Estrogen stimulates microglia and brain recovery from hypoxia-ischemia in normoglycemic but not diabetic female mice

Zhang, Liqun; Nair, Arun; Krady, Kyle; Corpe, Christopher; Bonneau, Robert H.; Simpson, Ian A.; Vannucci, Susan J.

doi:10.1172/jci200418336

Cited by 71 publications

(12 citation statements)

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“…This picture totally contrasted with WT brains that showed resting/quiescent microglia harboring a ramified morphology with slender sensing arms. We confirmed the activation status of microglia by probing for mRNA levels of the microglial activation marker A1 [ 38 , 39 ]. A1 mRNA levels were significantly higher in CX and HC (approximately seven-fold) of A20 KO as compared to WT mice (Figure 2 B).…”

Section: Resultsmentioning

confidence: 79%

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A20 deficiency causes spontaneous neuroinflammation in mice

Guedes

Csizmadia

Moll

et al. 2014

J Neuroinflammation

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BackgroundA20 (TNFAIP3) is a pleiotropic NFκB-dependent gene that terminates NFκB activation in response to inflammatory stimuli. The potent anti-inflammatory properties of A20 are well characterized in several organs. However, little is known about its role in the brain. In this study, we investigated the brain phenotype of A20 heterozygous (HT) and knockout (KO) mice.MethodsThe inflammatory status of A20 wild type (WT), HT and KO brain was determined by immunostaining, quantitative PCR, and Western blot analysis. Cytokines secretion was evaluated by ELISA. Quantitative results were statistically analyzed by ANOVA followed by a post-hoc test.ResultsTotal loss of A20 caused remarkable reactive microgliosis and astrogliosis, as determined by F4/80 and GFAP immunostaining. Glial activation correlated with significantly higher mRNA and protein levels of the pro-inflammatory molecules TNF, IL-6, and MCP-1 in cerebral cortex and hippocampus of A20 KO, as compared to WT. Basal and TNF/LPS-induced cytokine production was significantly higher in A20 deficient mouse primary astrocytes and in a mouse microglia cell line. Brain endothelium of A20 KO mice demonstrated baseline activation as shown by increased vascular immunostaining for ICAM-1 and VCAM-1, and mRNA levels of E-selectin. In addition, total loss of A20 increased basal brain oxidative/nitrosative stress, as indicated by higher iNOS and NADPH oxidase subunit gp91phox levels, correlating with increased protein nitration, gauged by nitrotyrosine immunostaining. Notably, we also observed lower neurofilaments immunostaining in A20 KO brains, suggesting higher susceptibility to axonal injury. Importantly, A20 HT brains showed an intermediate phenotype, exhibiting considerable, albeit not statistically significant, increase in markers of basal inflammation when compared to WT.ConclusionsThis is the first characterization of spontaneous neuroinflammation caused by total or partial loss of A20, suggesting its key role in maintenance of nervous tissue homeostasis, particularly control of inflammation. Remarkably, mere partial loss of A20 was sufficient to cause chronic, spontaneous low-grade cerebral inflammation, which could sensitize these animals to neurodegenerative diseases. These findings carry strong clinical relevance in that they question implication of identified A20 SNPs that lower A20 expression/function (phenocopying A20 HT mice) in the pathophysiology of neuroinflammatory diseases.

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Section: Resultsmentioning

confidence: 79%

“…We confirmed microglial activation by demonstrating heightened A1 mRNA expression in the brains of A20 KO mice, as compared to WT. Expression of A1, a BCL2 gene family member, in the CNS is restricted to microglia, and is uniquely upregulated when these cells undergo activation [ 38 , 39 ].…”

Section: Discussionmentioning

confidence: 99%

A20 deficiency causes spontaneous neuroinflammation in mice

Guedes

Csizmadia

Moll

et al. 2014

J Neuroinflammation

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“…Immunostaining for glial fibrillary acidic protein (GFAP, 1:10) and the neuronal marker Tg2 (1:100) was carried out as described by Zhang et al (2004). In situ hybridization was carried out as described above and before dipping the slides in emulsion, the sections were rehydrated in decreasing ethanol solutions and phosphate‐buffered saline (PBS), followed by quenching endogenous peroxidase with 3% H 2 O 2 in water, washed in PBS, then blocked with normal horse serum for 20 min at room temperature.…”

Section: Methodsmentioning

confidence: 99%

Monocarboxylate transporter expression in the spontaneous hypertensive rat: Effect of stroke

