Sex Differences in Ischemic Stroke Sensitivity Are Influenced by Gonadal Hormones, Not by Sex Chromosome Complement

Manwani, Bharti; Bentivegna, Kathryn; Benashski, Sharon E.; Venna, Venugopal Reddy; Xu, Yan; Arnold, Arthur P.; McCullough, Louise D.

doi:10.1038/jcbfm.2014.186

Cited by 110 publications

(81 citation statements)

References 42 publications

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“…While emerging work may define the line between the effects of gonadal hormones and those of sex [35,36], the present study corroborates and extends early investigations on exogenous progesterone administration. Progesterone was effective in improving neurobehavioral outcome in (1) young OVX mice, (2) young male mice, (3) aged male mice, and (4) aged female mice up to 4 weeks after ICH.…”

Section: Discussionsupporting

confidence: 88%

Progesterone Improves Neurobehavioral Outcome in Models of Intracerebral Hemorrhage

Lei

Wang²,

Jeong³

et al. 2015

Neuroendocrinology

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In models of acute brain injury, progesterone improves recovery through several mechanisms including modulation of neuroinflammation. Secondary injury from neuroinflammation is a potential therapeutic target after intracerebral hemorrhage (ICH). For potential translation of progesterone as a clinical acute ICH therapeutic, the present study sought to define efficacy of exogenous progesterone administration in ICH-relevant experimental paradigms. Young and aged C57BL/6 male, female, and ovariectomized (OVX) mice underwent left intrastriatal collagenase (0.05-0.075 U) or autologous whole blood (35 μl) injection. Progesterone at varying doses (4-16 mg/kg) was administered at 2, 5, 24, 48, and 72 h after injury. Rotarod and Morris water maze latencies were measured on days 1-7 and days 28-31 after injury, respectively. Hematoma volume, brain water content (cerebral edema), complementary immunohistochemistry, multiplex cytokine arrays, and inflammatory proteins were assessed at prespecified time points after injury. Progesterone (4 mg/kg) administration improved rotarod and water maze latencies (p < 0.01), and decreased cerebral edema (p < 0.05), microglial proliferation, and neuronal loss (p < 0.01) in young and aged male, young OVX, and aged female mice. Brain concentration of proinflammatory cytokines and Toll-like receptor-associated proteins were also decreased after progesterone (4 mg/kg) treatment (p < 0.01). Progesterone-treated young female mice showed no detectable effects. Exogenous progesterone improved short- and long-term neurobehavioral recovery and modulated neuroinflammation in male and OVX mice after ICH. Future studies should validate these findings, and address timing and length of administration before translation to clinical trial.

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Section: Discussionsupporting

confidence: 88%

Progesterone Improves Neurobehavioral Outcome in Models of Intracerebral Hemorrhage

Lei

Wang²,

Jeong³

et al. 2015

Neuroendocrinology

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“…A recent study by Manwani and colleagues 28 demonstrated the central role of gonadal hormones in brain ischemic susceptibility. Earlier work has suggested multiple mechanisms for protection by estrogen, including anti-oxidant effects, immune regulatory effects, and effects on cell death pathways (for review).…”

Section: Discussionmentioning

confidence: 98%

IL-4 Is Required for Sex Differences in Vulnerability to Focal Ischemia in Mice

Xiong

Liang

et al. 2015

Stroke

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Background and Purpose IL-4 protects from middle cerebral artery occlusion (MCAO) in male mice. Females generally show less injury in response to the same ischemic challenge, but the underlying mechanisms are not fully understood. We tested the importance of IL-4 in female protection using IL-4 knockout (KO) mice. Methods IL-4KO and wild-type mice of both sexes were subjected to MCAO. Infarct volume was assessed by triphenyltetrazolium chloride staining and neurobehavioral outcome by neuroscore. T cell proliferation was assessed after ConA exposure. Ischemic brain immune cell populations were analyzed by FACS and immunostaining. Results Infarction in WT-females during estrus and proestrus phases was significantly smaller than in males; neurological score was better. Infarction volume was larger and neurological score worse in IL-4KO compared with WT in both sexes, with no sex difference. Proliferation of T cells was inhibited in WT-females with higher proliferation and no sex difference in IL-4KO. Macrophage numbers and total T cells in the ischemic hemisphere were lower in WT-females, and monocytes increased markedly in IL-4KOs with no sex difference. The reduced macrophage infiltration in WT-females was predominantly M2. Loss of IL-4 increased CD68+ and iNOS+ cells and reduced YM1+ and Arg1+ cells in both sexes. Conclusions IL-4 is required for female neuroprotection during the estrus phase of the estrus cycle. Protected WT-females show a predominance of M2 activated microglia/macrophages and reduced inflammatory infiltration. Increasing macrophage M2 polarization, with or without added inhibition of infiltration, may be a new approach to stroke treatment.

