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J W Simpkins

Publications and source records attributed to J W Simpkins.

170 records · Page 10Linked to original sources
PubMedDate not supplied

Neuroprotective effects of estrogens: potential mechanisms of action.

Epidemiological studies associate post-menopausal estrogen use with a reduction in risk of Alzheimer's disease, a reduction in risk of Parkinson's disease, and death from stroke. The neuroprotective efficacy of estrogens have been well described and may contribute to these clinical effects. Estrogen-mediated neuroprotection has been described in several neuronal culture model systems with toxicities including serum-deprivation, beta-amyloid-induced toxicity, excitotoxicity, and oxidative stress. In animal models, estrogens have been shown to attenuate neuronal death in rodent models of cerebral ischemia, traumatic injury, and Parkinson's disease. Although estrogens are known to exert several direct effects on neurons, the cellular mechanisms behind the neuroprotective efficacy of the steroid are only beginning to be elucidated. In this review, we summarize the data supporting a neuroprotective role for estrogens in both culture and animal models and discuss neuronal effects of estrogens that may contribute to the neuroprotective effects. These effects include activation of the nuclear estrogen receptor, altered expression of bcl-2 and related proteins, activation of the mitogen activated kinase pathway, activation of cAMP signal transduction pathways, modulation of intracellular calcium homeostasis, and direct antioxidant activity.

Animals↗
PubMedDate not supplied

Phenolic A ring requirement for the neuroprotective effects of steroids.

Estrogens are reported to reduce the incidence of Alzheimer's disease and 17beta-estradiol (betaE2), the potent, naturally occurring estrogen, exerts neuroprotective effects in a variety of in vivo and in vitro model systems. The present study elucidates the structural requirements of steroids and related compounds for neuroprotectivity at low nM doses. All estrogens tested with an intact phenolic A ring protected SK-N-SH neuroblastoma cells from the toxic effects of serum-deprivation. All 3-O-methyl ether cogeners tested were inactive indicating the importance of a phenolic A ring. The diphenolic estrogen mimic diethylstilbesterol (DES) was neuroprotective and retention of a single phenolic function was sufficient to retain neuroprotective activity. The di-O-methyl ether of DES was inactive. The following steroids which lack a phenolic A ring were also inactive: testosterone; dihydrotestosterone; progesterone; corticosterone; prednisolone; 6 alpha-methylprednisolone; aldosterone; and cholesterol. Finally, phenol, lipophilic phenols, and tetrahydronapthol were inactive. These results suggest that a phenolic A ring and at least three rings of the steroid nucleus are necessary for the neuroprotective activity of estrogens.

Estradiol↗
PubMedDate not supplied

Estradiol attenuation of beta-amyloid-induced toxicity: a comparison o.

17Beta-estradiol (betaE2) has been shown to attenuate the toxicity of beta-amyloid peptides (A beta) in neuronal cultures with the effective concentration of betaE2 ranging from low nM to high microM. This study compares the effective neuroprotective concentration of betaE2 against both A beta-mediated toxicity in a human neuroblastoma cell line, SK-N-SH using cellular reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) as an endpoint to the effective betaE2 concentration obtained using a calcein acetoxymethyl ester (calcein AM) viability assay. The minimum betaE2 concentration required for protection varied 1000-fold between the two viability assays with 1 nM betaE2 conferring significant protection in the calcein AM assay but 1 microM betaE2 required for significant protection in the MTT assay Interestingly, the maximal inhibition of MTT reduction occured at sub-toxic A beta concentrations and did not correlate with other markers of cellular viability including calcein fluorescence, dye exclusion (propidium iodide or trypan blue), cellular ATP levels, or reduction of another tetrazolium dye, 5-(3-carboxymethoxyphenyl)-2-(4,5-dimethylthiazolyl)-3-(4-sulfophenyl) tetrazolium (MTS). By contrast, there was no difference between the MTT and calcein AM assays with respect to H2O2 toxicity or the neuroprotective effectiveness of 10 nM betaE2 against H2O2 toxicity. These results indicate that low concentrations of betaE2 can attenuate A beta and H2O2 toxicity in a human neuroblastoma cell line. Further, these results suggest that the MTT assay is not an appropriate assay for the determination of betaE2-mediated attenuation of A beta toxicity.

Amyloid beta-Peptides↗
PubMedDate not supplied

Distribution of phenobarbital and phenytoin in pregnant rats and their fetuses.

