Sexual dimorphism following in vitro ischemia in the response to neurosteroids and mechanisms of injury

Background Cerebral ischemic stroke is a significant cause of morbidity and mortality. Sex differences exist following stroke in terms of incidence, symptoms, outcomes and response to some treatments. Importantly, molecular mechanisms of injury, activated following ischemia may differ between the sexes and if so may account, at least in part, for sex differences seen in treatment response. Here we aimed to determine, using single-sex organotypic hippocampal slice cultures, whether the effectiveness of a potential treatment option, i.e. sex steroids, exhibited any sexual dimorphism and whether sex affected the mechanisms of apoptosis activated following ischemia. Results Following exposure to ischemia, male-derived tissue exhibited higher levels of cell death than female-derived tissue. Various sex steroid hormones, i.e. progesterone, allopregnanolone, and estradiol, were protective in terms of reducing the amount of cell death in male- and female-derived tissue whereas medoxyprogesterone acetate (MPA) was only protective in female-derived tissue. The protective effect of progesterone was abolished in the presence of finasteride, a 5α-reductase inhibitor, suggesting it was largely mediated via its conversion to allopregnanolone. To test the hypothesis that sex differences exist in the activation of specific elements of the apoptotic pathway activated following ischemia we administered Q-VD-OPH, a caspase inhibitor, or PJ34, an inhibitor of poly (ADP ribose) polymerase (PARP). Caspase inhibition was only effective, in terms of reducing cell death, in female-derived tissue, whereas PARP inhibition was only protective in male-derived tissue. However, in both sexes, the protective effects of progesterone and estradiol were not observed in the presence of either caspase or PARP inhibition. Conclusions Sex differences exist in both the amount of cell death produced and those elements of the cell death pathway activated following an ischemic insult. There are also some sex differences in the effectiveness of steroid hormones to provide neuroprotection following an ischemic insult—namely MPA was only protective in female-derived tissue. This adds further support to the notion sex is an important factor to consider when investigating future drug targets for CNS disorders, such as ischemic stroke. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Altaee, Raeed [verfasserIn] Gibson, Claire L.

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2020

Schlagwörter:	Ischemia Sex Steroid hormones Neuroprotection Apoptosis

Anmerkung:	© The Author(s) 2020

Übergeordnetes Werk:	Enthalten in: BMC neuroscience - London : BioMed Central, 2000, 21(2020), 1 vom: 29. Jan.
Übergeordnetes Werk:	volume:21 ; year:2020 ; number:1 ; day:29 ; month:01

Links:	Volltext

DOI / URN:	10.1186/s12868-020-0553-1

Katalog-ID:	SPR027268179

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520			\|a Background Cerebral ischemic stroke is a significant cause of morbidity and mortality. Sex differences exist following stroke in terms of incidence, symptoms, outcomes and response to some treatments. Importantly, molecular mechanisms of injury, activated following ischemia may differ between the sexes and if so may account, at least in part, for sex differences seen in treatment response. Here we aimed to determine, using single-sex organotypic hippocampal slice cultures, whether the effectiveness of a potential treatment option, i.e. sex steroids, exhibited any sexual dimorphism and whether sex affected the mechanisms of apoptosis activated following ischemia. Results Following exposure to ischemia, male-derived tissue exhibited higher levels of cell death than female-derived tissue. Various sex steroid hormones, i.e. progesterone, allopregnanolone, and estradiol, were protective in terms of reducing the amount of cell death in male- and female-derived tissue whereas medoxyprogesterone acetate (MPA) was only protective in female-derived tissue. The protective effect of progesterone was abolished in the presence of finasteride, a 5α-reductase inhibitor, suggesting it was largely mediated via its conversion to allopregnanolone. To test the hypothesis that sex differences exist in the activation of specific elements of the apoptotic pathway activated following ischemia we administered Q-VD-OPH, a caspase inhibitor, or PJ34, an inhibitor of poly (ADP ribose) polymerase (PARP). Caspase inhibition was only effective, in terms of reducing cell death, in female-derived tissue, whereas PARP inhibition was only protective in male-derived tissue. However, in both sexes, the protective effects of progesterone and estradiol were not observed in the presence of either caspase or PARP inhibition. Conclusions Sex differences exist in both the amount of cell death produced and those elements of the cell death pathway activated following an ischemic insult. There are also some sex differences in the effectiveness of steroid hormones to provide neuroprotection following an ischemic insult—namely MPA was only protective in female-derived tissue. This adds further support to the notion sex is an important factor to consider when investigating future drug targets for CNS disorders, such as ischemic stroke.
