTwenty and 39 participants in the control and anesthesia groups, respectively, were included in the final analysis. The baseline cognitive scale score of the anesthesia group was statistically and clinically lower than that of the control group. The mean (SD) cognitive composite scores in the control and anesthesia group were 111.50 (11.71) and 97.13 (9.88), P<0.001. The mean difference [95% confidence interval (CI)] was -14.37 (-8.28 to -20.47). In the anesthesia group, the post-anesthesia cognitive composite score was statistically higher than that at baseline, but without clinical significance. The mean (SD) of baseline and post-anesthesia cognitive composite scores were 97.05 (9.85) and 101.28 (10.87), P=0.039, respectively. The mean difference (95% CI) was 4.23 (0.23-8.23). However, 7 (17.9%) participants had decreased cognitive composite scores after anesthesia exposure.ConclusionsChildren in the anesthesia group had lower baseline cognitive composite scores than those in the control group. The post-anesthesia cognitive score did not decrease compared with the baseline assessment. Anesthetic exposure resulted in a decline in the cognitive composite score in 17.9% of the participants.
| S-EPMC10416128 | biostudies-literature
Project description:BackgroundSevoflurane anesthesia induces Tau phosphorylation and cognitive impairment in neonatal but not in adult mice. This study tested the hypothesis that differences in brain Tau amounts and in the activity of mitochondria-adenosine triphosphate (ATP)-Nuak1-Tau cascade between the neonatal and adult mice contribute to the age-dependent effects of sevoflurane on cognitive function.Methods6- and 60-day-old mice of both sexes received anesthesia with 3% sevoflurane for 2 h daily for 3 days. Biochemical methods were used to measure amounts of Tau, phosphorylated Tau, Nuak1, ATP concentrations, and mitochondrial metabolism in the cerebral cortex and hippocampus. The Morris water maze test was used to evaluate cognitive function in the neonatal and adult mice.ResultsUnder baseline conditions and compared with 60-day-old mice, 6-day-old mice had higher amounts of Tau (2.6 ± 0.4 [arbitrary units, mean ± SD] vs. 1.3 ± 0.2; P < 0.001), Tau oligomer (0.3 ± 0.1 vs. 0.1 ± 0.1; P = 0.008), and Nuak1 (0.9 ± 0.3 vs. 0.3 ± 0.1; P = 0.025) but lesser amounts of ATP (0.8 ± 0.1 vs. 1.5 ± 0.1; P < 0.001) and mitochondrial metabolism (74.8 ± 14.1 [pmol/min] vs. 169.6 ± 15.3; P < 0.001) in the cerebral cortex. Compared with baseline conditions, sevoflurane anesthesia induced Tau phosphorylation at its serine 202/threonine 205 residues (1.1 ± 0.4 vs. 0.2 ± 0.1; P < 0.001) in the 6-day-old mice but not in the 60-day-old mice (0.05 ± 0.04 vs. 0.03 ± 0.01; P = 0.186). The sevoflurane-induced Tau phosphorylation and cognitive impairment in the neonatal mice were both attenuated by the inhibition of Nuak1 and the treatment of vitamin K2.ConclusionsHigher brain Tau concentrations and lower brain mitochondrial metabolism in neonatal compared with adult mice contribute to developmental stage-dependent cognitive dysfunction after sevoflurane anesthesia.
| S-EPMC7429299 | biostudies-literature
Project description:BACKGROUND:Currently, numerous animal studies have shown that exposure to commonly used general anesthetics during pregnancy may cause neurocognitive impairment in the offspring. Reportedly, exposure to sevoflurane during mid-trimester of pregnancy can inhibit proliferation of neural stem cells (NSCs) and lead to early apoptosis. Whether exposure to sevoflurane during pregnancy affects the differentiation of NSCs remains unclear. METHODS:In the present study, pregnant rats were exposed to 3% sevoflurane once for 2?h on gestational day 14 (G14) or 3 times for 2?h on G13, G14, and G15. Next, the differentiation of NSCs was measured using neuron marker ?-tubulin III and astrocyte marker glial fibrillary acidic protein (GFAP) in fetal brain tissues 24?h and 72?h after anesthesia and in hippocampus on postnatal day 28. Primary cultured rat NSCs were exposed to 4.1% sevoflurane to explore the mechanism. RESULTS:The results showed that during mid-trimester, multiple exposures to sevoflurane can cause premature differentiation of NSCs in developing brains of offspring and lead to long-term neuron reduction and astrocyte proliferation in hippocampus. The data from the present study indicated that repeated exposure to sevoflurane downregulated atrophin-1 (ATN1) expression and caused early differentiation of NSCs. Overexpression of ATN1 via lentivirus transfection attenuated the influence of sevoflurane. Using dual luciferase assay, ATN1 was found to be a target gene of microRNA-410-3p (miR-410-3p). MiR-410-3p suppression via lentivirus transfection recovered the ATN1 expression and differentiation of NSCs. CONCLUSIONS:The results from the present study demonstrated that repeated exposure to sevoflurane leads to early differentiation of NSCs and long-term effects via the miR-410-3p/ATN1 pathway.
