Chronic weight loss in lean and obese rats with a brain-enhanced chemical delivery system for estradiol

Simpkins, James W.; Anderson, Wesley R.; Dawson, Ralph; Seth, Asha; Brewster, Marcus E.; Estes, Kerry S.; Bodor, Nicholas

doi:10.1016/0031-9384(88)90321-6

Cited by 26 publications

(6 citation statements)

References 38 publications

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“…The effect of E2 and ERs on body weight is well recognized (Wade, 1986; Heine et al, 2000) and believed to occur via multiple mechanisms, including a reduction in food intake and the expression of lipogenic genes (Cooke and Naaz, 2004; D’Eon et al, 2005). Conversely, the OVX rodent model of menopause is characterized by weight gain (Simpkins et al, 1988), which is preventable by treatment with E2 (Meli et al, 2004). These effects on body weight in rodents are similar to those reported to occur with human menopause (Sowers et al, 2007).…”

Section: Resultsmentioning

confidence: 99%

Estradiol Reverses a Calcium-Related Biomarker of Brain Aging in Female Rats

Brewer¹,

Dowling²,

Curran-Rauhut³

et al. 2009

J. Neurosci.

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An increase in L-type voltage-gated calcium channel (LTCC) current is a prominent biomarker of brain aging and is believed to contribute to cognitive decline and vulnerability to neuropathologies. Studies examining age-related changes in LTCCs have focused primarily on males, although estrogen (17␤-estradiol, E2) affects calcium-dependent activities associated with cognition. Therefore, to better understand brain aging in females, the effects of chronic E2 replacement on LTCC current activity in hippocampal neurons of young and aged ovariectomized rats were determined. The zipper slice preparation was used to expose cornu ammonis 1 (CA1) pyramidal neurons for recording LTCC currents using the cell-attached patch-clamp technique. We found that an age-related increase in LTCC current in neurons from control animals was prevented by E2 treatment. In addition, in situ hybridization revealed that within stratum pyramidale of the CA1 area, mRNA expression of the Ca v 1.2 LTCC subunit, but not the Ca v 1.3 subunit, was decreased in aged E2-treated rats. Thus, the reported benefits of E2 on cognition and neuronal health may be attributed, at least in part, to its age-related decrease in LTCC current.

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Section: Resultsmentioning

confidence: 99%

Estradiol Reverses a Calcium-Related Biomarker of Brain Aging in Female Rats

Brewer¹,

Dowling²,

Curran-Rauhut³

et al. 2009

J. Neurosci.

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“…injection of E 2 -CDS (3 mg/kg) suppressed LH secretion by 88%, 86%, and 66% relative to DMSO controls at 12, 18, and 24 days, respectively, and that E 2 levels were not elevated relative to the DMSO control at any sampling time [465]. A single i. v. administration of doses as low as 0.5 mg/kg to ovariectomized rats induced prolonged (3-6 weeks) pharmacological effects as measured by LH suppression [463,465,473], reduced rate of weight gain [466,[471][472][473], or, in castrated male rats, reestablishment of copulatory behavior [464]. A large number of other very encouraging results have been obtained in various animal models; most of them have been reviewed previously [33,340,475,476,478,484].…”

Section: Estradiol-cds Estradiol-cds (Estredoxmentioning

confidence: 97%

Retrometabolism‐Based Drug Design and Targeting

Bodor

Buchwald

2010

Burger's Medicinal Chemistry and Drug Discovery

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Retrometabolic drug design (RMDD) approaches are systematic methodologies aimed to design safe compounds with an improved therapeutic index. RMDDs thoroughly integrate structure– activity and structure‐metabolism considerations into the entire design process and incorporate two major concepts aimed to design soft drugs and chemical delivery systems, respectively. Soft drugs (SDs) are new, active therapeutic agents designed to undergo predictable metabolism resulting in inactive metabolites after exerting their desired therapeutic effect(s). Chemical delivery systems (CDSs) are biologically inert molecules that provide enhanced and targeted delivery of an active drug to a particular organ or site through a designed sequential metabolism that involves several steps. Here, we present a comprehensive review including a general overview of the RMDD principles and a large number of specific examples from various pharmacological areas, including many recent developments, to illustrate RMDD concepts. Whenever possible, the rationale for the design as well as the pharmacokinetic and pharmacodynamic properties of the new therapeutic agents are briefly summarized and compared to those of the other compounds used in the same field.

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“…Since its first synthesis in 1986 (115), E 2 -CDS (5) has been investigated in several models (116)(117)(118)(119)(120)(121)(122)(123)(124)(125)(126)(127)(128)(129)(130). In vitro studies with rat organ homogenates as the test matrix indicated half-lives of 156.6 min, 29.9 min, and 29.2 min (T at the 17 position) in plasma, liver, and brain homogenates, respectively (115).…”

Section: Estradiol-cdsmentioning

confidence: 98%

“…Studies in orchidectomized rats proved that a single IV injection of E 2 -CDS (3 mg/kg) suppressed LH secretion by 88%, 86%, and 66% relative to dimethyl sulfoxide (DMSO) controls at 12, 18, and 24 days, respectively, and that E 2 levels were not elevated relative to the DMSO control at any sampling time (118). A single IV administration of doses as low as 0.5 mg/kg to ovariectomized rats induced prolonged (3-6 weeks) pharmacological effects as measured by LH suppression (116,118,125), reduced rate of weight gain (119,(123)(124)(125), or, in castrated male rats, re-establishment of copulatory behavior (117). A large number of other encouraging results have been obtained in various animal models and phase I/II clinical trials; most of them have been reviewed previously (74,126,128).…”

Section: Estradiol-cdsmentioning

confidence: 98%