Michael Vagell - Academia.edu (original) (raw)
Papers by Michael Vagell
Journal of Neuroendocrinology, Jun 1, 1997
This study assessed the role of aromatization in the expression of male reproductive behavior by ... more This study assessed the role of aromatization in the expression of male reproductive behavior by testing the effects of the aromatase inhibitor, fadrozole, on the restoration of male sexual behavior and partner preference in testosterone-treated gonadectomized rats. We measured nuclear estrogen receptor occupation to determine whether fadrozole blocked brain aromatase. In addition, nuclear androgen receptor assays were used to verify that fadrozole does not block androgen receptors. Mini-osmotic pumps fitted to brain infusion cannulas were used to deliver fadrozole (20 mg/day) into the right lateral ventricle. The majority of animals receiving fadrozole treatment with two, 10 mm testosterone filled Silastic capsules (T/F group) failed to display any sexual behavior 7 and 13 days following implant surgery. In contrast, animals receiving fadrozole treatment which were implanted with two, 10 mm testosterone capsules and one, 5 mm 1% estradiol capsule (T/F/E group) copulated normally, indicating that fadrozole's inhibition of male sex behavior was specifically due to blocking aromatase activity. Moreover, the animals which received only one, 5 mm 1% estradiol capsule (E group) also failed to exhibit male sexual behavior. Partner preference for either a sexually receptive female or a non-receptive female was measured in a three chambered apparatus for an index of sexual motivation. Repeated measures contrasts on the group x test interaction indicated that the T/F group was not significantly different from the T group. In addition, the E group did not show a preference for the receptive females and was significantly different from the T group. Fadrozole treatment resulted in a 59% decrease in brain nuclear estrogen receptor occupation relative to the T group. Fadrozole had no significant effect on brain nuclear androgen receptor occupation. Our results lend support to the hypothesis that both androgen receptor activation and aromatization are necessary for the restoration of male sexual behavior in rats. However, we found that estradiol is neither necessary nor sufficient for the restoration of partner preference.
Hormones and Behavior, Jun 1, 1998
This work tested the hypothesis that gonadal steroid receptor activation was necessary for the re... more This work tested the hypothesis that gonadal steroid receptor activation was necessary for the restoration of several sociosexual behaviors (such as copulatory behavior, partner preference, 50-kHz vocalizations, and scent marking) in testosterone-treated gonadectomized male rats. Gonadal steroid receptors were blocked by systemic administration of the antiandrogen hydroxyflutamide, the antiestrogen RU 58668, or both antagonists simultaneously in a restoration paradigm. Inhibiting androgen receptors with hydroxyflutamide blocked the restoration of male copulatory behavior, partner preference (time spent with a sexually receptive female over a nonreceptive female), 50-kHz ultrasonic vocalizations, and scent marking. On the other hand, we did not find that blocking estrogen receptors with RU 58668 inhibited the restoration of copulatory behavior or partner preference in testosterone-treated gonadectomized male rats, even though the level of brain nuclear estrogen receptor occupation was significantly reduced to the level found in gonadectomized males. However, the restoration of scent marking and 50-kHz vocalizations were impaired by RU 58668. Blocking both nuclear androgen and estrogen receptors with the two antagonists simultaneously did not have a greater inhibitory effect than treatment with each antagonist alone. Therefore, the activation of nuclear estrogen receptors is necessary for the restoration of some, but not all, sociosexual behaviors, which are also androgen receptor-dependent. Besides nuclear estrogen receptors, there are additional, but unknown, targets of estradiol that play a role in mediating copulatory behavior in adult male rats. Moreover, the signals from multiple gonadal steroid signaling pathways converge in the regulation of some sociosexual behaviors in adult male rats.
Brain Research Bulletin, Dec 1, 1991
For further characterization of the olfactory bulb's role in the mediation of chronobiological ph... more For further characterization of the olfactory bulb's role in the mediation of chronobiological phenomena, we examined basal cyclic-3',5'-adenosine monophosphate (CAMP) levels in the suprachiasmatic nuclei (SCN) and lateral hippocampus (LHIP) following bilateral olfactory bulbectomy (OBX) to assess the effects of olfactory bulb removal on the biological clock. Two groups of adult Long-Evans rats underwent OBX or sham control surgery (SHAM). Eight weeks postoperative, the animals were decapitated at the time of maximal CAMP accumulation (circadian time 9-11 h), brains were removed, frozen in liquid nitrogen, and sectioned on a cryostat. Individual brain nuclei (SCN and LHIP) were microdissected using the Palkovits punch technique and analyzed by scintillation proximity assay for CAMP. We report a 83.6% increase in basal CAMP levels in the SCN following OBX (OBX=63.7 pmol cAMP/mg protein, SHAM = 34.7 pmol cAMP/mg protein, p<O.Ol). No significant differences in LHIP CAMP levels were found. This specific increase in SCN CAMP, at the time of maximum CAMP accumulation, may give insight into the biochemical basis for altered activity levels following OBX.
