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.

Effects of 17beta-estradiol on glucose transporter 1 expression and endothelial cell survival following focal ischemia in the rats.

Estrogen replacement therapy in postmenopausal women is associated with a decreased mortality and morbidity from stroke. The present study was undertaken to investigate the effects of estrogen on endothelial cell glucose transporter 1 (GLUT 1) and on the cell viability during focal ischemia in a rat model. Female rats were ovariectomized (OVX) and 2 weeks later 17beta-estradiol (E2) was injected subcutaneously at a dose of 100 microg/kg 2 h before unilateral middle cerebral artery (MCA) occlusion.

17beta-estradiol attenuates CREB decline in the rat hippocampus following seizure.

Cyclic AMP response element-binding protein (CREB) is a transcription factor that has been implicated in the activation of a number of genes. We reported that CREB levels decline following a severe hypoglycemic episode in the hippocampus and cortex in the male rat brain. The present experiment was undertaken to investigate whether 17beta-estradiol prevents the decline in CREB-immunoreactive cells following seizure in female rats.

Hypoglycemia enhances the expression of mRNA encoding beta-amyloid precursor protein in rat primary cortical astroglial cells.

Deposition of beta-amyloid (A beta) is a characteristic feature of the pathology of Alzheimer's disease (AD). Since glucose metabolism and the consequential ATP production are depressed in the temporal and parietal regions of the cortex in patients with AD, we designed the present study to investigate the possible role of hypometabolism in the pathogenesis of AD. We incubated rat primary cortical astroglial cells for 2 h to 4 days in a media deprived of 95% of its glucose and assessed the expression and alternative splicing of the mRNA that encoding beta-amyloid precursor protein (APP) using RT-PCR.

Estrogens may reduce mortality and ischemic damage caused by middle cerebral artery occlusion in the female rat.

The present study was undertaken to determine if estrogens protect female rats from the neurodegenerative effects of middle cerebral artery (MCA) occlusion. The rats were ovariectomized and 7 or 8 days later various estrogen preparations were administered before or after MCA occlusion. Pretreatment with 17beta-estradiol (17beta-E2) or a brain-targeted 17beta-E2 chemical delivery system (CDS) decreased mortality from 65% in ovariectomized rats to 22% in 17beta-E2-treated and 16% in 17beta-E2 CDS-treated rats.

Role of estrogen replacement therapy in memory enhancement and the prevention of neuronal loss associated with Alzheimer's disease.

Recent evidence supports a role for estrogens in both normal neural development and neuronal maintenance throughout life. Women spend 25-33% of their life in an estrogen-deprived state and retrospective studies have shown an inverse correlation between dose and duration of estrogen replacement therapy (ERT) and incidence of Alzheimer's disease (AD), suggesting a role for estrogen in the prevention and/or treatment of neurodegenerative diseases. To explore these observations further, an animal model was developed using ovariectomy (OVX) and ovariectomy with estradiol replacement (E2) in female Sprague-Dawley rats to mimic postmenopausal changes.

17 beta-estradiol attenuates fimbrial lesion-induced decline of ChAT-immunoreactive neurons in the rat medial septum.

We investigated the neuroprotective effects of 17 beta-estradiol (E2) on medial septal cholinergic neurons following partial unilateral lesion of the fimbriafornix. Adult female rats were ovariectomized (OVX) and, 5 days later, treated with a single intravenous (iv) injection of an estradiol (E2)-chemical delivery system (E2-CDS) or its vehicle hydroxypropyl-beta-cyclodextrin (HPCD). All rats were subjected to partial unilateral electrolytic fimbrial lesion the following day.

17 beta-Estradiol modulation of glucose transporter 1 expression in blood-brain barrier.

The present study was designed to evaluate 17 beta-estradiol (E2) modulation of glucose transporter 1 (GLUT-1) protein and mRNA expression in blood-brain barrier (BBB) endothelium. Female rats were ovariectomized (OVX) for 12-14 days, then E2 was injected at dosages of 1-100 micrograms/kg sc at 2-16 h before sampling. Glucose transport into BBB endothelial cells was assessed using 2-deoxy-[14C]glucose (2-[14C]DG) uptake.