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allfields	10.1186/s12868-020-0553-1 doi (DE-627)SPR027268179 (SPR)s12868-020-0553-1-e DE-627 ger DE-627 rakwb eng Altaee, Raeed verfasserin aut Sexual dimorphism following in vitro ischemia in the response to neurosteroids and mechanisms of injury 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2020 Background Cerebral ischemic stroke is a significant cause of morbidity and mortality. Sex differences exist following stroke in terms of incidence, symptoms, outcomes and response to some treatments. Importantly, molecular mechanisms of injury, activated following ischemia may differ between the sexes and if so may account, at least in part, for sex differences seen in treatment response. Here we aimed to determine, using single-sex organotypic hippocampal slice cultures, whether the effectiveness of a potential treatment option, i.e. sex steroids, exhibited any sexual dimorphism and whether sex affected the mechanisms of apoptosis activated following ischemia. Results Following exposure to ischemia, male-derived tissue exhibited higher levels of cell death than female-derived tissue. Various sex steroid hormones, i.e. progesterone, allopregnanolone, and estradiol, were protective in terms of reducing the amount of cell death in male- and female-derived tissue whereas medoxyprogesterone acetate (MPA) was only protective in female-derived tissue. The protective effect of progesterone was abolished in the presence of finasteride, a 5α-reductase inhibitor, suggesting it was largely mediated via its conversion to allopregnanolone. To test the hypothesis that sex differences exist in the activation of specific elements of the apoptotic pathway activated following ischemia we administered Q-VD-OPH, a caspase inhibitor, or PJ34, an inhibitor of poly (ADP ribose) polymerase (PARP). Caspase inhibition was only effective, in terms of reducing cell death, in female-derived tissue, whereas PARP inhibition was only protective in male-derived tissue. However, in both sexes, the protective effects of progesterone and estradiol were not observed in the presence of either caspase or PARP inhibition. Conclusions Sex differences exist in both the amount of cell death produced and those elements of the cell death pathway activated following an ischemic insult. There are also some sex differences in the effectiveness of steroid hormones to provide neuroprotection following an ischemic insult—namely MPA was only protective in female-derived tissue. This adds further support to the notion sex is an important factor to consider when investigating future drug targets for CNS disorders, such as ischemic stroke. Ischemia (dpeaa)DE-He213 Sex (dpeaa)DE-He213 Steroid hormones (dpeaa)DE-He213 Neuroprotection (dpeaa)DE-He213 Apoptosis (dpeaa)DE-He213 Gibson, Claire L. (orcid)0000-0002-3358-7341 aut Enthalten in BMC neuroscience London : BioMed Central, 2000 21(2020), 1 vom: 29. Jan. (DE-627)326643648 (DE-600)2041344-0 1471-2202 nnns volume:21 year:2020 number:1 day:29 month:01 https://dx.doi.org/10.1186/s12868-020-0553-1 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 21 2020 1 29 01
spelling	10.1186/s12868-020-0553-1 doi (DE-627)SPR027268179 (SPR)s12868-020-0553-1-e DE-627 ger DE-627 rakwb eng Altaee, Raeed verfasserin aut Sexual dimorphism following in vitro ischemia in the response to neurosteroids and mechanisms of injury 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2020 Background Cerebral ischemic stroke is a significant cause of morbidity and mortality. Sex differences exist following stroke in terms of incidence, symptoms, outcomes and response to some treatments. Importantly, molecular mechanisms of injury, activated following ischemia may differ between the sexes and if so may account, at least in part, for sex differences seen in treatment response. Here we aimed to determine, using single-sex organotypic hippocampal slice cultures, whether the effectiveness of a potential treatment option, i.e. sex steroids, exhibited any sexual dimorphism and whether sex affected the mechanisms of apoptosis activated following ischemia. Results Following exposure to ischemia, male-derived tissue exhibited higher levels of cell death than female-derived tissue. Various sex steroid hormones, i.e. progesterone, allopregnanolone, and estradiol, were protective in terms of reducing the amount of cell death in male- and female-derived tissue whereas medoxyprogesterone acetate (MPA) was only protective in female-derived tissue. The