Journal of the Ghana Science Association, Mar 1, 2001
ABSTRACT
Journal of Neuroendocrinology, Oct 1, 1997
The purpose of this study was to determine if injections of the 11ß-substituted steroidal antioes... more The purpose of this study was to determine if injections of the 11ß-substituted steroidal antioestrogen, RU 58668, would block two measures of oestrogen receptor action in ovariectomized adult female rats. Using an in vitro nuclear exchange assay, it was found that RU 58668 reduced cell nuclear [3H]-oestradiol binding in brain tissue 24 h after it was injected. However, pituitary cell nuclear [3H]oestradiol binding was significantly reduced just 2 h after the antioestrogen was injected. Our results demonstrate that RU 58668 can reach the brain following a subcutaneous injection, but that it needs more time to reach the brain than it does to reach the pituitary. Since the levels of hypothalamic and pituitary progestin receptors are known to be regulated by oestradiol, cytosolic [3H]-R5020 binding was used as an in vitro assay of endogenous oestrogen receptor action. RU 58668 blocked induction by oestradiol of cytosolic [3H]-R5020 binding in both the brain and pituitary 48 h after it was injected. In the absence of oestradiol, RU 58668 did not stimulate cell nuclear [3H]-oestradiol binding or cytosolic [3H]-R5020 binding in either brain or pituitary. In conclusion, injections of RU 58668 blocked two measures of oestrogen receptor action in the brain and pituitary without showing oestrogenic activity itself.
Current Medicinal Chemistry, 2006
Brain Research Bulletin, 1996
RU 58668 is a steroidal antiestrogen believed to be devoid of any partial agonist activity. Most ... more RU 58668 is a steroidal antiestrogen believed to be devoid of any partial agonist activity. Most of the work with RU 58668 has focused on its potential as an antineoplastic agent in the treatment of breast cancer, but it has not been tested for its effects on the brain and behavior. Other antiestrogens are problematic because most are either partial agonists or do not cross the blood-brain barrier. The purpose of this study was to test if RU 58668 blocks two classic estrogen-dependent behaviors: female sexual behavior and feeding behavior. We used a repeated measures design to examine if RU 58668 reversibly blocked female sexual behavior. RU 58668 significantly reduced both the level of sexual receptivity and the level of proceptivity in a reversible manner. Changes in body and food weight were also measured. Our results show that RU 58668 blocked estrogen's suppressive effects on feeding behavior and body weight. Therefore, RU 58668 is the first antiestrogen that blocks estrediors effects on female sexual behavior while also inhibiting estradiol's effects on feeding behavior and body weight.
The Society for Neuroscience Abstracts, 1999
J Neuroendocrinol, 2003
This study assessed the role of aromatization in the expression of male reproductive behavior by ... more This study assessed the role of aromatization in the expression of male reproductive behavior by testing the effects of the aromatase inhibitor, fadrozole, on the restoration of male sexual behavior and partner preference in testosterone-treated gonadectomized rats. We measured nuclear estrogen receptor occupation to determine whether fadrozole blocked brain aromatase. In addition, nuclear androgen receptor assays were used to verify that fadrozole does not block androgen receptors. Mini-osmotic pumps fitted to brain infusion cannulas were used to deliver fadrozole (20 micrograms/day) into the right lateral ventricle. The majority of animals receiving fadrozole treatment with two, 10 mm testosterone filled Silastic capsules (T/F group) failed to display any sexual behavior 7 and 13 days following implant surgery. In contrast, animals receiving fadrozole treatment which were implanted with two, 10 mm testosterone capsules and one, 5 mm 1% estradiol capsule (T/F/E group) copulated normally, indicating that fadrozole's inhibition of male sex behavior was specifically due to blocking aromatase activity. Moreover, the animals which received only one, 5 mm 1% estradiol capsule (E group) also failed to exhibit male sexual behavior. Partner preference for either a sexually receptive female or a non-receptive female was measured in a three chambered apparatus for an index of sexual motivation. Repeated measures contrasts on the group x test interaction indicated that the T/F group was not significantly different from the T group. In addition, the E group did not show a preference for the receptive females and was significantly different from the T group. Fadrozole treatment resulted in a 59% decrease in brain nuclear estrogen receptor occupation relative to the T group. Fadrozole had no significant effect on brain nuclear androgen receptor occupation. Our results lend support to the hypothesis that both androgen receptor activation and aromatization are necessary for the restoration of male sexual behavior in rats. However, we found that estradiol is neither necessary nor sufficient for the restoration of partner preference.