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“…However, other genes associated with microglial reactivity were shown to be upregulated in both sexes (Sorge et al, 2015); therefore, perhaps P2X4R present on brain cells other than microglia neutralized the P2X4R-mediated acute neuroprotection in the males. Sex differences in stroke have been largely attributed to neuroprotection due to the activational effects of gonadal hormones such as estrogen (Manwani et al, 2015). However, we observed a similar degree of neuroprotection in both ovxed and intact MS P2X4R KO mice, suggesting that the protection we observed was not related to the acute activational effects of estrogen.…”

Section: Discussionmentioning

confidence: 99%

Deletion of the P2X4 receptor is neuroprotective acutely, but induces a depressive phenotype during recovery from ischemic stroke

Verma

Cronin

Hudobenko

et al. 2017

Brain, Behavior, and Immunity

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Introduction Acute ischemic injury leads to severe neuronal loss. One of the key mechanisms responsible for this effect is inflammation, which is characterized by the activation of myeloid cells, including resident microglia and infiltrating monocytes/macrophages. P2X4 receptors (P2X4Rs) present on these immune cells modulate the inflammatory response. For example, excessive release of adenosine triphosphate during acute ischemic stroke triggers stimulation of P2X4Rs, leading to myeloid cell activation and proliferation and further exacerbating post-ischemic inflammation. In contrast, during recovery P2X4Rs activation on microglia leads to the release of brain-derived neurotrophic factor (BDNF), which alleviate depression, maintain synaptic plasticity and hasten post-stroke behavioral recovery. Therefore, we hypothesized that deletion of the P2X4R specifically from myeloid cells would have differential effects on acute versus chronic recovery following stroke. Methods We subjected global or myeloid-specific (MS) P2X4R knock-out (KO) mice and wild-type littermates of both sexes to right middle cerebral artery occlusion (60 min). We performed histological, behavioral (sensorimotor and depressive), and biochemical (quantitative PCR and flow cytometry) analyses to determine the acute (three days after occlusion) and chronic (30 days after occlusion) effects of receptor deletion. Results Global P2X4R deletion led to reduced infarct size in both sexes. In MS P2X4R KO mice, only females showed reduced infarct size, an effect that did not change with ovariectomy. MS P2X4R KO mice of both sexes showed swift recovery from sensorimotor deficits during acute recovery but exhibited a more pronounced post-stroke depressive behavior phenotype that was independent of infarct size. Quantitative PCR analysis of whole cell lysate as well as flow-sorted myeloid cells from the perilesional cortex showed increased cellular interleukin 1 beta (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-α) mRNA levels but reduced plasma levels of these cytokines in MS P2X4R KO mice after stroke. The expression levels of BDNF and other depression-associated genes were reduced in MS P2X4R KO mice after stroke. Conclusions P2X4R deletion protects against stroke acutely but predisposes to depression-like behavior chronically after stroke. Thus, a time-sensitive approach should be considered when targeting P2X4Rs after stroke.

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Sex Differences in Ischemic Stroke Sensitivity Are Influenced by Gonadal Hormones, Not by Sex Chromosome Complement

Cited by 110 publications

References 42 publications

Progesterone Improves Neurobehavioral Outcome in Models of Intracerebral Hemorrhage

Progesterone Improves Neurobehavioral Outcome in Models of Intracerebral Hemorrhage

IL-4 Is Required for Sex Differences in Vulnerability to Focal Ischemia in Mice

Deletion of the P2X4 receptor is neuroprotective acutely, but induces a depressive phenotype during recovery from ischemic stroke

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