protective effect of progesterone was abolished in the presence of finasteride, a 5α-reductase inhibitor, suggesting it was largely mediated via its conversion to allopregnanolone. To test the hypothesis that sex differences exist in the activation of specific elements of the apoptotic pathway activated following ischemia we administered Q-VD-OPH, a caspase inhibitor, or PJ34, an inhibitor of poly (ADP ribose) polymerase (PARP). Caspase inhibition was only effective, in terms of reducing cell death, in female-derived tissue, whereas PARP inhibition was only protective in male-derived tissue. However, in both sexes, the protective effects of progesterone and estradiol were not observed in the presence of either caspase or PARP inhibition. Conclusions Sex differences exist in both the amount of cell death produced and those elements of the cell death pathway activated following an ischemic insult. There are also some sex differences in the effectiveness of steroid hormones to provide neuroprotection following an ischemic insult—namely MPA was only protective in female-derived tissue. This adds further support to the notion sex is an important factor to consider when investigating future drug targets for CNS disorders, such as ischemic stroke. Ischemia (dpeaa)DE-He213 Sex (dpeaa)DE-He213 Steroid hormones (dpeaa)DE-He213 Neuroprotection (dpeaa)DE-He213 Apoptosis (dpeaa)DE-He213 Gibson, Claire L. (orcid)0000-0002-3358-7341 aut Enthalten in BMC neuroscience London : BioMed Central, 2000 21(2020), 1 vom: 29. Jan. (DE-627)326643648 (DE-600)2041344-0 1471-2202 nnns volume:21 year:2020 number:1 day:29 month:01 https://dx.doi.org/10.1186/s12868-020-0553-1 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 21 2020 1 29 01
allfields_unstemmed	10.1186/s12868-020-0553-1 doi (DE-627)SPR027268179 (SPR)s12868-020-0553-1-e DE-627 ger DE-627 rakwb eng Altaee, Raeed verfasserin aut Sexual dimorphism following in vitro ischemia in the response to neurosteroids and mechanisms of injury 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2020 Background Cerebral ischemic stroke is a significant cause of morbidity and mortality. Sex differences exist following stroke in terms of incidence, symptoms, outcomes and response to some treatments. Importantly, molecular mechanisms of injury, activated following ischemia may differ between the sexes and if so may account, at least in part, for sex differences seen in treatment response. Here we aimed to determine, using single-sex organotypic hippocampal slice cultures, whether the effectiveness of a potential treatment option, i.e. sex steroids, exhibited any sexual dimorphism and whether sex affected the mechanisms of apoptosis activated following ischemia. Results Following exposure to ischemia, male-derived tissue exhibited higher levels of cell death than female-derived tissue. Various sex steroid hormones, i.e. progesterone, allopregnanolone, and estradiol, were protective in terms of reducing the amount of cell death in male- and female-derived tissue whereas medoxyprogesterone acetate (MPA) was only protective in female-derived tissue. The protective effect of progesterone was abolished in the presence of finasteride, a 5α-reductase inhibitor, suggesting it was largely mediated via its conversion to allopregnanolone. To test the hypothesis that sex differences exist in the activation of specific elements of the apoptotic pathway activated following ischemia we administered Q-VD-OPH, a caspase inhibitor, or PJ34, an inhibitor of poly (ADP ribose) polymerase (PARP). Caspase inhibition was only effective, in terms of reducing cell death, in female-derived tissue, whereas PARP inhibition was only protective in male-derived tissue. However, in both sexes, the protective effects of progesterone and estradiol were not observed in the presence of either caspase or PARP inhibition. Conclusions Sex differences exist in both the amount of cell death produced and those elements of the cell death pathway activated following an ischemic insult. There are also some sex differences in the effectiveness of steroid hormones to provide neuroprotection following an ischemic insult—namely MPA was only protective in female-derived tissue. This adds further support to the notion sex is an important factor to consider when investigating future drug targets for CNS disorders, such as ischemic stroke. Ischemia (dpeaa)DE-He213 Sex (dpeaa)DE-He213 Steroid hormones (dpeaa)DE-He213 Neuroprotection (dpeaa)DE-He213 Apoptosis (dpeaa)DE-He213 Gibson, Claire L. (orcid)0000-0002-3358-7341 aut Enthalten in BMC neuroscience London : BioMed Central, 2000 21(2020), 1 vom: 29. Jan. (DE-627)326643648 (DE-600)2041344-0 1471-2202 nnns volume:21 year:2020 number:1 day:29 month:01 https://dx.doi.org/10.1186/s12868-020-0553-1 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 21 2020 1 29 01