Current Medicinal Chemistry
ABSTRACT
Current medicinal chemistry, 2006
The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-dep... more The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-dependent transcription factor that controls the expression of specific target genes involved in adipogenesis, inflammatory responses, and lipid metabolism. Atherosclerotic plaque progression is influenced by intraplaque inflammation and extracellular matrix deposition. Anti-inflammatory, anti-proliferative and anti-protease activity of PPARgamma may modulate the atherosclerotic process. PPARgamma is expressed in atherosclerotic lesions of human coronary arteries and has direct anti-inflammatory effects in the vascular wall. Thiazolidinediones (TZD) are ligands for PPARgamma used therapeutically to enhance insulin-mediated glucose uptake in persons with type 2 diabetes. These agents may also exert anti-atherogenic effects on cells of the vessel wall including macrophages, vascular endothelium and vascular smooth muscle. This review discusses the impact of PPARgamma and its activators in the...
Journal of the Ghana Science Association, 2001
ABSTRACT
Journal of Neuroendocrinology, 2003
The purpose of this study was to determine if injections of the 11 beta-substituted steroidal ant... more The purpose of this study was to determine if injections of the 11 beta-substituted steroidal antioestrogen, RU 58668, would block two measures of oestrogen receptor action in ovariectomized adult female rats. Using an in vitro nuclear exchange assay, it was found that RU 58668 reduced cell nuclear [3H]-oestradiol binding in brain tissue 24 h after it was injected. However, pituitary cell nuclear [3H]-oestradiol binding was significantly reduced just 2 h after the antioestrogen was injected. Our results demonstrate that RU 58668 can reach the brain following a subcutaneous injection, but that it needs more time to reach the brain than it does to reach the pituitary. Since the levels of hypothalamic and pituitary progestin receptors are known to be regulated by oestradiol, cytosolic [3H]-R5020 binding was used as an in vitro assay of endogenous oestrogen receptor action. RU 58668 blocked induction by oestradiol of cytosolic [3H]-R5020 binding in both the brain and pituitary 48 h after it was injected. In the absence of oestradiol, RU 58668 did not stimulate cell nuclear [3H]-oestradiol binding or cytosolic [3H]-R5020 binding in either brain or pituitary. In conclusion, injections of RU 58668 blocked two measures of oestrogen receptor action in the brain and pituitary without showing oestrogenic activity itself.
Hormones and Behavior, 1998
This work tested the hypothesis that gonadal steroid receptor activation was necessary for the re... more This work tested the hypothesis that gonadal steroid receptor activation was necessary for the restoration of several sociosexual behaviors (such as copulatory behavior, partner preference, 50-kHz vocalizations, and scent marking) in testosterone-treated gonadectomized male rats. Gonadal steroid receptors were blocked by systemic administration of the antiandrogen hydroxyflutamide, the antiestrogen RU 58668, or both antagonists simultaneously in a restoration paradigm. Inhibiting androgen receptors with hydroxyflutamide blocked the restoration of male copulatory behavior, partner preference (time spent with a sexually receptive female over a nonreceptive female), 50-kHz ultrasonic vocalizations, and scent marking. On the other hand, we did not find that blocking estrogen receptors with RU 58668 inhibited the restoration of copulatory behavior or partner preference in testosterone-treated gonadectomized male rats, even though the level of brain nuclear estrogen receptor occupation was significantly reduced to the level found in gonadectomized males. However, the restoration of scent marking and 50-kHz vocalizations were impaired by RU 58668. Blocking both nuclear androgen and estrogen receptors with the two antagonists simultaneously did not have a greater inhibitory effect than treatment with each antagonist alone. Therefore, the activation of nuclear estrogen receptors is necessary for the restoration of some, but not all, sociosexual behaviors, which are also androgen receptor-dependent. Besides nuclear estrogen receptors, there are additional, but unknown, targets of estradiol that play a role in mediating copulatory behavior in adult male rats. Moreover, the signals from multiple gonadal steroid signaling pathways converge in the regulation of some sociosexual behaviors in adult male rats.