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Project description:Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder in the Western world. PTEN (phosphatase/tensin homolog on chromosome 10)-induced putative kinase 1 (PINK1), a putative kinase that is mutated in autosomal recessive forms of PD, is also implicated in sporadic cases of the disease. Although the mutations appear to result in a loss of function, the roles of this protein and the pathways involved in PINK1 PD are poorly understood. Here, we generated a vertebrate model of PINK1 insufficiency using morpholino oligonucleotide knockdown in zebrafish (Danio rerio). PINK1 knockdown results in a severe developmental phenotype that is rescued by wild-type human PINK1 mRNA. Morphants display a moderate decrease in the numbers of central dopaminergic neurons and alterations of mitochondrial function, including increases in caspase-3 activity and reactive oxygen species (ROS) levels. When the morphants were exposed to several drugs with antioxidant properties, ROS levels were normalized and the associated phenotype improved. In addition, GSK3beta-related mechanisms can account for some of the effects of PINK1 knockdown, as morphant fish show elevated GSK3beta activity and their phenotype is partially abrogated by GSK3beta inhibitors, such as LiCl and SB216763 [3-(2,4-dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)1H-pyrrole-2,5-dione]. This provides new insights into the biology of PINK1 and a possible therapeutic avenue for further investigation.
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Project description:Neurogenesis is altered in neurodegenerative disorders, partly regulated by inflammatory factors. We have investigated whether microglia, the innate immune brain cells, regulate hippocampal neurogenesis in neurodegeneration. Using the ME7 model of prion disease we applied gain- or loss-of CSF1R function, as means to stimulate or inhibit microglial proliferation, respectively, to dissect the contribution of these cells to neurogenesis. We found that increased hippocampal neurogenesis correlates with the expansion of the microglia population. The selective inhibition of microglial proliferation caused a reduction in neurogenesis and a restoration of normal neuronal differentiation, supporting a pro-neurogenic role for microglia. Using a gene screening strategy, we identified TGFβ as a molecule controlling the microglial pro-neurogenic response in chronic neurodegeneration, supported by loss-of-function mechanistic experiments. By the selective targeting of microglial proliferation we have been able to uncover a pro-neurogenic role for microglia in chronic neurodegeneration, suggesting promising therapeutic targets to normalise the neurogenic niche during neurodegeneration.
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Project description:Developmental neurons received with sevoflurane, the commonly used inhalational anesthetic agent in clinical surgery, several times tend to be destroyed. Microglia, the resident immune cells of the central nervous system (CNS), are activated after sevoflurane exposure, accompanied by releasing proinflammatory cytokines that damage developing neurons. The sevoflurane-induced neurotoxicity could be attributed to activated microglia presenting proinflammatory and anti-inflammatory functions. Proinflammatory microglia release cytokines to impair the CNS, while anti-inflammatory microglia engulf damaged neurons to maintain CNS homeostasis. Sevoflurane exposure promotes the secretion of proinflammatory cytokines by microglia, inhibiting the microglial phagocytic function. Microglia with poor phagocytic function cannot engulf damaged neurons, leading to the accumulation of damaged neurons. The mechanism underlying poor phagocytic function may be attributed to mitochondrial dysfunction of microglia induced by sevoflurane exposure, in which affected mitochondria cannot generate adequate ATP and NAD to satisfy the energy demand. We discovered that sevoflurane treatment impaired the mitochondrial metabolism of microglia, which resulted in NAD deficiency and couldn't produce sufficient energy to clear damaged neurons to maintain CNS development. Our findings provide an explanation of a new mechanism underlying sevoflurane-induced neurotoxicity.
