Gender and the injured brain

Herson, Paco S.; Hurn, Patricia D.

doi:10.1016/b978-0-444-53630-3.00012-9

Cited by 22 publications

(14 citation statements)

References 106 publications

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“…Therefore, one possibility is that ischemia results in larger generation of ADPr in males versus females. In fact, others have shown that male cells are highly vulnerable to excessive oxidant production and subsequent over-activation of poly (ADPribose) polymerase (PARP), whereas female cell death involves caspase-dependent apoptosis (for review see Lang and McCullough, 2008;Herson and Hurn, 2010). Thus, male-specific over-activation of PARP may be key because PARP-generated ADPr activates TRPM2 following neuronal exposure to exogenous H 2 O 2 (Fonfria et al, 2004), while TRPM2 channels may also be activated directly by H 2 O 2 (Kolisek et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Sex Differences in Neuroprotection Provided by Inhibition of TRPM2 Channels following Experimental Stroke

Jia

Verma

Nakayama

et al. 2011

J Cereb Blood Flow Metab

113

135

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The calcium-permeable transient receptor potential M2 (TRPM2) ion channel is activated following oxidative stress and has been implicated in ischemic damage; however, little experimental evidence exists linking TRPM2 channel activation to damage following cerebral ischemia. We directly assessed the involvement of TRPM2 channels in ischemic brain injury using pharmacological inhibitors and short-hairpin RNA (shRNA)-mediated knockdown of TRPM2 expression. Each of the four TRPM2 inhibitors tested provided significant protection to male neurons following in vitro ischemia (oxygen-glucose deprivation, OGD), while having no effect in female neurons. Similarly, TRPM2 knockdown by TRPM2 shRNA resulted in significantly reduced neuronal cell death following OGD only in male neurons. The TRPM2 inhibitor clotrimazole reduced infarct volume in male mice, while having no effect on female infarct volume. Finally, intrastriatal injection of lentivirus expressing shRNA against TRPM2 resulted in significantly smaller striatal infarcts only in male mice following middle cerebral artery occlusion, having no significant effect in female mice. Data presented in the current study demonstrate that TRPM2 inhibition and knockdown preferentially protects male neurons and brain against ischemia in vitro and in vivo, indicating that TRPM2 inhibitors may provide a new therapeutic approach to the treatment of stroke in men.

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Section: Discussionmentioning

confidence: 99%

Sex Differences in Neuroprotection Provided by Inhibition of TRPM2 Channels following Experimental Stroke

Jia

Verma

Nakayama

et al. 2011

J Cereb Blood Flow Metab

113

135

View full text Add to dashboard Cite

show abstract

“…There is growing evidence that the common link of age and the various modifiable risk factors mentioned above may be an elevated inflammatory profile resulting in a stroke-prone state [93, 108]. Sex is another important factor significantly affecting stroke incidence and outcome [51]. …”

Section: Modeling Risk Factors and Comorbiditymentioning

confidence: 99%

Ischemic stroke: experimental models and reality

2017

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The vast majority of cerebral stroke cases are caused by transient or permanent occlusion of a cerebral blood vessel (“ischemic stroke”) eventually leading to brain infarction. The final infarct size and the neurological outcome depend on a multitude of factors such as the duration and severity of ischemia, the existence of collateral systems and an adequate systemic blood pressure, etiology and localization of the infarct, but also on age, sex, comorbidities with the respective multimedication and genetic background. Thus, ischemic stroke is a highly complex and heterogeneous disorder. It is immediately obvious that experimental models of stroke can cover only individual specific aspects of this multifaceted disease. A basic understanding of the principal molecular pathways induced by ischemia-like conditions comes already from in vitro studies. One of the most frequently used in vivo models in stroke research is the endovascular suture or filament model in rodents with occlusion of the middle cerebral artery (MCA), which causes reproducible infarcts in the MCA territory. It does not require craniectomy and allows reperfusion by withdrawal of the occluding filament. Although promptly restored blood flow is far from the pathophysiology of spontaneous human stroke, it more closely mimics the therapeutic situation of mechanical thrombectomy which is expected to be increasingly applied to stroke patients. Direct transient or permanent occlusion of cerebral arteries represents an alternative approach but requires craniectomy. Application of endothelin-1, a potent vasoconstrictor, allows induction of transient focal ischemia in nearly any brain region and is frequently used to model lacunar stroke. Circumscribed and highly reproducible cortical lesions are characteristic of photothrombotic stroke where infarcts are induced by photoactivation of a systemically given dye through the intact skull. The major shortcoming of this model is near complete lack of a penumbra. The two models mimicking human stroke most closely are various embolic stroke models and spontaneous stroke models. Closeness to reality has its price and goes along with higher variability of infarct size and location as well as unpredictable stroke onset in spontaneous models versus unpredictable reperfusion in embolic clot models.