Current Medicinal Chemistry, 2006
Page 1. Current Medicinal Chemistry, 2006, 13, 3227-3238 3227 PPAR Activity in the Vessel Wall: A... more Page 1. Current Medicinal Chemistry, 2006, 13, 3227-3238 3227 PPAR Activity in the Vessel Wall: Anti-Atherogenic Properties Allison B. Reiss* and Michael E. Vagell Vascular Biology Institute, Department of Medicine, Winthrop ...
Brain Research Bulletin, 1996
RU 58668 is a steroidal antiestrogen believed to be devoid of any partial agonist activity. Most ... more RU 58668 is a steroidal antiestrogen believed to be devoid of any partial agonist activity. Most of the work with RU 58668 has focused on its potential as an antineoplastic agent in the treatment of breast cancer, but it has not been tested for its effects on the brain and behavior. Other antiestrogens are problematic because most are either partial agonists or do not cross the blood-brain barrier. The purpose of this study was to test if RU 58668 blocks two classic estrogen-dependent behaviors: female sexual behavior and feeding behavior. We used a repeated measures design to examine if RU 58668 reversibly blocked female sexual behavior. RU 58668 significantly reduced both the level of sexual receptivity and the level of proceptivity in a reversible manner. Changes in body and food weight were also measured. Our results show that RU 58668 blocked estrogen's suppressive effects on feeding behavior and body weight. Therefore, RU 58668 is the first antiestrogen that blocks estrediors effects on female sexual behavior while also inhibiting estradiol's effects on feeding behavior and body weight.
Brain Research Bulletin, 1991
For further characterization of the olfactory bulb's role in the mediation of chronobiological ph... more For further characterization of the olfactory bulb's role in the mediation of chronobiological phenomena, we examined basal cyclic-3',5'-adenosine monophosphate (CAMP) levels in the suprachiasmatic nuclei (SCN) and lateral hippocampus (LHIP) following bilateral olfactory bulbectomy (OBX) to assess the effects of olfactory bulb removal on the biological clock. Two groups of adult Long-Evans rats underwent OBX or sham control surgery (SHAM). Eight weeks postoperative, the animals were decapitated at the time of maximal CAMP accumulation (circadian time 9-11 h), brains were removed, frozen in liquid nitrogen, and sectioned on a cryostat. Individual brain nuclei (SCN and LHIP) were microdissected using the Palkovits punch technique and analyzed by scintillation proximity assay for CAMP. We report a 83.6% increase in basal CAMP levels in the SCN following OBX (OBX=63.7 pmol cAMP/mg protein, SHAM = 34.7 pmol cAMP/mg protein, p<O.Ol). No significant differences in LHIP CAMP levels were found. This specific increase in SCN CAMP, at the time of maximum CAMP accumulation, may give insight into the biochemical basis for altered activity levels following OBX.
Journal of Neuroendocrinology - J NEUROENDOCRINOL, 2003
This study assessed the role of aromatization in the expression of male reproductive behavior by ... more This study assessed the role of aromatization in the expression of male reproductive behavior by testing the effects of the aromatase inhibitor, fadrozole, on the restoration of male sexual behavior and partner preference in testosterone-treated gonadectomized rats. We measured nuclear estrogen receptor occupation to determine whether fadrozole blocked brain aromatase. In addition, nuclear androgen receptor assays were used to verify that fadrozole does not block androgen receptors. Mini-osmotic pumps fitted to brain infusion cannulas were used to deliver fadrozole (20 micrograms/day) into the right lateral ventricle. The majority of animals receiving fadrozole treatment with two, 10 mm testosterone filled Silastic capsules (T/F group) failed to display any sexual behavior 7 and 13 days following implant surgery. In contrast, animals receiving fadrozole treatment which were implanted with two, 10 mm testosterone capsules and one, 5 mm 1% estradiol capsule (T/F/E group) copulated normally, indicating that fadrozole's inhibition of male sex behavior was specifically due to blocking aromatase activity. Moreover, the animals which received only one, 5 mm 1% estradiol capsule (E group) also failed to exhibit male sexual behavior. Partner preference for either a sexually receptive female or a non-receptive female was measured in a three chambered apparatus for an index of sexual motivation. Repeated measures contrasts on the group x test interaction indicated that the T/F group was not significantly different from the T group. In addition, the E group did not show a preference for the receptive females and was significantly different from the T group. Fadrozole treatment resulted in a 59% decrease in brain nuclear estrogen receptor occupation relative to the T group. Fadrozole had no significant effect on brain nuclear androgen receptor occupation. Our results lend support to the hypothesis that both androgen receptor activation and aromatization are necessary for the restoration of male sexual behavior in rats. However, we found that estradiol is neither necessary nor sufficient for the restoration of partner preference.