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Project description:Aluminum (Al) is neurotoxic to adults and also to infants. In this study, we investigated the developmental exposure effect of AlCl3 on postnatal hippocampal neurogenesis. Pregnant mice were administered 0-, 900-, or 1800-ppm AlCl3 via drinking water from gestational day 6 to postnatal day (PND) 21, with their offspring examined on PND 21 and PND 77. On PND 21, GFAP-immunoreactive (+) neural stem cells (NSCs) and p21Cip1/Waf1+ cells were decreased in number in the subgranular zone at 900 and ≥900 ppm, respectively. Pcna transcript level examined at 1800 ppm was decreased in the dentate gyrus. These results suggest induction of compromised cell quiescence that caused impaired self-renewal capacity of NSCs accompanying slowing down of cell cycling, which ultimately resulted in exhaustion of the NSC pool. At 1800 ppm, Reelin+ hilar GABAergic interneurons were also decreased, suggesting a contribution to the NSC reduction. At this dose, TBR2+ or DCX+ progenitor and immature granule cells and PVALB+ interneurons were increased. Moreover, COX-2+ granule cells were increased at ≥900 ppm. These results suggest facilitation of transient progenitor cell proliferation and differentiation during exposure. Moreover, TUNEL+ or Morin-stained granule cells were increased, together with Casp12 transcript upregulation, suggesting induction of Al accumulation-related endoplasmic reticulum stress-mediated granule cell apoptosis. Transcript expression changes on cholinergic and glutamatergic signals and synaptic plasticity suggested contribution to disruptive neurogenesis. The NSC-targeting effects sustained through the adult stage despite no sustained Al-accumulation. These results suggest that developmental AlCl3-exposure irreversibly affects postnatal hippocampal neurogenesis involving multiple functions in mice.
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Project description:Perinatal infection is a well-identified risk factor for a number of neurodevelopmental disorders, including brain white matter injury (WMI) and Autism Spectrum Disorders (ASD). The underlying mechanisms by which early life inflammatory events cause aberrant neural, cytoarchitectural, and network organization, remain elusive. This study is aimed to investigate how systemic lipopolysaccharide (LPS)-induced neuroinflammation affects microglia phenotypes and early neural developmental events in rats. We show here that LPS exposure at early postnatal day 3 leads to a robust microglia activation which is characterized with mixed microglial proinflammatory (M1) and anti-inflammatory (M2) phenotypes. More specifically, we found that microglial M1 markers iNOS and MHC-II were induced at relatively low levels in a regionally restricted manner, whereas M2 markers CD206 and TGF? were strongly upregulated in a sub-set of activated microglia in multiple white and gray matter structures. This unique microglial response was associated with a marked decrease in naturally occurring apoptosis, but an increase in cell proliferation in the subventricular zone (SVZ) and the dentate gyrus (DG) of hippocampus. LPS exposure also leads to a significant increase in oligodendrocyte lineage population without causing discernible hypermyelination. Moreover, LPS-exposed rats exhibited significant impairments in communicative and cognitive functions. These findings suggest a possible role of M2-like microglial activation in abnormal neural development that may underlie ASD-like behavioral impairments.
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Project description:Memories acquired incidentally from exposure to food information in the environment may often become active to later affect food preferences. Because conscious use of these memories is not requested or required, these incidental learning effects constitute a form of indirect memory. In an experiment using a novel food preference paradigm (n = 617), we found that brief incidental exposure to hedonic versus healthy food features indirectly affected food preferences a day later, explaining approximately 10% of the variance in preferences for tasty versus healthy foods. It follows that brief incidental exposure to food information can affect food preferences indirectly for at least a day. When hedonic and health exposure were each compared to a no-exposure baseline, a general effect of hedonic exposure emerged across individuals, whereas health exposure only affected food preferences for high-BMI individuals. This pattern suggests that focusing attention on hedonic food features engages common affective processes across the general population, whereas focusing attention on healthy food features engages eating restraint goals associated with high BMI. Additionally, incidental exposure to food features primarily changed preferences for infrequently consumed foods, having less impact on habitually consumed foods. These findings offer insight into how hedonic information in the obesogenic food environment contributes to unhealthy eating behavior that leads to overweight and obesity. These findings further motivate the development of interventions that counteract the effects of exposure to hedonic food information and that broaden the effects of exposure to healthy food information.
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