Luteinizing hormone-releasing hormone (LHRH) attenuates morphine-induced inhibition of cyclic AMP (cAMP) in opioid-responsive SK-N-SH cells.

SK-N-SH cells were used to assess the effects of luteinizing hormone-releasing hormone (LHRH) on opioid receptor-mediated changes in cyclic AMP (cAMP). Prostaglandin E1 (PGE1, 1 microM) caused a dramatic increase in cAMP levels. Treatment with 10 microM morphine (MOR) significantly inhibited the stimulatory effect of PGE1, LHRH (0.

17 alpha-estradiol exerts neuroprotective effects on SK-N-SH cells.

Estradiol (E2) has been shown to exert organizational, neurotrophic, and neuroprotective effects in the CNS. The present study assessed the specificity of the neuroprotective effects of estradiol for the potent 17 beta-isomer. SK-N-SH cells from a human neuroblastoma cell line, which we have shown to be estrogen-responsive, were cultured at low or high plating density.

Synthesis and evaluation of brain-targeted chemical delivery systems for the neurotrophomodulator 4-methylcatechol.

Since various 4-alkylcatechols stimulate nerve growth factor (NGF) biosynthesis both in-vitro and in-vivo, delivery of these agents to the brain may provide beneficial effect for the treatment of neurodegenerative diseases such as Alzheimer's. Several dihydropyridine-pyridinium salt type redox chemical delivery systems (CDS) of 4-methylcatechol (4-methylcatechol) were prepared as potential brain selective targetry forms for 4-methylcatechol. After preliminary evaluation by in-vitro stability studies in various buffer solutions and biological media, a selected CDS was further investigated in the rat to determine its in-vivo distribution.

Estradiol protects against beta-amyloid (25-35)-induced toxicity in SK-N-SH human neuroblastoma cells.

Estrogen-replacement therapy has been associated with a reduced incidence of Alzheimer's disease (AD) and improved cognition in several small open clinical trials. We assessed the possibility that estrogens may reduce toxicity of beta-amyloid (A beta) by testing the effects of beta-estradiol on the toxicity of the neurotoxic fragment of beta-amyloid (A beta 25-35) in SK-N-SH neuroblastoma cells. A beta 25-35 caused a dose-dependent death in SK-N-SH cells with a LD50 of 28.

Analgesic and immunomodulatory effects of codeine and codeine 6-glucuronide.

Purpose: The antinociceptive and immunosuppressive effects of codeine and codeine 6-glucuronide were determined in rats after intracerebroventricular administration.

Methods: Codeine 6-glucuronide was synthesized using a modification of the Koenigs-Knorr reaction. A lipophilic intermediate formed during synthesis, methyl [codein-6-yl-2,3,4-tri-O-acetyl-beta-D-glucopyranosid] uronate, was also tested.

The effect of ovariectomy and estradiol replacement on brain-derived neurotrophic factor messenger ribonucleic acid expression in cortical and hippocampal brain regions of female Sprague-Dawley rats.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder whose etiology is presently unknown. Probably the most consistent and widespread deficit seen in this syndrome is that of the basal forebrain cholinergic system. We have previously demonstrated that estradiol (E2) modulates the function of these neurons and plays a role in their maintenance by preventing the ovariectomy-induced decrease in choline acetyltransferase activity.

Effects of age, reproductive status and ambient temperature on skin temperature regulation in the female rat.

In the present study, we evaluated a large population of aged Long-Evans female rats for the occurrence of spontaneous tail skin temperature (TST) surges. Young (5-7 months) normally cycling (NC) rats and aged (19-29 months), repeated pseudopregnant (PP) and constant estrous (CE) rats were placed in an environmentally controlled room with ambient temperatures of 24-25 degrees C or 29-30 degrees C and TST was monitored at 5 min intervals for 2 h. In young NC and aged PP rats, the incidence of TST surges (flushes) was 8-17% at low and 28-33% at high ambient temperature.

Estradiol enhances brain glucose uptake in ovariectomized rats.