Journal of Neuroendocrinology, Jun 1, 1997
This study assessed the role of aromatization in the expression of male reproductive behavior by ... more This study assessed the role of aromatization in the expression of male reproductive behavior by testing the effects of the aromatase inhibitor, fadrozole, on the restoration of male sexual behavior and partner preference in testosterone-treated gonadectomized rats. We measured nuclear estrogen receptor occupation to determine whether fadrozole blocked brain aromatase. In addition, nuclear androgen receptor assays were used to verify that fadrozole does not block androgen receptors. Mini-osmotic pumps fitted to brain infusion cannulas were used to deliver fadrozole (20 mg/day) into the right lateral ventricle. The majority of animals receiving fadrozole treatment with two, 10 mm testosterone filled Silastic capsules (T/F group) failed to display any sexual behavior 7 and 13 days following implant surgery. In contrast, animals receiving fadrozole treatment which were implanted with two, 10 mm testosterone capsules and one, 5 mm 1% estradiol capsule (T/F/E group) copulated normally, indicating that fadrozole's inhibition of male sex behavior was specifically due to blocking aromatase activity. Moreover, the animals which received only one, 5 mm 1% estradiol capsule (E group) also failed to exhibit male sexual behavior. Partner preference for either a sexually receptive female or a non-receptive female was measured in a three chambered apparatus for an index of sexual motivation. Repeated measures contrasts on the group x test interaction indicated that the T/F group was not significantly different from the T group. In addition, the E group did not show a preference for the receptive females and was significantly different from the T group. Fadrozole treatment resulted in a 59% decrease in brain nuclear estrogen receptor occupation relative to the T group. Fadrozole had no significant effect on brain nuclear androgen receptor occupation. Our results lend support to the hypothesis that both androgen receptor activation and aromatization are necessary for the restoration of male sexual behavior in rats. However, we found that estradiol is neither necessary nor sufficient for the restoration of partner preference.
Hormones and Behavior, Jun 1, 1998
This work tested the hypothesis that gonadal steroid receptor activation was necessary for the re... more This work tested the hypothesis that gonadal steroid receptor activation was necessary for the restoration of several sociosexual behaviors (such as copulatory behavior, partner preference, 50-kHz vocalizations, and scent marking) in testosterone-treated gonadectomized male rats. Gonadal steroid receptors were blocked by systemic administration of the antiandrogen hydroxyflutamide, the antiestrogen RU 58668, or both antagonists simultaneously in a restoration paradigm. Inhibiting androgen receptors with hydroxyflutamide blocked the restoration of male copulatory behavior, partner preference (time spent with a sexually receptive female over a nonreceptive female), 50-kHz ultrasonic vocalizations, and scent marking. On the other hand, we did not find that blocking estrogen receptors with RU 58668 inhibited the restoration of copulatory behavior or partner preference in testosterone-treated gonadectomized male rats, even though the level of brain nuclear estrogen receptor occupation was significantly reduced to the level found in gonadectomized males. However, the restoration of scent marking and 50-kHz vocalizations were impaired by RU 58668. Blocking both nuclear androgen and estrogen receptors with the two antagonists simultaneously did not have a greater inhibitory effect than treatment with each antagonist alone. Therefore, the activation of nuclear estrogen receptors is necessary for the restoration of some, but not all, sociosexual behaviors, which are also androgen receptor-dependent. Besides nuclear estrogen receptors, there are additional, but unknown, targets of estradiol that play a role in mediating copulatory behavior in adult male rats. Moreover, the signals from multiple gonadal steroid signaling pathways converge in the regulation of some sociosexual behaviors in adult male rats.
Brain Research Bulletin, Dec 1, 1991
For further characterization of the olfactory bulb's role in the mediation of chronobiological ph... more For further characterization of the olfactory bulb's role in the mediation of chronobiological phenomena, we examined basal cyclic-3',5'-adenosine monophosphate (CAMP) levels in the suprachiasmatic nuclei (SCN) and lateral hippocampus (LHIP) following bilateral olfactory bulbectomy (OBX) to assess the effects of olfactory bulb removal on the biological clock. Two groups of adult Long-Evans rats underwent OBX or sham control surgery (SHAM). Eight weeks postoperative, the animals were decapitated at the time of maximal CAMP accumulation (circadian time 9-11 h), brains were removed, frozen in liquid nitrogen, and sectioned on a cryostat. Individual brain nuclei (SCN and LHIP) were microdissected using the Palkovits punch technique and analyzed by scintillation proximity assay for CAMP. We report a 83.6% increase in basal CAMP levels in the SCN following OBX (OBX=63.7 pmol cAMP/mg protein, SHAM = 34.7 pmol cAMP/mg protein, p<O.Ol). No significant differences in LHIP CAMP levels were found. This specific increase in SCN CAMP, at the time of maximum CAMP accumulation, may give insight into the biochemical basis for altered activity levels following OBX.
