Tamoxifen attenuates inflammatory‐mediated damage and improves functional outcome after spinal cord injury in rats

Tian, Dai-Shi; Liu, Junli; Xie, Mingxing; Zhan, Yuan; Qu, Wensheng; Yu, Zhiyuan; Tang, Zhouping; Pan, Dengji; Wang, Wei

doi:10.1111/j.1471-4159.2009.06077.x

Cited by 92 publications

(89 citation statements)

References 53 publications

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“…13,16,17 The current study demonstrated significantly increased BSCB permeability at 5 and 24 h post-injury as determined by EB extravasation and albumin immunoreactivity. Such results are consistent with previous studies after weight drop, 46 clip compression, 47 transection, 48 and forceps compression 49 models of SCI. Increased barrier permeability early post-injury is likely from mechanical disruption given the severe hemorrhage observed.…”

Section: Discussionsupporting

confidence: 83%

Substance P as a Mediator of Neurogenic Inflammation after Balloon Compression Induced Spinal Cord Injury

Leonard

Thornton

Vink

2013

Journal of Neurotrauma

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Authors may also deposit this version on his/her funder's or funder's designated repository at the funder's request or as a result of a legal obligation, provided it is not made publicly available until 12 months after official publication. Such an open environment precludes the measurement of intrathecal pressure (ITP), whose increase after SCI has been linked to the development of greater tissue damage and functional deficits. Raised ITP may be potentiated by edema, which we have recently shown to be associated with substance P (SP) induced neurogenic inflammation in both traumatic brain injury and stroke. The present study investigates whether SP plays a similar role as a mediator of neurogenic inflammation after SCI. A closed balloon compression injury was induced at T10 in New Zealand white rabbits. Animals were thereafter assessed for blood spinal cord barrier (BSCB) permeability, edema, ITP, histological outcome, and functional outcome from 5 h to 2 weeks post-SCI. The balloon compression model produced significant increases in BSCB permeability, edema, and ITP along with significant functional deficits that persisted for 2 weeks. Histological assessment demonstrated decreased SP immunoreactivity in the injured spinal cord while NK1 receptor immunoreactivity initially increased before returning to sham levels. In addition, aquaporin 4 immunoreactivity increased early post-SCI, implicating this water channel in the development of edema after SCI. The changes described in the present study support a role for SP as a mediator of neurogenic inflammation after SCI.

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Section: Discussionsupporting

confidence: 83%

Substance P as a Mediator of Neurogenic Inflammation after Balloon Compression Induced Spinal Cord Injury

Leonard

Thornton

Vink

2013

Journal of Neurotrauma

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“…GEN did not affect the IL-1s demonstrating that various phytoestrogen may have very different effects on tumor biology. Our data support previous studies showing an attenuation of the inflammatory response by tamoxifen and phytoestrogens (44,45). We conclude that IL-1Ra may be involved in estrogendependent breast cancer growth and that treatment with IL-1Ra to tumor-bearing mice decreased estrogen-dependent breast cancer growth.…”

Section: Discussionsupporting

confidence: 81%

Tamoxifen, Flaxseed, and the Lignan Enterolactone Increase Stroma- and Cancer Cell–Derived IL-1Ra and Decrease Tumor Angiogenesis in Estrogen-Dependent Breast Cancer

et al. 2011

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The proinflammatory cytokines IL-1a and IL-1b promote tumor angiogenesis that might be counteracted by the IL-1 receptor antagonist (IL-1Ra), anakinra, a clinically approved agent. A diet with high amounts of phytoestrogens, such as flaxseed (Flax), genistein (GEN), and the mammalian lignan enterolactone (ENL), may affect breast cancer progression in a similar fashion as the antiestrogen tamoxifen. Both cancer cells and tumor stroma may be targets for cancer therapy. By using microdialysis in a model of human breast cancers in nude mice, we could perform species-specific analyses of released proteins in the microenvironment. We show that tumors treated with tamoxifen and fed Flax or ENL exhibited decreased in vivo release of IL-1b derived from the murine stroma and decreased microvessel density whereas dietary GEN had no effects. Cancer cell-released IL1Ra were approximately 5 times higher than stroma-derived IL-1Ra. Tamoxifen, Flax, and ENL increased IL-1Ra levels significantly whereas GEN did not. The tumor stroma contained macrophages, which expressed the estrogen receptor. In vitro, estradiol decreased IL-1Ra released from breast cancer cells and from cultured macrophages. IL-1Ra decreased endothelial cell proliferation significantly in vitro whereas breast cancer cell proliferation was unaffected in presence of estradiol. Finally, IL-1Ra therapy of tumor-bearing mice opposed estrogen-dependent breast cancer growth and decreased angiogenesis. We conclude that the release of IL-1s both by cancer cells and the stroma, where macrophages are a key component, may offer feasible targets for antiestrogen therapy and dietary interventions against breast cancer. Cancer Res; 71(1); 51-60. Ó2011 AACR.

