Aging causes exacerbated ischemic brain injury and failure of sevoflurane post-conditioning: Role of B-cell lymphoma-2

Dong, Ping; Zhao, Jinjuan; Zhang, Y.; Dong, Jing; Zhang, L.; Li, D.; Li, L.; Zhang, X.; Yang, Bo; W, Lei

doi:10.1016/j.neuroscience.2014.05.064

Cited by 19 publications

(16 citation statements)

References 43 publications

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“…This finding is also consistent with previous studies showing larger infarct volumes and less functional recovery in aged mice (DiNapoli et al, 2008; Dinapoli et al, 2006; Dong et al, 2014; Rosen et al, 2005; Tan et al, 2009). We found that the striatum was especially affected in the aged animals after stroke.…”

Section: Discussionsupporting

confidence: 93%

White matter injury and microglia/macrophage polarization are strongly linked with age-related long-term deficits in neurological function after stroke

Suenaga

Hu²,

Pu³

et al. 2015

Experimental Neurology

161

118

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Most of the successes in experimental models of stroke have not translated well to the clinic. One potential reason for this failure is that stroke mainly afflicts the elderly and the majority of experimental stroke studies rely on data gathered from young adult animals. Therefore, in the present study we established a reliable, reproducible model of stroke with low mortality in aged (18 month) male mice and contrasted their pathophysiological changes with those in young (2 month) animals. To this end, mice were subjected to permanent tandem occlusion of the left distal middle cerebral artery (dMCAO) with ipsilateral common carotid artery occlusion (CCAO). Cerebral blood flow (CBF) was evaluated repeatedly during and after stroke. Reduction of CBF was more dramatic and sustained in aged mice. Aged mice exhibited more severe long-term sensorimotor deficits, as manifested by deterioration of performance in the Rotarod and hanging wire tests up to 35d after stroke. Aged mice also exhibited significantly worse long-term cognitive deficits after stroke, as measured by the Morris water maze test. Consistent with these behavioral observations, brain infarct size and neuronal tissue loss after dMCAO were significantly larger in aged mice at 2d and 14d, respectively. The young versus aged difference in neuronal tissue loss, however, did not persist until 35d after dMCAO. In contrast to the transient difference in neuronal tissue loss, we found significant and long lasting deterioration of white matter in aged animals, as revealed by the loss of myelin basic protein (MBP) staining in the striatum at 35d after dMCAO. We further examined the expression of M1 (CD16/CD32) and M2 (CD206) markers in Iba-1+ microglia by double immunofluorescent staining. In both young and aged mice, the expression of M2 markers peaked around 7d after stroke whereas the expression of M1 markers peaked around 14d after stroke, suggesting a progressive M2-to-M1 phenotype shift in both groups. However, aged mice exhibited significantly reduced M2 polarization compared to young adults. Remarkably, we discovered a strong positive correlation between favorable neurological outcomes after dMCAO and MBP levels or the number of M2 microglia/macrophages. In conclusion, our studies suggest that the distal MCAO stroke model consistently results in ischemic brain injury with long-term behavioral deficits, and is therefore suitable for the evaluation of long-term stroke outcomes. Furthermore, aged mice exhibit deterioration of functional outcomes after stroke and this deterioration is linked to white matter damage and reductions in M2 microglia/macrophage polarization.

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Section: Discussionsupporting

confidence: 93%

White matter injury and microglia/macrophage polarization are strongly linked with age-related long-term deficits in neurological function after stroke

Suenaga

Hu²,

Pu³

et al. 2015

Experimental Neurology

161

118

View full text Add to dashboard Cite

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“…However, studies examining the outcome of ischemia and the effects of aging in male animals have produced varying results. Similar to the results observed in females, several studies have shown that aged male rodents exhibit larger infarcts, increased edema, and worse neurological functional deficits compared to adult males (Dong et al, 2014; Miao et al, 2013; Tennant et al, 2014). The accelerated development of degenerating neurons and apoptotic cells following ischemia in males may contribute to the poorer outcomes (Popa-Wagner et al, 2007).…”

Section: Introductionsupporting

confidence: 77%

“…In aged animals this protection was due to a reduction in the number of activated microglia, T cells, and dendritic cells in the ischemic hemisphere following MCAO, however, treatment in adult mice reduced the percentage of T cells and macrophages in the spleen (Dotson et al, 2014). Furthermore, post-conditioning with sevoflurane significantly reduced infarct size and edema formation, and improved the neurological outcome in adult male rats but failed to alter these in aged males (Dong et al, 2014). Interestingly, overexpression of adiponectin, an adipose-specific plasma protein, reduced ischemic brain injury and promoted neurobehavioral outcomes in aged male mice more efficiently than in adult animals (Miao et al, 2013).…”