This study was designed to investigate the effects of 17 beta-estradiol benzoate (E2B) on brain glucose uptake and transport across the blood-brain barrier (BBB). Both a time- and dose-response evaluation of the effect of E2B on glucose uptake in the central nervous system (CNS) were conducted. E2B, in doses ranging from 1 to 100 micrograms/kg body weight, was injected subcutaneously at 2 to 24 h prior to evaluation.

Estradiol treatment increases viability of glioma and neuroblastoma cells in vitro.

The present study provides evidence that 17-beta-estradiol (E2) exerts cytoprotective effects on both glial and neuronal cell lines. In C6 rat glioma cells, the addition of E2 to serum free media enhances live cell number by 40% at 24 h and 75% at 96 h when compared to serum free media conditions. E2 treatment of C6 cells in serum free medium did not increase thymidine uptake at any sampling time, indicating that the observed effect of E2 on C6 cell number was not due to a mitogenic effect of the steroid hormone.

Ovarian steroid deprivation results in a reversible learning impairment and compromised cholinergic function in female Sprague-Dawley rats.

We hypothesized that estradiol (E2) serves as a neurotrophomodulatory substance for basal forebrain cholinergic neurons thought to be involved in learning and memory. Learning/memory was assessed using the two-way active avoidance paradigm and the Morris water task. Female Sprague-Dawley rats were either ovariectomized (OVX) or OVX for 3 weeks, followed by s.

Effects of aging on morphine withdrawal in the rat.

Little is known about the effects of aging on the process of opiate dependence and withdrawal in the rat. The present study was undertaken to quantitate naloxone-precipitated opiate withdrawal in young (3-4 months old) and aged (24 month old) Long-Evan female rats. Following addiction to morphine, young and aged rats were evaluated for tail skin temperature (TST), rectal temperature (Tr), behavior, rhinorrhea, lacrimation, salivation, and diarrhea in response to naloxone administration.

Effects of chronic stimulation or antagonism of opiate receptors on GH secretion in male and female rats.

The present study was undertaken to assess the role of endogenous opioid systems in the sexually dimorphic pattern of growth hormone (GH) secretion. To this end, male rats were treated chronically (6 to 12 h) with morphine and estrogen-exposed, ovariectomized female rats with morphine or naloxone. Chronic morphine exposure of male rats caused a 12-fold increase in basal GH levels and a modest rise in GH pulse frequency.

Suppression of plasma testosterone and prostate carcinoma size by a redox-based, brain-targeted estrogen delivery system in the rat.

Studies were undertaken to examine the effects of an estradiol-chemical delivery system (E2-CDS) or castration (CAST) on plasma testosterone (T) and growth of the Segaloff 11095 carcinoma. Fischer 344 rats were implanted subcutaneously with the Segaloff 11095 tumor and tumor growth was monitored thereafter. After optimal tumor growth, when the average tumor size was approximately 25 x 15 mm (length x width; 4-5 g wet weight), rats were randomized into (1) testis-intact controls; (2) CAST; (3) intact+E2-CDS groups (rats received weekly injection of the E2-CDS at 0.

Synthesis and in vitro dopaminergic activity of (2-aminoethyl)-1-hydroxy-2-pyridone type dopamine analogs.

Two isoteric/isoelectronic dopamine analogs based of (2'-aminoethyl)-1-hydroxy-2-pyridone without having the COMT vulnerable m-hydroxy group were synthesized via ten synthetic steps. Their dopaminergic activities were evaluated by measuring the inhibitory effects of prolactin secretion from the anterior pituitary in rats. The compounds 1 and 2 caused a reduction of prolactin secretion at the 10(-6) M concentration.

A strategy for delivering peptides into the central nervous system by sequential metabolism.

Most peptides do not enter the central nervous system because of their hydrophilic character and the presence of peptidolytic enzymes in the lipoidal blood-brain barrier. To achieve brain delivery of a peptide conjugate, an opioid peptide (enkephalin) was placed in a molecular environment that disguises its peptide nature and provides biolabile, lipophilic functions to penetrate the blood-brain barrier by passive transport. The strategy also incorporates a 1,4-dihydrotrigonellinate targetor that undergoes an enzymatically mediated oxidation to a hydrophilic, membrane-impermeable trigonellinate salt.