Mechanisms of Estrogenic Protection against gp120-Induced Neurotoxicity

Howard, Sarah A.; Brooke, Sheila M.; Sapolsky, Robert M.

doi:10.1006/exnr.2000.7619

Cited by 33 publications

(20 citation statements)

References 54 publications

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“…43,44) The antioxidant mechanism of estrogen protection has been suggested to be independent of receptor binding. 45,46) Other steroids have been suggested to participate in protecting brain tissue against oxidative stress induced by different injuries. For example, dehydroepiandrosterone supplementation greatly reduces oxidative damage in synaptosomes isolated from diabetic rats 47) and dehydroepiandrosterone sulfate added to the medium demonstrated a nueroprotective effect against ischemic neuronal injury in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…12,13) Estrogen is an antioxidant and is capable of both reducing lipoprotein oxidation and decreasing artery wall production of superoxide anion.…”

Section: )mentioning

confidence: 99%

“…33,34) The 17b-estradiol contents in rat serum are shown in Table 6. The 17b-estradiol level in the OVX group was decreased by 1.66-fold compared with the CON group.…”

Section: Fig 1 Scavenging Effects Of Salicornia Herbacea (Sh) On Dpmentioning

confidence: 99%

“…9,10) Estrogens have antioxidant properties and can inhibit lipid peroxidation in vitro, which might contribute directly to their neuroprotective effect, 11) and the antioxidant metabolism of estrogen protection has been suggested to be independent of receptor binding. 12,13) Estrogen is an antioxidant and is capable of both reducing lipoprotein oxidation and decreasing artery wall production of superoxide anion. [14][15][16][17] Women undergo natural menopause, called the primary event of the aging process, in their 40-50s.…”

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confidence: 99%

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The Role of <i>Salicornia herbacea</i> in Ovariectomy-Induced Oxidative Stress

Lee

Kim

et al. 2006

Biological & Pharmaceutical Bulletin

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Reactive oxygen species (ROS), which include hydrogen peroxide and other chemical forms known as free radicals, such as superoxide anion, hydroxyl, and peroxyl radicals, are produced as part of normal and essential biological processes.1) Diverse antioxidant systems, both enzymatic and nonenzymatic, operate to control excessive levels of ROS. 1)A cell is generally able to maintain an appropriate balance between oxidants and antioxidants under normal conditions. When this balance is perturbed and shifts toward oxidative stress, either by an increase in oxidants or by a decrease in antioxidants, the cell becomes more susceptible to injuries, such as inflammation, 2) ischemia/reperfusion damage, 2,3) diabetes, 4) and atherosclerosis. 5-7) The oxidative stress established by excessive free radical generation may induce a number of alterations of cell constituents, including inactivation of enzymes, generation of reactive nitrogen species, damage of nucleic acid bases and proteins, and peroxidation of membrane lipids.To protect against the damage caused by oxidative stress, cells have a number of antioxidant enzymes and repair activities, most of which are expressed at low levels during normal growth. In mammalian cells, ROS are normally scavenged by three major types of primary antioxidant enzymes: copper-, zinc-, and manganese-dependent superoxide dismutase (CuZn-SOD and Mn-SOD), catalase (CAT) and glutathione peroxidase (GPx). The SODs convert superoxide anion into hydrogen peroxide (H 2 O 2 ), while CAT and GPx degrade H 2 O 2 into water. Furthermore, GPx degrades H 2 O 2 that originates from the oxidation of polyunsaturated fatty acids (PUFAs) in the presence of reduced glutathione (GSH) which is a key component of the antioxidant defense system. 8) In addition, ovariectomy has been shown to cause an increase in peroxide production by the liver and brain.9,10) Estrogens have antioxidant properties and can inhibit lipid peroxidation in vitro, which might contribute directly to their neuroprotective effect, 11) and the antioxidant metabolism of estrogen protection has been suggested to be independent of receptor binding. 12,13) Estrogen is an antioxidant and is capable of both reducing lipoprotein oxidation and decreasing artery wall production of superoxide anion.14-17) Women undergo natural menopause, called the primary event of the aging process, in their 40-50s. Estrogen declines precipitously in postmenopause. This ovarian hormone deficiency increases the generation of ROS. The excessive ROS induces oxidative stress that results in cell damage or death. Age-related increases in serum and tissue lipid peroxides have been demonstrated in rodents, 18) and increased levels of serum lipid peroxides have been found in elderly humans. 19)Salicornia herbacea (SH) is an annual herb growing in salt marshes and on muddy seashores. In Oriental medicine, SH has been used to treat a variety of conditions such as constipation, obesity, diabetes, asthma, arthritis, and cancer. 21) This plant has previously been shown to stim...