Zhang

Vannucci

Philp

et al. 2004

J of Neuroscience Research

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The expression of the monocarboxylate transporters (MCT) 1, 2, and 4 have been studied in the brains of spontaneous hypertensive (SH) rats after an ischemic insult induced by a permanent occlusion of the left middle cerebral artery (MCAO). Profound temporal changes in MCT1 expression were observed in various regions of the ipsilateral hemisphere over the period of 1 hr to 5 days after MCAO. Initially, a very rapid and transient increase in MCT1 mRNA was observed in neurons in the second layer of the cortex and in the piriform cortex at 1-3 hr. A slower but sustained increase in MCT1 mRNA expression was observed in astrocytes in the peri-infarct region beginning at 6 hr after MCAO and persisting over a period of 120 hr coinciding with their activation, migration, and involvement in scar formation. An increase in MCT1 expression in endothelial cells was seen over the same period. These increases in MCT1 expression in astrocytes and endothelial cells were accompanied by a corresponding increase in MCT1 protein. Finally at 120 hr post-MCAO, increases in MCT1, MCT2, and MCT4 expression were observed in cells within the infarct and bordering the scar, the identity of which remains to be determined. Consistent with cell death, the levels of MCT1, MCT2, and MCT4 mRNA decreased with cell death within the infarcted area but unlike MCT1, no increases in either MCT2 or 4 were observed within the remaining ipsilateral hemisphere. These studies reveal that the pattern of regulation of MCT1 expression after MCAO is similar to that observed previously for glucose transporter 1 (GLUT1) and suggest that the regulation of MCT1 mRNA expression is mediated by the hypoxia-inducible transcription factor HIF1.

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“…By contrast, ERT has been shown to reduce the overall incidence of stroke in diabetic women . Regarding pre‐clinical research, the effect of E 2 in animal models of diabetic stroke remains controversial because it has been reported to be neurotoxic, neuroprotective or to have no effect . This mixed evidence, along with other undesirable effects, has shifted the focus onto other ligands of the oestrogen receptors (ER), especially the “selective oestrogen receptor modulators” (SERMs).…”

Section: Introductionmentioning

confidence: 99%

The selective oestrogen receptor modulator, bazedoxifene, mimics the neuroprotective effect of 17β‐oestradiol in diabetic ischaemic stroke by modulating oestrogen receptor expression and the MAPK/ERK1/2 signalling pathway

Burguete

Jover‐Mengual

López‐Morales

et al. 2019

J Neuroendocrinology

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Because neuroprotection in stroke should be revisited in the era of recanalisation, the present study analysed the potential neuroprotective effect of the selective oestrogen receptor modulator, bazedoxifene acetate (BZA), in an animal model of diabetic ischaemic stroke that mimics thrombectomy combined with adjuvant administration of a putative neuroprotectant. Four weeks after induction of diabetes (40 mg kg -1 streptozotocin, i.p.), male Wistar rats were subjected to transient middle cerebral artery occlusion (intraluminal thread technique, 60 minutes) and assigned to one of three groups treated with either: vehicle, BZA (3 mg kg -1 day -1 , i.p.) or 17β-oestradiol (E 2 ) (100 μg kg -1 day -1 , i.p.). At 24 hours post-ischaemia-reperfusion, brain damage (neurofunctional score, infarct size and apoptosis), expression of oestrogen receptors (ER)α, ERβ and G protein-coupled oestrogen receptor), and activity of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK)1/2 and phosphoinositide 3-kinase/Akt pathways were analysed. At 24 hours after the ischaemic insult, both BZA-and E 2 -treated animals showed lower brain damage in terms of improved neurofunctional condition, decreased infarct size and decreased apoptotic cell death.Ischaemia-reperfusion induced a significant decrease in ERα and ERβ expression without affecting that of G protein-coupled oestrogen receptor, whereas BZA and E 2 reversed such a decrease. The ischaemic insult up-regulated the activity of both the MAPK/ERK1/2 and phosphoinositide 3-kinase/Akt pathways; BZA and E 2 attenuated the increased activity of the ERK1/2 pathway, without affecting that of the Akt pathway. The results of the present study lend further support to the consideration of BZA as an effective and safer alternative overcoming the drawbacks of E 2 with respect to improving diabetic ischaemic stroke outcome after successful reperfusion. K E Y W O R D S 17β-oestradiol, apoptosis, bazedoxifene, diabetes, ischaemic stroke, selective oestrogen receptor modulators How to cite this article: Burguete MC, Jover-Mengual T, López-Morales MA, et al. The selective oestrogen receptor modulator, bazedoxifene, mimics the neuroprotective effect of 17β-oestradiol in diabetic ischaemic stroke by modulating oestrogen receptor expression and the MAPK/ERK1/2 signalling pathway. J Neuroendocrinol. 2019;31:e12751.

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Estrogen stimulates microglia and brain recovery from hypoxia-ischemia in normoglycemic but not diabetic female mice

Cited by 71 publications

References 50 publications

A20 deficiency causes spontaneous neuroinflammation in mice

A20 deficiency causes spontaneous neuroinflammation in mice

Monocarboxylate transporter expression in the spontaneous hypertensive rat: Effect of stroke

The selective oestrogen receptor modulator, bazedoxifene, mimics the neuroprotective effect of 17β‐oestradiol in diabetic ischaemic stroke by modulating oestrogen receptor expression and the MAPK/ERK1/2 signalling pathway

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