Sex Steroids Do Not Modulate TRPM2-Mediated Injury in Females following Middle Cerebral Artery Occlusion

Quillinan, Nidia; Grewal, Himmat; Klawitter, Jost; Herson, Paco S.

doi:10.1523/eneuro.0022-14.2014

Cited by 11 publications

(16 citation statements)

References 39 publications

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“…The mechanism of neuroprotection by female sex steroids is primarily through inhibition of caspase dependent cell death, which is the dominant form of cell death in females (Liu et al, 2009; Liu et al, 2011). Our results obtained with TRPM2 KO demonstrating neuroprotection in male but not female mice are consistent with our previously published observations that activation of TRPM2-mediated cell death following cerebral ischemia is male specific (Jia et al, 2011; Verma et al, 2012; Nakayama et al, 2013; Shimizu et al, 2013; Quillinan et al, 2014). These results demonstrate for the first time male specificity of TRPM2 using genetic knockouts in global ischemia, and are consistent male specific neuroprotection with administration of AGK2 following CA/CPR.…”

Section: Discussionsupporting

confidence: 93%

“…Relevant to the male-specific PARP-mediated cell death pathway, we have recently demonstrated that the calcium-permeable ion channel transient receptor potential channels, M2 (TRPM2) contributes to male-specific injury following cerebral ischemia in a PARP-dependent manner (Shimizu et al, 2013). Inhibition or knock-down of TRPM2 is protective in males, but not females using in vitro and in vivo models of cerebral ischemia (Jia et al, 2011; Verma et al, 2012; Nakayama et al, 2013; Quillinan et al, 2014). A distinguishing property of TRPM2 channels is that they are gated by ADP ribose (ADPr), likely generated following the activation of PARP (Fonfria et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Sirtuin-2 mediates male specific neuronal injury following experimental cardiac arrest through activation of TRPM2 ion channels

Shimizu

Quillinan

Orfila

et al. 2016

Experimental Neurology

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Objective Sirtuins (Sirt) are a class of deacetylase enzymes that play an important role in cell proliferation. Sirt2 activation produces O-acetylated-ADPribose (OAADPr) which can act as a ligand for transient receptor potential cation channel, M2 (TRPM2). We tested the hypothesis that Sirt2 is activated following global cerebral ischemia and contributes to neuronal injury through activation of TRPM2. Methods Adult male and female mice (8–12 weeks old) C57Bl/6 and TRPM2 knock-out mice were subjected to 8 min of cardiac arrest followed by cardiopulmonary resuscitation (CA/CPR). The Sirt2 inhibitor AGK-2 was administered intravenously 30 min after resuscitation. Hippocampal CA1 injury was analyzed at 3 days after CA/CPR. Acute Sirt2 activity was analyzed at 3 and 24 h after CA/CPR. Long-term hippocampal function was assessed using slice electrophysiology 7 days after CA/CPR. Results AGK-2 significantly reduced CA1 injury in WT but not TRPM2 knock-out males and had no effect on CA1 injury in females. Elevated Sirt2 activity was observed in hippocampal tissue from males at 24 h after cardiac arrest and was reduced by AGK-2. In contrast, Sirt2 activity in females was increased at 3 but not 24 h. Finally, we observed long-term benefit of AGK-2 on hippocampal function, with a protection of long-term potentiation at CA1 synapses at 7 and 30 days after ischemia. Conclusions In summary, we observed a male specific activation of Sirt2 that contributes to neuronal injury and functional deficits after ischemia specifically in males. These results are consistent with a role of Sirt2 in activating TRPM2 following global ischemia in a sex specific manner. These results support the growing body of literature showing that oxidative stress mechanisms predominate in males and converge on TRPM2 activation as a mediator of cell death.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Sirtuin-2 mediates male specific neuronal injury following experimental cardiac arrest through activation of TRPM2 ion channels

Shimizu

Quillinan

Orfila

et al. 2016

Experimental Neurology

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“…We have taken advantage of this signaling pathway in designing tat-M2NX that targets the ADPr binding pocket of TRPM2, thereby inhibiting its activation. The possibility remains that the lack of effect in females could be due to inadequate dosing of tat-M2NX, though we have performed extensive studies using in vitro neuronal cultures and TRPM2 KO mice in combination with several known TRPM2 channel inhibitors and have never observed a protective effect in female cells or animals (Jia et al, 2011; Verma et al, 2012; Nakayama et al, 2013; Shimizu et al, 2013; Quillinan et al, 2014). Therefore, it is highly unlikely that the lack of protection observed in female mice in the current study using tat-M2NX is related to incorrect dosing.…”