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“…Since neurotrophic signals induced by hop/STI1:PrP C interaction in central neurons depend on α7nAChR (Beraldo et al, 2010), and the latter has been implicated in neuronal resistance induced by either nicotine or melatonin against hypoxia (Hejmadi et al, 2003; Parada et al, 2014), the hop/STI1:PrP C :α7nAChR signaling complex may be a major player in neuroprotection against ischemic insults. Interestingly, examples of sexually dimorphic, ischemic brain injury mediated by both hormonal and non hormonal mechanisms (Liu et al, 2009; Herson and Hurn, 2010; Manwani and McCullough, 2011; Fairbanks et al, 2012; Herson et al, 2013; Zuo et al, 2013; Sanches et al, 2015) include the sensitivity of hippocampal neurons to ischemia in PrP C -null mice (Sakurai-Yamashita et al, 2005), and evidence has been reported of both sexually-dimorphic α-bungarotoxin binding (Arimatsu et al, 1981; Arimatsu and Seto, 1982) as well as changed content of α7nAChR following prenatal stress (Schulz et al, 2013). These data warrant a critical examination of the stoichiometry of hop/STI1:PrPC:α7nAChR complexes in the context of sensitivity to ischemic insults, especially in view of the variegated homo- and/or hetero-multimeric, cholinergic receptors that may assembled around α7nAChR subunits, as indicated by experimental work with various cell types (Bertrand et al, 2015; Wu et al, 2016).…”

Section: The Prion Protein As a Cell Surface Scaffold Proteinmentioning

confidence: 99%

The Biological Function of the Prion Protein: A Cell Surface Scaffold of Signaling Modules

Linden

2017

Front. Mol. Neurosci.

116

104

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The prion glycoprotein (PrPC) is mostly located at the cell surface, tethered to the plasma membrane through a glycosyl-phosphatydil inositol (GPI) anchor. Misfolding of PrPC is associated with the transmissible spongiform encephalopathies (TSEs), whereas its normal conformer serves as a receptor for oligomers of the β-amyloid peptide, which play a major role in the pathogenesis of Alzheimer’s Disease (AD). PrPC is highly expressed in both the nervous and immune systems, as well as in other organs, but its functions are controversial. Extensive experimental work disclosed multiple physiological roles of PrPC at the molecular, cellular and systemic levels, affecting the homeostasis of copper, neuroprotection, stem cell renewal and memory mechanisms, among others. Often each such process has been heralded as the bona fide function of PrPC, despite restricted attention paid to a selected phenotypic trait, associated with either modulation of gene expression or to the engagement of PrPC with a single ligand. In contrast, the GPI-anchored prion protein was shown to bind several extracellular and transmembrane ligands, which are required to endow that protein with the ability to play various roles in transmembrane signal transduction. In addition, differing sets of those ligands are available in cell type- and context-dependent scenarios. To account for such properties, we proposed that PrPC serves as a dynamic platform for the assembly of signaling modules at the cell surface, with widespread consequences for both physiology and behavior. The current review advances the hypothesis that the biological function of the prion protein is that of a cell surface scaffold protein, based on the striking similarities of its functional properties with those of scaffold proteins involved in the organization of intracellular signal transduction pathways. Those properties are: the ability to recruit spatially restricted sets of binding molecules involved in specific signaling; mediation of the crosstalk of signaling pathways; reciprocal allosteric regulation with binding partners; compartmentalized responses; dependence of signaling properties upon posttranslational modification; and stoichiometric requirements and/or oligomerization-dependent impact on signaling. The scaffold concept may contribute to novel approaches to the development of effective treatments to hitherto incurable neurodegenerative diseases, through informed modulation of prion protein-ligand interactions.

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Gender and the injured brain

Cited by 22 publications

References 106 publications

Sex Differences in Neuroprotection Provided by Inhibition of TRPM2 Channels following Experimental Stroke

Sex Differences in Neuroprotection Provided by Inhibition of TRPM2 Channels following Experimental Stroke

Ischemic stroke: experimental models and reality

The Biological Function of the Prion Protein: A Cell Surface Scaffold of Signaling Modules

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