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Sex Steroids Do Not Modulate TRPM2-Mediated Injury in Females following Middle Cerebral Artery Occlusion(1,2,3).

Quillinan N, Grewal H, Klawitter J, Herson PS - eNeuro (2014)

Bottom Line: Interestingly, treatment of female mice with the potent androgen receptor agonist DHT had no effect on ischemic injury and did not permit CTZ neuroprotection.Similarly, DHT-treated females did not exhibit increased levels of ADPribose, the TRPM2 ligand generated by PARP, following ischemia.In conclusion, our data demonstrate that while circulating androgens are necessary for PARP-mediated TRPM2 injury in males, they are not sufficient to produce TRPM2 activation in females.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Anesthesiology, University of Colorado School of Medicine, Aurora, Colorado 80045.

ABSTRACT
Calcium-permeable transient receptor potential M2 (TRPM2) ion channel activation contributes to cerebral ischemic injury specifically in males. In male mice, circulating androgens are required for TRPM2 inhibition with clotrimazole (CTZ) to provide protection following experimental stroke. Sufficient levels of circulating androgens are necessary to support ischemia-induced activation of poly ADP ribose polymerase (PARP) and consequent activation of TRPM2 channels. In this study, we tested whether differences in sex steroids contribute to the lack of CTZ neuroprotection in females. Middle cerebral artery occlusion (MCAO) was performed using adult female mice that were hormonally intact, ovariectomized (OVX) or dihydrotestosterone (DHT) treated. CTZ or vehicle was administered at the time of reperfusion, animals were euthanized 24 h later and brains and serum were collected. Infarct analysis revealed no effect of CTZ in intact females or females lacking endogenous sex steroids (OVX). Interestingly, treatment of female mice with the potent androgen receptor agonist DHT had no effect on ischemic injury and did not permit CTZ neuroprotection. Similarly, DHT-treated females did not exhibit increased levels of ADPribose, the TRPM2 ligand generated by PARP, following ischemia. No differences in TRPM2 or androgen receptor expression were observed between males and females. These data suggest that the lack of TRPM2 activation in females following experimental stroke is not due to the presence of estrogen or the absence of androgens. In conclusion, our data demonstrate that while circulating androgens are necessary for PARP-mediated TRPM2 injury in males, they are not sufficient to produce TRPM2 activation in females.

No MeSH data available.


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Clotrimazole administered to overarectomized females fails reduce infarct size. Female mice were ovarectomized and MCAO was performed 7 d later. Infarct analysis 24 h after MCAO revealed no difference between vehicle- and CTZ-treated females (Student’s t test; p = 0.79).
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Figure 2: Clotrimazole administered to overarectomized females fails reduce infarct size. Female mice were ovarectomized and MCAO was performed 7 d later. Infarct analysis 24 h after MCAO revealed no difference between vehicle- and CTZ-treated females (Student’s t test; p = 0.79).

Mentions: To investigate whether circulating female hormones prevent TRPM2 activation, female mice were ovariectomized. MCAO was performed 1 week after OVX to allow for depletion of hormones (Dubal et al., 2001) and CTZ or vehicle were administered at the time of reperfusion. Infarct was analyzed 24 h after MCAO. Consistent with extensive literature demonstrating a protective effect of endogenous estrogen (Alkayed et al., 1998; Fukuda et al., 2000; Herson et al., 2009), we observed significant increase in infarct volume in OVX mice compared to intact females (p = 0.0008f). However, CTZ administered at the time of reperfusion had no effect on infarct volume in OVX females compared to vehicle-treated OVX females (vehicle: 51.69 ± 5.59%; CTZ: 54.58 ± 8.88%, n = 10, p = 0.79g) (Fig. 2).


Sex Steroids Do Not Modulate TRPM2-Mediated Injury in Females following Middle Cerebral Artery Occlusion(1,2,3).

Quillinan N, Grewal H, Klawitter J, Herson PS - eNeuro (2014)

Clotrimazole administered to overarectomized females fails reduce infarct size. Female mice were ovarectomized and MCAO was performed 7 d later. Infarct analysis 24 h after MCAO revealed no difference between vehicle- and CTZ-treated females (Student’s t test; p = 0.79).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4596140&req=5

Figure 2: Clotrimazole administered to overarectomized females fails reduce infarct size. Female mice were ovarectomized and MCAO was performed 7 d later. Infarct analysis 24 h after MCAO revealed no difference between vehicle- and CTZ-treated females (Student’s t test; p = 0.79).
Mentions: To investigate whether circulating female hormones prevent TRPM2 activation, female mice were ovariectomized. MCAO was performed 1 week after OVX to allow for depletion of hormones (Dubal et al., 2001) and CTZ or vehicle were administered at the time of reperfusion. Infarct was analyzed 24 h after MCAO. Consistent with extensive literature demonstrating a protective effect of endogenous estrogen (Alkayed et al., 1998; Fukuda et al., 2000; Herson et al., 2009), we observed significant increase in infarct volume in OVX mice compared to intact females (p = 0.0008f). However, CTZ administered at the time of reperfusion had no effect on infarct volume in OVX females compared to vehicle-treated OVX females (vehicle: 51.69 ± 5.59%; CTZ: 54.58 ± 8.88%, n = 10, p = 0.79g) (Fig. 2).

Bottom Line: Interestingly, treatment of female mice with the potent androgen receptor agonist DHT had no effect on ischemic injury and did not permit CTZ neuroprotection.Similarly, DHT-treated females did not exhibit increased levels of ADPribose, the TRPM2 ligand generated by PARP, following ischemia.In conclusion, our data demonstrate that while circulating androgens are necessary for PARP-mediated TRPM2 injury in males, they are not sufficient to produce TRPM2 activation in females.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Anesthesiology, University of Colorado School of Medicine, Aurora, Colorado 80045.

ABSTRACT
Calcium-permeable transient receptor potential M2 (TRPM2) ion channel activation contributes to cerebral ischemic injury specifically in males. In male mice, circulating androgens are required for TRPM2 inhibition with clotrimazole (CTZ) to provide protection following experimental stroke. Sufficient levels of circulating androgens are necessary to support ischemia-induced activation of poly ADP ribose polymerase (PARP) and consequent activation of TRPM2 channels. In this study, we tested whether differences in sex steroids contribute to the lack of CTZ neuroprotection in females. Middle cerebral artery occlusion (MCAO) was performed using adult female mice that were hormonally intact, ovariectomized (OVX) or dihydrotestosterone (DHT) treated. CTZ or vehicle was administered at the time of reperfusion, animals were euthanized 24 h later and brains and serum were collected. Infarct analysis revealed no effect of CTZ in intact females or females lacking endogenous sex steroids (OVX). Interestingly, treatment of female mice with the potent androgen receptor agonist DHT had no effect on ischemic injury and did not permit CTZ neuroprotection. Similarly, DHT-treated females did not exhibit increased levels of ADPribose, the TRPM2 ligand generated by PARP, following ischemia. No differences in TRPM2 or androgen receptor expression were observed between males and females. These data suggest that the lack of TRPM2 activation in females following experimental stroke is not due to the presence of estrogen or the absence of androgens. In conclusion, our data demonstrate that while circulating androgens are necessary for PARP-mediated TRPM2 injury in males, they are not sufficient to produce TRPM2 activation in females.

No MeSH data available.


Related in: MedlinePlus