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Section: Discussionmentioning

confidence: 99%

“…12,13) Estrogen is an antioxidant and is capable of both reducing lipoprotein oxidation and decreasing artery wall production of superoxide anion.…”

Section: )mentioning

confidence: 99%

“…33,34) The 17b-estradiol contents in rat serum are shown in Table 6. The 17b-estradiol level in the OVX group was decreased by 1.66-fold compared with the CON group.…”

Section: Fig 1 Scavenging Effects Of Salicornia Herbacea (Sh) On Dpmentioning

confidence: 99%

mentioning

confidence: 99%

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The Role of <i>Salicornia herbacea</i> in Ovariectomy-Induced Oxidative Stress

Lee

Kim

et al. 2006

Biological & Pharmaceutical Bulletin

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“…For example, 17a-E2 and 17b-E2 are equipotent in their ability to moderate neuronal toxicity resulting from gp120 exposure, a pathology induced by a combination of N-methyl-D-aspartate (NMDA) receptor activation, accumulation of intracellular calcium, and downstream degenerative events including generation of reactive oxygen species and lipid peroxidation. Again, tamoxifen does not reduce the protection afforded by either 17b-E2 or 17a-E2, suggesting that the mechanism is independent of classical estrogen receptors ERa and ERb [Howard et al, 2000]. Similarly, 17b-E2, 17a-E2, and estrone all attenuate neuronal death induced by excitotoxicity, direct oxidative stress, and serum-deprivation-induced apoptosis in mouse cortical neurons [Bae et al, 2000].…”

Section: Introductionmentioning

confidence: 88%

17β‐ and 17α‐estradiol are non‐competitive inhibitors of dopamine uptake: implications for Parkinson's disease models and therapeutics

Dykens¹,

Wersinger

Sidhu

2005

Drug Development Research

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Despite compelling literature documenting the cyto-and neuro-protective activities of various estrogens in a wide variety of cell and animal models, several large clinical trials of hormone replacement therapies have failed to detect such beneficial responses in humans. To some degree, this failure stems from profound hormonal responses that counterbalance the protective effects. This limitation could be circumvented by the development of less hormonally active estrogen analogs that retain the cytoprotective activities of the parental hormones. For example, 17a-estradiol (17a-E2) is at least 200-fold less active than 17b-estradiol (17b-E2) as a transactivating hormone, yet it is equipotent as a cytoprotectant in many cell types exposed to a variety of stressors, such as amyloid toxicity, serum withdrawal, oxidative stress, and glutamate excitotoxicity. Both estradiol isomers stabilize mitochondrial function under pathogenic conditions, and both have shown efficacy in animal models of stroke. The results for models of Parkinson's disease differ, and 17b-E2, but not 17a-E2, has been reported previously to provide neuroprotection against MPTP toxicity. However, such findings must be regarded in light of reports that 17b-E2 impedes cellular uptake of MPTP by the dopamine transporter (DAT), thereby forestalling development of the lesion rather than providing authentic cytoprotection. We report here that both 17a-E2 and 17b-E2 show classical, non-competitive, inhibition of dopamine uptake by the human DAT (hDAT) transfected into Ltk À mouse fibroblasts, HEK293 human embryonic kidney cells, and SH-SY5Y human neuroblastoma cells. IC 50 values vary slightly with cell type, but are 400 and 70 nM for 17a-E2 and 17b-E2, respectively, in SH-SY5Y cells. We also evaluated 17a-E2 in the 6-OH-dopamine (6-OHDA) model of PD, where toxin uptake occurs via the DAT. In these studies, treatment with estrogen was delayed for 6 hr after unilateral intrastriatal 6-OHDA injection to allow for toxin uptake. After 6 hr, a loading dose of 17a-E2 (100 mg/kg in sesame oil) was injected s.c., accompanied by implanting of a sustained release silastic device. After 21 days, animals treated with 17a-E2 showed significant improvements in both gait asymmetry and apo-morphine induced rotational defects. These positive results encourage evaluation of 17a-E2 in a host of neurodegenerative diseases. Drug Dev.

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Neurological infections in pregnancy

Mukerji

Lyons

2015

Neurological Illness in Pregnancy

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Mechanisms of Estrogenic Protection against gp120-Induced Neurotoxicity

Cited by 33 publications

References 54 publications

The Role of <i>Salicornia herbacea</i> in Ovariectomy-Induced Oxidative Stress

The Role of <i>Salicornia herbacea</i> in Ovariectomy-Induced Oxidative Stress

17β‐ and 17α‐estradiol are non‐competitive inhibitors of dopamine uptake: implications for Parkinson's disease models and therapeutics

Neurological infections in pregnancy

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