Section: Discussionmentioning

confidence: 99%

“…ADPr is generated by PARP-1 in response to oxidative stress and cerebral ischemia, which is particularly relevant in the setting of reperfusion injury after ischemia (Shimizu et al, 2013). Inhibition of TRPM2 ion channels with clotrimazole (CTZ) or genetic knockdown reduces ischemic injury in males, but not females (Jia et al, 2011; Verma et al, 2012; Shimizu et al, 2013; Quillinan et al, 2014; Shimizu et al, 2016). While we have previously shown that CTZ can be administered up to 2 h after onset of ischemia in stroke models (Shimizu et al, 2013), we have not previously investigated whether inhibiting TRPM2 at more extended time points provides neuroprotection.…”

Section: Introductionmentioning

confidence: 99%

Extended therapeutic window of a novel peptide inhibitor of TRPM2 channels following focal cerebral ischemia

Shimizu

Dietz

Cruz‐Torres

et al. 2016

Experimental Neurology

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Introduction TRPM2 channels have been suggested to play a role in ischemic neuronal injury, specifically in males. A major hindrance to TRPM2 research has been the lack of specific TRPM2 inhibitors. The current study characterized the specificity and neuroprotective efficacy of a novel TRPM2 inhibitor. Methods Fluorescent calcium imaging (Fluo5F) was used to determine inhibitor efficacy of the TRPM2 peptide inhibitor (tat-M2NX) in HEK293 cells stably expressing hTRPM2. Adult (2–3months) and aged (18–20 months) mice were subjected to 60 min middle cerebral artery occlusion (MCAO) and injected with tat-M2NX, control scrambled peptide (tat-SCR) or clotrimazole (CTZ) either 20 min prior or 3 h after reperfusion. Infarct size was assessed using TTC staining. Results TRPM2 inhibition by tat-M2NX was observed by decreased Ca2+ influx following H2O2 exposure human TRPM2 expressing cells. Male mice pre-treated with tat-M2NX had smaller infarct volume compared to tat-SCR. No effect of tat-M2NX on infarct size was observed in female mice. Importantly, male TRPM2−/− mice were not further protected by tat-M2NX, demonstrating selectivity of tat-M2NX. Administration of tat-M2NX 3 h after reperfusion provided significant protection to males when analyzed at 24 h or 4 days after MCAO. Finally, we observed that tat-M2NX reduced ischemic injury in aged male mice. Conclusions These data demonstrate the development of a new peptide inhibitor of TRPM2 channels that provides protection from ischemic stroke in young adult and aged male animals with a clinically relevant therapeutic window.

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“…Interpretation of in vivo experiments using this compound is difficult. The sexual dimorphic nature of the effects of clotrimazole on stroke is claimed to be caused by androgen-dependent production of ADPR after an ischemic stroke 66 , although simply administering androgens to females did not cause a TRPM2-dependent increase in cerebral infarct 67 . It should be noted here that clotrimazole is used medically as an anti-fungal compound and is not a selective TRPM2 blocker.…”

Section: Redox Regulation Of Trpm2mentioning

confidence: 99%

Redox regulation of transient receptor potential channels in the endothelium

Pires

Earley

2017

Microcirculation

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Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are important mediators of signaling pathways in the endothelium. Specific members of the transient receptor potential (TRP) superfamily of cation channels act as important Ca2+ influx pathways in endothelial cells, and are involved in endothelium-dependent vasodilation, regulation of barrier permeability, and angiogenesis. ROS and RNS can modulate the activity of certain TRP channels mainly by modifying specific cysteine residues or by stimulating the production of second messengers. In this review we highlight the recent literature describing in redox regulation of TRP channel activity in endothelial cells as well as the physiological importance of these pathways and implication for cardiovascular diseases.

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Sex Steroids Do Not Modulate TRPM2-Mediated Injury in Females following Middle Cerebral Artery Occlusion

Abstract: TRPM2 is an ion channel that is activated by ischemia in stroke and contributes to neuronal injury only in males. We tested whether the lack of TRPM2 activation following stroke in females is caused by differences in sex steroids.

Cited by 11 publications

References 39 publications

Sirtuin-2 mediates male specific neuronal injury following experimental cardiac arrest through activation of TRPM2 ion channels

Sirtuin-2 mediates male specific neuronal injury following experimental cardiac arrest through activation of TRPM2 ion channels

Extended therapeutic window of a novel peptide inhibitor of TRPM2 channels following focal cerebral ischemia

Redox regulation of transient receptor potential channels in the endothelium

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