allfieldsGer	10.1186/s12868-020-0553-1 doi (DE-627)SPR027268179 (SPR)s12868-020-0553-1-e DE-627 ger DE-627 rakwb eng Altaee, Raeed verfasserin aut Sexual dimorphism following in vitro ischemia in the response to neurosteroids and mechanisms of injury 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2020 Background Cerebral ischemic stroke is a significant cause of morbidity and mortality. Sex differences exist following stroke in terms of incidence, symptoms, outcomes and response to some treatments. Importantly, molecular mechanisms of injury, activated following ischemia may differ between the sexes and if so may account, at least in part, for sex differences seen in treatment response. Here we aimed to determine, using single-sex organotypic hippocampal slice cultures, whether the effectiveness of a potential treatment option, i.e. sex steroids, exhibited any sexual dimorphism and whether sex affected the mechanisms of apoptosis activated following ischemia. Results Following exposure to ischemia, male-derived tissue exhibited higher levels of cell death than female-derived tissue. Various sex steroid hormones, i.e. progesterone, allopregnanolone, and estradiol, were protective in terms of reducing the amount of cell death in male- and female-derived tissue whereas medoxyprogesterone acetate (MPA) was only protective in female-derived tissue. The protective effect of progesterone was abolished in the presence of finasteride, a 5α-reductase inhibitor, suggesting it was largely mediated via its conversion to allopregnanolone. To test the hypothesis that sex differences exist in the activation of specific elements of the apoptotic pathway activated following ischemia we administered Q-VD-OPH, a caspase inhibitor, or PJ34, an inhibitor of poly (ADP ribose) polymerase (PARP). Caspase inhibition was only effective, in terms of reducing cell death, in female-derived tissue, whereas PARP inhibition was only protective in male-derived tissue. However, in both sexes, the protective effects of progesterone and estradiol were not observed in the presence of either caspase or PARP inhibition. Conclusions Sex differences exist in both the amount of cell death produced and those elements of the cell death pathway activated following an ischemic insult. There are also some sex differences in the effectiveness of steroid hormones to provide neuroprotection following an ischemic insult—namely MPA was only protective in female-derived tissue. This adds further support to the notion sex is an important factor to consider when investigating future drug targets for CNS disorders, such as ischemic stroke. Ischemia (dpeaa)DE-He213 Sex (dpeaa)DE-He213 Steroid hormones (dpeaa)DE-He213 Neuroprotection (dpeaa)DE-He213 Apoptosis (dpeaa)DE-He213 Gibson, Claire L. (orcid)0000-0002-3358-7341 aut Enthalten in BMC neuroscience London : BioMed Central, 2000 21(2020), 1 vom: 29. Jan. (DE-627)326643648 (DE-600)2041344-0 1471-2202 nnns volume:21 year:2020 number:1 day:29 month:01 https://dx.doi.org/10.1186/s12868-020-0553-1 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 21 2020 1 29 01
allfieldsSound	10.1186/s12868-020-0553-1 doi (DE-627)SPR027268179 (SPR)s12868-020-0553-1-e DE-627 ger DE-627 rakwb eng Altaee, Raeed verfasserin aut Sexual dimorphism following in vitro ischemia in the response to neurosteroids and mechanisms of injury 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2020 Background Cerebral ischemic stroke is a significant cause of morbidity and mortality. Sex differences exist following stroke in terms of incidence, symptoms, outcomes and response to some treatments. Importantly, molecular mechanisms of injury, activated following ischemia may differ between the sexes and if so may account, at least in part, for sex differences seen in treatment response. Here we aimed to determine, using single-sex organotypic hippocampal slice cultures, whether the effectiveness of a potential treatment option, i.e. sex steroids, exhibited any sexual dimorphism and whether sex affected the mechanisms of apoptosis activated following ischemia. Results Following exposure to ischemia, male-derived tissue exhibited higher levels of cell death than female-derived