Journal of the Ghana Science Association, Mar 1, 2001
ABSTRACT
Journal of Neuroendocrinology, Oct 1, 1997
The purpose of this study was to determine if injections of the 11ß-substituted steroidal antioes... more The purpose of this study was to determine if injections of the 11ß-substituted steroidal antioestrogen, RU 58668, would block two measures of oestrogen receptor action in ovariectomized adult female rats. Using an in vitro nuclear exchange assay, it was found that RU 58668 reduced cell nuclear [3H]-oestradiol binding in brain tissue 24 h after it was injected. However, pituitary cell nuclear [3H]oestradiol binding was significantly reduced just 2 h after the antioestrogen was injected. Our results demonstrate that RU 58668 can reach the brain following a subcutaneous injection, but that it needs more time to reach the brain than it does to reach the pituitary. Since the levels of hypothalamic and pituitary progestin receptors are known to be regulated by oestradiol, cytosolic [3H]-R5020 binding was used as an in vitro assay of endogenous oestrogen receptor action. RU 58668 blocked induction by oestradiol of cytosolic [3H]-R5020 binding in both the brain and pituitary 48 h after it was injected. In the absence of oestradiol, RU 58668 did not stimulate cell nuclear [3H]-oestradiol binding or cytosolic [3H]-R5020 binding in either brain or pituitary. In conclusion, injections of RU 58668 blocked two measures of oestrogen receptor action in the brain and pituitary without showing oestrogenic activity itself.
Current Medicinal Chemistry, 2006
Brain Research Bulletin, 1996
RU 58668 is a steroidal antiestrogen believed to be devoid of any partial agonist activity. Most ... more RU 58668 is a steroidal antiestrogen believed to be devoid of any partial agonist activity. Most of the work with RU 58668 has focused on its potential as an antineoplastic agent in the treatment of breast cancer, but it has not been tested for its effects on the brain and behavior. Other antiestrogens are problematic because most are either partial agonists or do not cross the blood-brain barrier. The purpose of this study was to test if RU 58668 blocks two classic estrogen-dependent behaviors: female sexual behavior and feeding behavior. We used a repeated measures design to examine if RU 58668 reversibly blocked female sexual behavior. RU 58668 significantly reduced both the level of sexual receptivity and the level of proceptivity in a reversible manner. Changes in body and food weight were also measured. Our results show that RU 58668 blocked estrogen's suppressive effects on feeding behavior and body weight. Therefore, RU 58668 is the first antiestrogen that blocks estrediors effects on female sexual behavior while also inhibiting estradiol's effects on feeding behavior and body weight.
The Society for Neuroscience Abstracts, 1999
J Neuroendocrinol, 2003
This study assessed the role of aromatization in the expression of male reproductive behavior by ... more This study assessed the role of aromatization in the expression of male reproductive behavior by testing the effects of the aromatase inhibitor, fadrozole, on the restoration of male sexual behavior and partner preference in testosterone-treated gonadectomized rats. We measured nuclear estrogen receptor occupation to determine whether fadrozole blocked brain aromatase. In addition, nuclear androgen receptor assays were used to verify that fadrozole does not block androgen receptors. Mini-osmotic pumps fitted to brain infusion cannulas were used to deliver fadrozole (20 micrograms/day) into the right lateral ventricle. The majority of animals receiving fadrozole treatment with two, 10 mm testosterone filled Silastic capsules (T/F group) failed to display any sexual behavior 7 and 13 days following implant surgery. In contrast, animals receiving fadrozole treatment which were implanted with two, 10 mm testosterone capsules and one, 5 mm 1% estradiol capsule (T/F/E group) copulated normally, indicating that fadrozole's inhibition of male sex behavior was specifically due to blocking aromatase activity. Moreover, the animals which received only one, 5 mm 1% estradiol capsule (E group) also failed to exhibit male sexual behavior. Partner preference for either a sexually receptive female or a non-receptive female was measured in a three chambered apparatus for an index of sexual motivation. Repeated measures contrasts on the group x test interaction indicated that the T/F group was not significantly different from the T group. In addition, the E group did not show a preference for the receptive females and was significantly different from the T group. Fadrozole treatment resulted in a 59% decrease in brain nuclear estrogen receptor occupation relative to the T group. Fadrozole had no significant effect on brain nuclear androgen receptor occupation. Our results lend support to the hypothesis that both androgen receptor activation and aromatization are necessary for the restoration of male sexual behavior in rats. However, we found that estradiol is neither necessary nor sufficient for the restoration of partner preference.