Section: Introductionmentioning

confidence: 97%

Astrocytic response to cerebral ischemia is influenced by sex differences and impaired by aging

Chisholm

Sohrabji

2016

Neurobiology of Disease

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Ischemic stroke occurs more often among the elderly, and within this demographic, women are at an increased risk for stroke and have poorer functional recovery than men. This is also well replicated in animal studies where aging females are shown to have more extensive brain tissue loss as compared to adult females. Astrocytes provide nutrients for neurons, regulate glutamate levels, and release neurotrophins and thus play a key role in the events that occur following ischemia. In addition, astrocytes express receptors for gonadal hormones and synthesize several neurosteroids suggesting that the sex differences in stroke outcome may be mediated through astrocytes. This review discusses key astrocytic responses to ischemia including, reactive gliosis, excitotoxicity, and neuroinflammation. In light of the age and sex differences in stroke outcomes, this review highlights how aging and gonadal hormones influence these responses. Lastly, astrocyte specific changes in gene expression and epigenetic modifications during aging and following ischemia are discussed as possible molecular mechanisms for impaired astrocytic functioning.

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“…Generally, sevoflurane pretreatment occurs before ischemia to improve ischemic tolerance; while post-treatment with sevoflurane is focused on the intraoperative or postoperative lung injury during CPB to reduce ischemic injury in the acute phase (Orriach et al, 2013;Zhou et al, 2013). By the suppression of advanced glycation end products synthesis and activation, sevoflurane post-treatment was suggested to eventually contribute to the downregulation of inflammatory mediators (Dong et al, 2014). In this meta-analysis, serum IL-6 and IL-8 levels in patients who received post-treatment of sevoflurane were much higher than in those who received pretreatment of sevoflurane, indicating that pretreatment of sevoflurane might be beneficial to patients after CPB through suppressing the release or expression of inflammatory cytokines and thereby reducing the degree of inflammation after CPB.…”

Section: Discussionmentioning

confidence: 99%

Sevoflurane downregulates interleukin-6 and interleukin-8 levels in patients after cardiopulmonary bypass surgery: a meta-analysis

et al. 2015

Genet. Mol. Res.

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ABSTRACT. This study aimed to investigate the effect of sevoflurane on serum levels of interleukin (IL)-6 and IL-8 in patients who underwent cardiopulmonary bypass (CPB). The strength of the association between sevoflurane treatment and serum level of IL-6 and IL-8 was determined in patients who underwent CPB by summary standard mean differences (SMDs); 95% confidence interval (CI) was used. In total, seven casecontrol studies showed decreased IL-6 and IL-8 levels in sevofluranetreated patients than in controls (IL-6: SMD = 1.56, 95%CI: 0.95-2.17, P < 0.001; IL-8: SMD = 2.17, 95%CI: 1.40-2.95, P < 0.001, respectively). Further, IL-6 and IL-8 levels were significantly higher in sevofluranetreated patients than in sevoflurane-pretreated patients (IL-6 post vs pre: SMD = 2.17, 95%CI: 1.40-2.95, P < 0.001; IL-8 post vs pre: SMD = 4.01, 95%CI: 2.80-5.21, P < 0.001, respectively). CPB-stratified analysis showed significant decrease in IL-6 and IL-8 levels in sevoflurane-treated patients than in controls, irrespective of the time after CPB surgery (P < 0.05). IL-6 and IL-8 in sevoflurane-treated patients 19017©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (4): 19016-19027 (2015) Moreover, sevoflurane-pretreated patients under the <12-h subgroup showed decreased IL-6 levels (P = 0.698), while all other subgroups showed decreased IL-8 levels (P < 0.05). Further, subgroup analysis by different dose of sevoflurane showed decreased IL-6 and IL-8 levels in subgroups administered with a dose of <2 and ≥2% sevoflurane under the case vs control and pre-vs post-treatment of sevoflurane models. Serum IL-6 and IL-8 levels were significantly lower in sevoflurane-treated patients who underwent CPB, suggesting sevoflurane pretreatment to be more beneficial than post-treatment.

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Aging causes exacerbated ischemic brain injury and failure of sevoflurane post-conditioning: Role of B-cell lymphoma-2

Cited by 19 publications

References 43 publications

White matter injury and microglia/macrophage polarization are strongly linked with age-related long-term deficits in neurological function after stroke

White matter injury and microglia/macrophage polarization are strongly linked with age-related long-term deficits in neurological function after stroke

Astrocytic response to cerebral ischemia is influenced by sex differences and impaired by aging

Sevoflurane downregulates interleukin-6 and interleukin-8 levels in patients after cardiopulmonary bypass surgery: a meta-analysis

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