tissue. Various sex steroid hormones, i.e. progesterone, allopregnanolone, and estradiol, were protective in terms of reducing the amount of cell death in male- and female-derived tissue whereas medoxyprogesterone acetate (MPA) was only protective in female-derived tissue. The protective effect of progesterone was abolished in the presence of finasteride, a 5α-reductase inhibitor, suggesting it was largely mediated via its conversion to allopregnanolone. To test the hypothesis that sex differences exist in the activation of specific elements of the apoptotic pathway activated following ischemia we administered Q-VD-OPH, a caspase inhibitor, or PJ34, an inhibitor of poly (ADP ribose) polymerase (PARP). Caspase inhibition was only effective, in terms of reducing cell death, in female-derived tissue, whereas PARP inhibition was only protective in male-derived tissue. However, in both sexes, the protective effects of progesterone and estradiol were not observed in the presence of either caspase or PARP inhibition. Conclusions Sex differences exist in both the amount of cell death produced and those elements of the cell death pathway activated following an ischemic insult. There are also some sex differences in the effectiveness of steroid hormones to provide neuroprotection following an ischemic insult—namely MPA was only protective in female-derived tissue. This adds further support to the notion sex is an important factor to consider when investigating future drug targets for CNS disorders, such as ischemic stroke. Ischemia (dpeaa)DE-He213 Sex (dpeaa)DE-He213 Steroid hormones (dpeaa)DE-He213 Neuroprotection (dpeaa)DE-He213 Apoptosis (dpeaa)DE-He213 Gibson, Claire L. (orcid)0000-0002-3358-7341 aut Enthalten in BMC neuroscience London : BioMed Central, 2000 21(2020), 1 vom: 29. Jan. (DE-627)326643648 (DE-600)2041344-0 1471-2202 nnns volume:21 year:2020 number:1 day:29 month:01 https://dx.doi.org/10.1186/s12868-020-0553-1 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 21 2020 1 29 01
language	English
source	Enthalten in BMC neuroscience 21(2020), 1 vom: 29. Jan. volume:21 year:2020 number:1 day:29 month:01
sourceStr	Enthalten in BMC neuroscience 21(2020), 1 vom: 29. Jan. volume:21 year:2020 number:1 day:29 month:01
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Ischemia Sex Steroid hormones Neuroprotection Apoptosis
isfreeaccess_bool	true
container_title	BMC neuroscience
authorswithroles_txt_mv	Altaee, Raeed @@aut@@ Gibson, Claire L. @@aut@@
publishDateDaySort_date	2020-01-29T00:00:00Z
hierarchy_top_id	326643648
id	SPR027268179
language_de	englisch
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Sex differences exist following stroke in terms of incidence, symptoms, outcomes and response to some treatments. Importantly, molecular mechanisms of injury, activated following ischemia may differ between the sexes and if so may account, at least in part, for sex differences seen in treatment response. Here we aimed to determine, using single-sex organotypic hippocampal slice cultures, whether the effectiveness of a potential treatment option, i.e. sex steroids, exhibited any sexual dimorphism and whether sex affected the mechanisms of apoptosis activated following ischemia. Results Following exposure to ischemia, male-derived tissue exhibited higher levels of cell death than female-derived tissue. Various sex steroid hormones, i.e. progesterone, allopregnanolone, and estradiol, were protective in terms of reducing the amount of cell death in male- and female-derived tissue whereas medoxyprogesterone acetate (MPA) was only protective in female-derived tissue. The protective effect of progesterone was abolished in the presence of finasteride, a 5α-reductase inhibitor, suggesting it was largely mediated via its conversion to allopregnanolone. To test the hypothesis that sex differences exist in the activation of specific elements of the apoptotic pathway activated following ischemia we administered Q-VD-OPH, a caspase inhibitor, or PJ34, an inhibitor of poly (ADP ribose) polymerase (PARP). Caspase inhibition was only effective, in terms of reducing cell death, in female-derived tissue, whereas PARP inhibition was only protective in male-derived tissue. However, in both sexes, the protective effects of progesterone and estradiol were not observed in the presence of either caspase or PARP inhibition. Conclusions Sex differences exist in both the amount of cell death produced and those elements of the cell death pathway activated following an ischemic insult. There are also some sex differences in the effectiveness of steroid hormones to provide neuroprotection following an ischemic insult—namely MPA was only protective in female-derived tissue. 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author	Altaee, Raeed
