Targeting 17β-estradiol biosynthesis in neural stem cells improves stroke outcome

Patkar, Shalmali; Uwanogho, Dafe; Modo, Mike; Tate, Rothwelle J.; Plevin, Robin; Carswell, Hilary V O

doi:10.3389/fncel.2022.917181

Cited by 6 publications

(5 citation statements)

References 52 publications

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“…The function of estrogen, primarily 17β-estradiol , extends beyond its reproductive role to impact pathological processes, particularly in the CNS ( Rexrode et al, 2022 ; Zhang et al, 2023 ). Numerous studies highlight its protective role in brain injuries following ischemic stroke, involving the modulation of local and systemic immune responses post-stroke onset ( Petrone et al, 2014 ; Patkar et al, 2022 ). After a stroke, 17β-estradiol demonstrates neuroprotective effects by moderating inflammation, activating macrophages, and releasing anti-inflammatory cytokines (IL-10 and TGF-β) ( Akabori et al, 2010 ; Acosta-Martinez, 2020 ).…”

Section: Potential Therapeutic Targetsmentioning

confidence: 99%

Out of the core: the impact of focal ischemia in regions beyond the penumbra

Koukalova,

Chmelova,

Amlerova

et al. 2024

Front. Cell. Neurosci.

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The changes in the necrotic core and the penumbra following induction of focal ischemia have been the focus of attention for some time. However, evidence shows, that ischemic injury is not confined to the primarily affected structures and may influence the remote areas as well. Yet many studies fail to probe into the structures beyond the penumbra, and possibly do not even find any significant results due to their short-term design, as secondary damage occurs later. This slower reaction can be perceived as a therapeutic opportunity, in contrast to the ischemic core defined as irreversibly damaged tissue, where the window for salvation is comparatively short. The pathologies in remote structures occur relatively frequently and are clearly linked to the post-stroke neurological outcome. In order to develop efficient therapies, a deeper understanding of what exactly happens in the exo-focal regions is necessary. The mechanisms of glia contribution to the ischemic damage in core/penumbra are relatively well described and include impaired ion homeostasis, excessive cell swelling, glutamate excitotoxic mechanism, release of pro-inflammatory cytokines and phagocytosis or damage propagation via astrocytic syncytia. However, little is known about glia involvement in post-ischemic processes in remote areas. In this literature review, we discuss the definitions of the terms “ischemic core”, “penumbra” and “remote areas.” Furthermore, we present evidence showing the array of structural and functional changes in the more remote regions from the primary site of focal ischemia, with a special focus on glia and the extracellular matrix. The collected information is compared with the processes commonly occurring in the ischemic core or in the penumbra. Moreover, the possible causes of this phenomenon and the approaches for investigation are described, and finally, we evaluate the efficacy of therapies, which have been studied for their anti-ischemic effect in remote areas in recent years.

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Section: Potential Therapeutic Targetsmentioning

confidence: 99%

Out of the core: the impact of focal ischemia in regions beyond the penumbra

Koukalova,

Chmelova,

Amlerova

et al. 2024

Front. Cell. Neurosci.

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“…In fact, our data showed that aromatase is highly expressed in hippocampal SGZ of adult female mice (Figure 8C). Patkar et al also showed that aromatase is expressed in NSC and knockdown of Dax-1 can induce its overexpression [173]. As such, it is understandable that ubiquitous TPP2 depletion causes more severe impairment in learning and memory abilities than conditional TPP2 depletion, because all sources of estrogen may be damaged under ubiquitous TPP2 depletion.…”

Section: Figure 12mentioning

confidence: 99%

Tripeptidyl peptidase II coordinates the homeostasis of calcium and lipids in the central nervous system and its depletion causes presenile dementia in female mice through calcium/lipid dyshomeostasis-induced autophagic degradation of CYP19A1