Current Medicinal Chemistry
ABSTRACT
Current medicinal chemistry, 2006
The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-dep... more The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-dependent transcription factor that controls the expression of specific target genes involved in adipogenesis, inflammatory responses, and lipid metabolism. Atherosclerotic plaque progression is influenced by intraplaque inflammation and extracellular matrix deposition. Anti-inflammatory, anti-proliferative and anti-protease activity of PPARgamma may modulate the atherosclerotic process. PPARgamma is expressed in atherosclerotic lesions of human coronary arteries and has direct anti-inflammatory effects in the vascular wall. Thiazolidinediones (TZD) are ligands for PPARgamma used therapeutically to enhance insulin-mediated glucose uptake in persons with type 2 diabetes. These agents may also exert anti-atherogenic effects on cells of the vessel wall including macrophages, vascular endothelium and vascular smooth muscle. This review discusses the impact of PPARgamma and its activators in the...
Journal of the Ghana Science Association, 2001
ABSTRACT
Journal of Neuroendocrinology, 2003
The purpose of this study was to determine if injections of the 11 beta-substituted steroidal ant... more The purpose of this study was to determine if injections of the 11 beta-substituted steroidal antioestrogen, RU 58668, would block two measures of oestrogen receptor action in ovariectomized adult female rats. Using an in vitro nuclear exchange assay, it was found that RU 58668 reduced cell nuclear [3H]-oestradiol binding in brain tissue 24 h after it was injected. However, pituitary cell nuclear [3H]-oestradiol binding was significantly reduced just 2 h after the antioestrogen was injected. Our results demonstrate that RU 58668 can reach the brain following a subcutaneous injection, but that it needs more time to reach the brain than it does to reach the pituitary. Since the levels of hypothalamic and pituitary progestin receptors are known to be regulated by oestradiol, cytosolic [3H]-R5020 binding was used as an in vitro assay of endogenous oestrogen receptor action. RU 58668 blocked induction by oestradiol of cytosolic [3H]-R5020 binding in both the brain and pituitary 48 h after it was injected. In the absence of oestradiol, RU 58668 did not stimulate cell nuclear [3H]-oestradiol binding or cytosolic [3H]-R5020 binding in either brain or pituitary. In conclusion, injections of RU 58668 blocked two measures of oestrogen receptor action in the brain and pituitary without showing oestrogenic activity itself.
Hormones and Behavior, 1998
This work tested the hypothesis that gonadal steroid receptor activation was necessary for the re... more This work tested the hypothesis that gonadal steroid receptor activation was necessary for the restoration of several sociosexual behaviors (such as copulatory behavior, partner preference, 50-kHz vocalizations, and scent marking) in testosterone-treated gonadectomized male rats. Gonadal steroid receptors were blocked by systemic administration of the antiandrogen hydroxyflutamide, the antiestrogen RU 58668, or both antagonists simultaneously in a restoration paradigm. Inhibiting androgen receptors with hydroxyflutamide blocked the restoration of male copulatory behavior, partner preference (time spent with a sexually receptive female over a nonreceptive female), 50-kHz ultrasonic vocalizations, and scent marking. On the other hand, we did not find that blocking estrogen receptors with RU 58668 inhibited the restoration of copulatory behavior or partner preference in testosterone-treated gonadectomized male rats, even though the level of brain nuclear estrogen receptor occupation was significantly reduced to the level found in gonadectomized males. However, the restoration of scent marking and 50-kHz vocalizations were impaired by RU 58668. Blocking both nuclear androgen and estrogen receptors with the two antagonists simultaneously did not have a greater inhibitory effect than treatment with each antagonist alone. Therefore, the activation of nuclear estrogen receptors is necessary for the restoration of some, but not all, sociosexual behaviors, which are also androgen receptor-dependent. Besides nuclear estrogen receptors, there are additional, but unknown, targets of estradiol that play a role in mediating copulatory behavior in adult male rats. Moreover, the signals from multiple gonadal steroid signaling pathways converge in the regulation of some sociosexual behaviors in adult male rats.