spellingShingle	Altaee, Raeed misc Ischemia misc Sex misc Steroid hormones misc Neuroprotection misc Apoptosis Sexual dimorphism following in vitro ischemia in the response to neurosteroids and mechanisms of injury
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topic_title	Sexual dimorphism following in vitro ischemia in the response to neurosteroids and mechanisms of injury Ischemia (dpeaa)DE-He213 Sex (dpeaa)DE-He213 Steroid hormones (dpeaa)DE-He213 Neuroprotection (dpeaa)DE-He213 Apoptosis (dpeaa)DE-He213
topic	misc Ischemia misc Sex misc Steroid hormones misc Neuroprotection misc Apoptosis
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title	Sexual dimorphism following in vitro ischemia in the response to neurosteroids and mechanisms of injury
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title_full	Sexual dimorphism following in vitro ischemia in the response to neurosteroids and mechanisms of injury
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author_browse	Altaee, Raeed Gibson, Claire L.
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title_sort	sexual dimorphism following in vitro ischemia in the response to neurosteroids and mechanisms of injury
title_auth	Sexual dimorphism following in vitro ischemia in the response to neurosteroids and mechanisms of injury
abstract	Background Cerebral ischemic stroke is a significant cause of morbidity and mortality. Sex differences exist following stroke in terms of incidence, symptoms, outcomes and response to some treatments. Importantly, molecular mechanisms of injury, activated following ischemia may differ between the sexes and if so may account, at least in part, for sex differences seen in treatment response. Here we aimed to determine, using single-sex organotypic hippocampal slice cultures, whether the effectiveness of a potential treatment option, i.e. sex steroids, exhibited any sexual dimorphism and whether sex affected the mechanisms of apoptosis activated following ischemia. Results Following exposure to ischemia, male-derived tissue exhibited higher levels of cell death than female-derived tissue. Various sex steroid hormones, i.e. progesterone, allopregnanolone, and estradiol, were protective in terms of reducing the amount of cell death in male- and female-derived tissue whereas medoxyprogesterone acetate (MPA) was only protective in female-derived tissue. The protective effect of progesterone was abolished in the presence of finasteride, a 5α-reductase inhibitor, suggesting it was largely mediated via its conversion to allopregnanolone. To test the hypothesis that sex differences exist in the activation of specific elements of the apoptotic pathway activated following ischemia we administered Q-VD-OPH, a caspase inhibitor, or PJ34, an inhibitor of poly (ADP ribose) polymerase (PARP). Caspase inhibition was only effective, in terms of reducing cell death, in female-derived tissue, whereas PARP inhibition was only protective in male-derived tissue. However, in both sexes, the protective effects of progesterone and estradiol were not observed in the presence of either caspase or PARP inhibition. Conclusions Sex differences exist in both the amount of cell death produced and those elements of the cell death pathway activated following an ischemic insult. There are also some sex differences in the effectiveness of steroid hormones to provide neuroprotection following an ischemic insult—namely MPA was only protective in female-derived tissue. This adds further support to the notion sex is an important factor to consider when investigating future drug targets for CNS disorders, such as ischemic stroke. © The Author(s) 2020