Studies were conducted to determine the extent of fetal exposure to phenobarbital (PB) and phenytoin (PHT) in pregnant rats. Two groups of rats determined to be in the third week of pregnancy received 30 mg/kg as a single intraperitoneal (i.p.) dose of either PB or PHT. At various times (from 15 min to 48 h for PB and from 20 min to 16 h for PHT), the rats were killed and whole blood, plasma, maternal brain, fetal brain and liver, whole fetuses, and placentas were rapidly collected. Concentrations of PB, PHT, and its major metabolite, p-hydroxyphenytoin (HPPH), were measured by high-performance liquid chromatography (HPLC). PB and PHT appeared rapidly in plasma and all tissues; the maximum HPPH concentrations appeared much later. The highest PB concentrations were detected in plasma, followed by placenta, whole fetus, maternal brain, fetal liver, and fetal brain. In contrast, PHT concentrations were higher in fetal brain and liver than in whole fetuses. HPPH concentrations were much lower than PHT and were not detected in maternal brain. These results show that PB and PHT readily distribute to the rat fetus, that drug distribution within the fetus is regional, and that changes in maternal plasma concentrations of these antiepileptic drugs (AEDs) are accompanied by parallel changes in fetal tissue.

Animals↗
PubMedDate not supplied

Solubilization of ovine growth hormone with 2-hydroxypropyl-beta-cyclodextrin.

Studies were undertaken to determine the effects of 2-hydroxypropyl-beta-cyclodextrin (HPCD) on the solubility of ovine-Growth Hormone (o-GH) in aqueous solution. HPCD, which is believed to form inclusion complexes with hydrophobic amino acid residues of peptides, markedly increased o-GH solubility at all o-GH and all HPCD concentrations tested. In HPCD solutions, o-GH was completely solubilized between pH 7.5 and 8.5, while in water, o-GH was not solubilized until a pH of 11.5 was reached. Temperature and repeated freeze-thaw cycles had little effect on o-GH solubility in HPCD. Vigorous shaking of solution of o-GH in HPCD did not result in precipitation of the peptide. These studies document that HPCD enhances o-GH solubility in aqueous solutions. Preparations of GH in HPCD may eliminate solubility problems observed in current human GH preparations intended for parenteral use.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMedDate not supplied

The potential use of cyclodextrins in parenteral formulations.

The general use of cyclodextrins in drug formulations is reviewed. The ability of cyclodextrins to form reversible inclusion complexes with many drugs can eliminate various undesirable physicochemical properties. While beta-cyclodextrin is extremely useful in many of these applications, it is toxic when given parenterally, precluding its use in i.v. and other formulations. Chemically modified cyclodextrins such as 2-hydroxypropyl-beta-cyclodextrin are amorphous isomeric mixtures which are potent complexing agents and innocuous when administered i.e., either acutely or subchronically. The use of these modified cyclodextrins in parenteral formulations and to solubilize and stabilize various proteins and peptides is presented.

Chemical Phenomena↗
PubMedDate not supplied

Pharmacokinetics of imipramine and its major metabolites in pregnant rats and their fetuses following a single dose.

The pharmacokinetic profiles of imipramine (IMI) and its major active metabolites were determined in pregnant rats following an acute 30 mg/kg ip IMI dose. At timed intervals from 10 min to 18 hr, groups of five animals were sacrificed and whole blood, plasma, maternal and fetal brain, fetal liver, placental tissue, and whole fetus were retained for measurements of drug concentrations. IMI, 2-hydroxyimipramine (2-OH-IMI), and desipramine (DMI) rapidly appeared in all tissues and showed complex disposition kinetics. The 2-hydroxydesipramine (2-OH-DMI) metabolite was detectable in occasional samples. The area under the drug concentration-time curve for both IMI and DMI was more than 7-fold greater in whole fetus than in maternal plasma. Drug concentrations were greater in fetal brain than in whole fetus. The DMI concentration exceeded that of IMI in all tissues and DMI persisted in tissues longer: mean residence time for DMI in whole fetus was 21.2 hr compared to 3.5 hr for IMI. The area under the curve of DMI in fetal brain was 5.35 times greater than that of IMI. These results demonstrate that IMI and two of its major metabolites freely distribute to the rat fetus, that drug distribution within the fetus is regional, and that the major drug to which the fetal brain is exposed following maternally administered IMI is DMI. Studies of the teratogenic effects of extensively biotransformed drugs like IMI should consider the effects of active metabolites.

Animals↗