Current Medicinal Chemistry, 2006
Page 1. Current Medicinal Chemistry, 2006, 13, 3227-3238 3227 PPAR Activity in the Vessel Wall: A... more Page 1. Current Medicinal Chemistry, 2006, 13, 3227-3238 3227 PPAR Activity in the Vessel Wall: Anti-Atherogenic Properties Allison B. Reiss* and Michael E. Vagell Vascular Biology Institute, Department of Medicine, Winthrop ...
Brain Research Bulletin, 1996
RU 58668 is a steroidal antiestrogen believed to be devoid of any partial agonist activity. Most ... more RU 58668 is a steroidal antiestrogen believed to be devoid of any partial agonist activity. Most of the work with RU 58668 has focused on its potential as an antineoplastic agent in the treatment of breast cancer, but it has not been tested for its effects on the brain and behavior. Other antiestrogens are problematic because most are either partial agonists or do not cross the blood-brain barrier. The purpose of this study was to test if RU 58668 blocks two classic estrogen-dependent behaviors: female sexual behavior and feeding behavior. We used a repeated measures design to examine if RU 58668 reversibly blocked female sexual behavior. RU 58668 significantly reduced both the level of sexual receptivity and the level of proceptivity in a reversible manner. Changes in body and food weight were also measured. Our results show that RU 58668 blocked estrogen's suppressive effects on feeding behavior and body weight. Therefore, RU 58668 is the first antiestrogen that blocks estrediors effects on female sexual behavior while also inhibiting estradiol's effects on feeding behavior and body weight.
Brain Research Bulletin, 1991
For further characterization of the olfactory bulb's role in the mediation of chronobiological ph... more For further characterization of the olfactory bulb's role in the mediation of chronobiological phenomena, we examined basal cyclic-3',5'-adenosine monophosphate (CAMP) levels in the suprachiasmatic nuclei (SCN) and lateral hippocampus (LHIP) following bilateral olfactory bulbectomy (OBX) to assess the effects of olfactory bulb removal on the biological clock. Two groups of adult Long-Evans rats underwent OBX or sham control surgery (SHAM). Eight weeks postoperative, the animals were decapitated at the time of maximal CAMP accumulation (circadian time 9-11 h), brains were removed, frozen in liquid nitrogen, and sectioned on a cryostat. Individual brain nuclei (SCN and LHIP) were microdissected using the Palkovits punch technique and analyzed by scintillation proximity assay for CAMP. We report a 83.6% increase in basal CAMP levels in the SCN following OBX (OBX=63.7 pmol cAMP/mg protein, SHAM = 34.7 pmol cAMP/mg protein, p<O.Ol). No significant differences in LHIP CAMP levels were found. This specific increase in SCN CAMP, at the time of maximum CAMP accumulation, may give insight into the biochemical basis for altered activity levels following OBX.
Journal of Neuroendocrinology - J NEUROENDOCRINOL, 2003
This study assessed the role of aromatization in the expression of male reproductive behavior by ... more This study assessed the role of aromatization in the expression of male reproductive behavior by testing the effects of the aromatase inhibitor, fadrozole, on the restoration of male sexual behavior and partner preference in testosterone-treated gonadectomized rats. We measured nuclear estrogen receptor occupation to determine whether fadrozole blocked brain aromatase. In addition, nuclear androgen receptor assays were used to verify that fadrozole does not block androgen receptors. Mini-osmotic pumps fitted to brain infusion cannulas were used to deliver fadrozole (20 micrograms/day) into the right lateral ventricle. The majority of animals receiving fadrozole treatment with two, 10 mm testosterone filled Silastic capsules (T/F group) failed to display any sexual behavior 7 and 13 days following implant surgery. In contrast, animals receiving fadrozole treatment which were implanted with two, 10 mm testosterone capsules and one, 5 mm 1% estradiol capsule (T/F/E group) copulated normally, indicating that fadrozole's inhibition of male sex behavior was specifically due to blocking aromatase activity. Moreover, the animals which received only one, 5 mm 1% estradiol capsule (E group) also failed to exhibit male sexual behavior. Partner preference for either a sexually receptive female or a non-receptive female was measured in a three chambered apparatus for an index of sexual motivation. Repeated measures contrasts on the group x test interaction indicated that the T/F group was not significantly different from the T group. In addition, the E group did not show a preference for the receptive females and was significantly different from the T group. Fadrozole treatment resulted in a 59% decrease in brain nuclear estrogen receptor occupation relative to the T group. Fadrozole had no significant effect on brain nuclear androgen receptor occupation. Our results lend support to the hypothesis that both androgen receptor activation and aromatization are necessary for the restoration of male sexual behavior in rats. However, we found that estradiol is neither necessary nor sufficient for the restoration of partner preference.