abstractGer	Background Cerebral ischemic stroke is a significant cause of morbidity and mortality. Sex differences exist following stroke in terms of incidence, symptoms, outcomes and response to some treatments. Importantly, molecular mechanisms of injury, activated following ischemia may differ between the sexes and if so may account, at least in part, for sex differences seen in treatment response. Here we aimed to determine, using single-sex organotypic hippocampal slice cultures, whether the effectiveness of a potential treatment option, i.e. sex steroids, exhibited any sexual dimorphism and whether sex affected the mechanisms of apoptosis activated following ischemia. Results Following exposure to ischemia, male-derived tissue exhibited higher levels of cell death than female-derived tissue. Various sex steroid hormones, i.e. progesterone, allopregnanolone, and estradiol, were protective in terms of reducing the amount of cell death in male- and female-derived tissue whereas medoxyprogesterone acetate (MPA) was only protective in female-derived tissue. The protective effect of progesterone was abolished in the presence of finasteride, a 5α-reductase inhibitor, suggesting it was largely mediated via its conversion to allopregnanolone. To test the hypothesis that sex differences exist in the activation of specific elements of the apoptotic pathway activated following ischemia we administered Q-VD-OPH, a caspase inhibitor, or PJ34, an inhibitor of poly (ADP ribose) polymerase (PARP). Caspase inhibition was only effective, in terms of reducing cell death, in female-derived tissue, whereas PARP inhibition was only protective in male-derived tissue. However, in both sexes, the protective effects of progesterone and estradiol were not observed in the presence of either caspase or PARP inhibition. Conclusions Sex differences exist in both the amount of cell death produced and those elements of the cell death pathway activated following an ischemic insult. There are also some sex differences in the effectiveness of steroid hormones to provide neuroprotection following an ischemic insult—namely MPA was only protective in female-derived tissue. This adds further support to the notion sex is an important factor to consider when investigating future drug targets for CNS disorders, such as ischemic stroke. © The Author(s) 2020
abstract_unstemmed	Background Cerebral ischemic stroke is a significant cause of morbidity and mortality. Sex differences exist following stroke in terms of incidence, symptoms, outcomes and response to some treatments. Importantly, molecular mechanisms of injury, activated following ischemia may differ between the sexes and if so may account, at least in part, for sex differences seen in treatment response. Here we aimed to determine, using single-sex organotypic hippocampal slice cultures, whether the effectiveness of a potential treatment option, i.e. sex steroids, exhibited any sexual dimorphism and whether sex affected the mechanisms of apoptosis activated following ischemia. Results Following exposure to ischemia, male-derived tissue exhibited higher levels of cell death than female-derived tissue. Various sex steroid hormones, i.e. progesterone, allopregnanolone, and estradiol, were protective in terms of reducing the amount of cell death in male- and female-derived tissue whereas medoxyprogesterone acetate (MPA) was only protective in female-derived tissue. The protective effect of progesterone was abolished in the presence of finasteride, a 5α-reductase inhibitor, suggesting it was largely mediated via its conversion to allopregnanolone. To test the hypothesis that sex differences exist in the activation of specific elements of the apoptotic pathway activated following ischemia we administered Q-VD-OPH, a caspase inhibitor, or PJ34, an inhibitor of poly (ADP ribose) polymerase (PARP). Caspase inhibition was only effective, in terms of reducing cell death, in female-derived tissue, whereas PARP inhibition was only protective in male-derived tissue. However, in both sexes, the protective effects of progesterone and estradiol were not observed in the presence of either caspase or PARP inhibition. Conclusions Sex differences exist in both the amount of cell death produced and those elements of the cell death pathway activated following an ischemic insult. There are also some sex differences in the effectiveness of steroid hormones to provide neuroprotection following an ischemic insult—namely MPA was only protective in female-derived tissue. This adds further support to the notion sex is an important factor to consider when investigating future drug targets for CNS disorders, such as ischemic stroke. © The Author(s) 2020
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title_short	Sexual dimorphism following in vitro ischemia in the response to neurosteroids and mechanisms of injury
url	https://dx.doi.org/10.1186/s12868-020-0553-1
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Sexual dimorphism following in vitro ischemia in the response to neurosteroids and mechanisms of injury

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