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“…This raises the question as to whether the neuronal injury results from direct TNFα actions on neurons or from TNFα-dependent reductions in blood supply (ie, ischemia resulting from altered autoregulation). Unfortunately, our attempts to separate the vascular and nonvascular TNFα effects using smooth muscle cell-targeted TNFα knockout mice ( Figure VI in the online-only Data Supplement) were confounded by tamoxifen's documented 42,43 protective effect against neurodegeneration (Fluoro-Jade; Figure VI in the online-only Data Supplement). As a result, SAH did not increase caspase-3-positive staining in these animals ( Figure VI in the online-only Data Supplement), a discrepancy that coincided with a higher baseline in smooth muscle-specific TNFα knockout sham mice (compared with Figure 6).…”

Section: Strokementioning

confidence: 99%

Therapeutically Targeting Tumor Necrosis Factor-α/Sphingosine-1-Phosphate Signaling Corrects Myogenic Reactivity in Subarachnoid Hemorrhage

Yagi

Lidington

Wan

et al. 2015

Stroke

148

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S ubarachnoid hemorrhage (SAH) affects ≈10 in 100 000 people/y.1 Although SAH accounts for only 5% to 10% of all strokes, it is particularly devastating: half of all SAH patients die within 1 month and half of those who survive will require life-long assistance for daily living (ie, ≈75% of patients die or are seriously debilitated).2,3 The poor clinical outcome can be attributed to the biphasic course of the disease, characterized by an initial hemorrhagic stroke that is frequently followed by delayed cerebral ischemia (DCI) within 4 to 12 days. 4,5 The latter is a primary therapeutic concern when treating SAH, because DCI causes at least half of the morbidity and mortality in SAH. 2The transition from the hemorrhagic insult to secondary ischemia is driven by prominent changes in cerebrovascular reactivity, which compromises cerebral autoregulation 6,7 and evokes angiographic vasospasm (ie, radiographically identifiable arterial narrowing in the proximal cerebrovascular circulation).2,8 Conceptually, both events originate from augmentedBackground and Purpose-Subarachnoid hemorrhage (SAH) is a complex stroke subtype characterized by an initial brain injury, followed by delayed cerebrovascular constriction and ischemia. Current therapeutic strategies nonselectively curtail exacerbated cerebrovascular constriction, which necessarily disrupts the essential and protective process of cerebral blood flow autoregulation. This study identifies a smooth muscle cell autocrine/paracrine signaling network that augments myogenic tone in a murine model of experimental SAH: it links tumor necrosis factor-α (TNFα), the cystic fibrosis transmembrane conductance regulator, and sphingosine-1-phosphate signaling. Methods-Mouse olfactory cerebral resistance arteries were isolated, cannulated, and pressurized for in vitro vascular reactivity assessments. Cerebral blood flow was measured by speckle flowmetry and magnetic resonance imaging. Standard Western blot, immunohistochemical techniques, and neurobehavioral assessments were also used. Results-We demonstrate that targeting TNFα and sphingosine-1-phosphate signaling in vivo has potential therapeutic application in SAH. Both interventions (1) eliminate the SAH-induced myogenic tone enhancement, but otherwise leave vascular reactivity intact; (2) ameliorate SAH-induced neuronal degeneration and apoptosis; and (3) improve neurobehavioral performance in mice with SAH. Furthermore, TNFα sequestration with etanercept normalizes cerebral perfusion in SAH. Conclusions-Vascular smooth muscle cell TNFα and sphingosine-1-phosphate signaling significantly enhance cerebral artery tone in SAH; anti-TNFα and anti-sphingosine-1-phosphate treatment may significantly improve clinical outcome.

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Tamoxifen attenuates inflammatory‐mediated damage and improves functional outcome after spinal cord injury in rats

Abstract: 1These two authors contributed equally to this work.Abbreviations used: BBB, Basso, Bresnahan, and Beattie; BSCB, blood-spinal cord barrier; LFB, Luxol Fast Blue; MAG, myelin-associated glycoprotein; OD, optical density.SCI, spinal cord injury.

Cited by 92 publications

References 53 publications

Substance P as a Mediator of Neurogenic Inflammation after Balloon Compression Induced Spinal Cord Injury

Substance P as a Mediator of Neurogenic Inflammation after Balloon Compression Induced Spinal Cord Injury

Tamoxifen, Flaxseed, and the Lignan Enterolactone Increase Stroma- and Cancer Cell–Derived IL-1Ra and Decrease Tumor Angiogenesis in Estrogen-Dependent Breast Cancer

Therapeutically Targeting Tumor Necrosis Factor-α/Sphingosine-1-Phosphate Signaling Corrects Myogenic Reactivity in Subarachnoid Hemorrhage

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