Zhao,

He,

Fan

et al. 2024

Theranostics

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Rationale: Tripeptidyl peptidase II (TPP2) has been proven to be related to human immune and neurological diseases. It is generally considered as a cytosolic protein which forms the largest known protease complex in eukaryotic cells to operate mostly downstream of proteasomes for degradation of longer peptides. However, this canonical function of TPP2 cannot explain its role in a wide variety of biological and pathogenic processes. The mechanistic interrelationships and hierarchical order of these processes have yet to be clarified. Methods: Animals, cells, plasmids, and viruses established and/or used in this study include: TPP2 knockout mouse line, TPP2 conditional knockout mouse lines (different neural cell type oriented), TRE-TPP2 knockin mouse line on the C57BL/6 background; 293T cells with depletion of TPP2, ATF6, IRE1, PERK, SYVN1, UCHL1, ATG5, CEPT1, or CCTα, respectively; 293T cells stably expressing TPP2, TPP2 S449A, TPP2 S449T, or CCTα-KDEL proteins on the TPP2-depleted background; Plasmids for eukaryotic transient expression of rat CYP19A1-Flag, CYP19A1 S118A-Flag, CYP19A1 S118D-Flag, Sac I ML GFP Strand 11 Long, OMMGFP 1-10, G-CEPIA1er, GCAMP2, CEPIA3mt, ACC-GFP, or SERCA1-GFP; AAV2 carrying the expression cassette of mouse CYP19A1-3 X Flag-T2A-ZsGreen. Techniques used in this study include: Flow cytometry, Immunofluorescence (IF) staining, Immunohistochemical (IHC) staining, Luxol fast blue (LFB) staining, β-galactosidase staining, Lipid droplet (LD) staining, Calcium (Ca 2+ ) staining, Stimulated emission depletion (STED) imaging, Transmission electron microscopic imaging, Two-photon imaging, Terminal deoxynucleotidyl transferase (TdT) dUTP nick-end Labeling (TUNEL) assay, Bromodeoxyuridine (BrdU) assay, Enzymatic activity assay, Proximity ligation assay (PLA), In vivo electrophysiological recording, Long-term potentiation (LTP) recording, Split-GFP-based mitochondria-associated membrane (MAM) detection, Immunoprecipitation (IP), Cellular fractionation, In situ hybridization, Semi-quantitative RT-PCR, Immunoblot, Mass spectrometry-based lipidomics, metabolomics, proteomics, Primary hippocampal neuron culture and Morris water maze (MWM) test. Results: We found that TPP2, independent of its enzymatic activity, plays a crucial role in maintaining the homeostasis of intracellular Ca 2+ and phosphatidylcholine (PC) in the central nervous system (CNS) of mice. In consistence with the critical importance of Ca 2+ and PC in the CNS, TPP2 gene ablation causes presenile dementia in female mice, which is closely associated with Ca 2+ /PC dysregulation-induced endoplasmic reticulum (ER) stress, abnormal autophagic degradation of CYP19A1 (aromatase), and estrogen depletion. This work therefore uncovers a new role of TPP2 in lipogenesis and neurosteroidogenesis which is tightly related to cognitive function of adult female mice. Conclusion: ...

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“…Accumulative evidence has demonstrated that estrogen, especially 17β-estradiol, has a protective role in brain injuries after ischemic stroke ( 16 ). This protective effect of 17β-estradiol is mediated by several mechanisms, including the regulation of local and systemic immune responses after stroke onset ( 17 ).…”

Section: Incidence and Severity Of Ischemic Stroke Based On Sexmentioning

confidence: 99%

Immunomodulatory role of estrogen in ischemic stroke: neuroinflammation and effect of sex

Zhong¹,

Sun²,

Lü³

et al. 2023

Front. Immunol.

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Although estrogen is predominantly related to the maintenance of reproductive functioning in females, it mediates various physiological effects in nearly all tissues, especially the central nervous system. Clinical trials have revealed that estrogen, especially 17β-estradiol, can attenuate cerebral damage caused by an ischemic stroke. One mechanism underlying this effect of 17β-estradiol is by modulating the responses of immune cells, indicating its utility as a novel therapeutic strategy for ischemic stroke. The present review summarizes the effect of sex on ischemic stroke progression, the role of estrogen as an immunomodulator in immune reactions, and the potential clinical value of estrogen replacement therapy. The data presented here will help better understand the immunomodulatory function of estrogen and may provide a basis for its novel therapeutic use in ischemic stroke.

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Targeting 17β-estradiol biosynthesis in neural stem cells improves stroke outcome

Cited by 6 publications

References 52 publications

Out of the core: the impact of focal ischemia in regions beyond the penumbra

Out of the core: the impact of focal ischemia in regions beyond the penumbra

Tripeptidyl peptidase II coordinates the homeostasis of calcium and lipids in the central nervous system and its depletion causes presenile dementia in female mice through calcium/lipid dyshomeostasis-induced autophagic degradation of CYP19A1

Immunomodulatory role of estrogen in ischemic stroke: neuroinflammation and effect of sex

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