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J W Simpkins

Publications and source records attributed to J W Simpkins.

At least 55 records · Page 3Linked to original sources
PubMed1996

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 28.9 muM. In cultures simultaneously exposed to 20 muM A beta and 17 beta-estradiol (2 nM). A beta-induced toxicity was reduced by 83 and 51% in two separate studies. Further studies show that 0.2 nM 17 beta-estradiol was as effective as the 2 nM concentration. 17 alpha-Estradiol (2 nM) conferred neuroprotection equivalent to that of 17 beta-estradiol. These data support the hypothesis that estrogens reduce beta-amyloid toxicity and this may help explain the beneficial effects of estrogens in AD.

Amyloid beta-Peptides↗
PubMed1995

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. The 4-h time point and 10 micrograms/kg dose of E2B produced the most widespread increases in glucose uptake. Six regions responded to E2B with elevated glucose uptake by as much as 120% when compared to oil-treated controls. We then evaluated the effects of E2B on transport of glucose across the BBB. E2B significantly increased the extraction of labeled sugar across the BBB by 40% without affecting extraction of the internal standard. Collectively, these studies indicate that physiological levels of estradiol (E2) may play an important role in modulating cerebral glucose homeostasis.

Animals↗
PubMed1995

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. Old CE rats exhibited a flushing incidence of 21% and 74% at ambient temperatures of 24-25 degrees C and 29-30 degrees C, respectively. The observed flushing episodes did not differ in their duration or amplitude among the three groups of rats. However, at both low and high ambient temperature, the frequency of flushes were significantly higher in old CE rats. Collectively, these data indicate that reproductive status, rather than age, is the important determinant of TST stability in the female rat. Further, elevated estrogen associated with the CE state may compromise, while elevated progesterone associated with the PP state has a protective effect on the stability of TST in the female rat.

Aging↗
PubMed1995

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. It has been postulated that the lack of neurotrophic support may contribute at least in part to degeneration of cholinergic neurons in AD. As such, it is hypothesized that E2 may affect cholinergic function by modulating the levels of certain neurotrophic factors. We have shown that 3 months after ovariectomy (OVX) there was a significant reduction in NGF messenger RNA (mRNA) levels. In the present study, we extended the hypothesis that E2 may serve a neurotrophomodulatory role by assessing the effect of OVX and E2 replacement on brain-derived nerve factor (BDNF) mRNA levels using in situ hybridization. BDNF mRNA levels were quantified in three groups of animals: ovary-intact animals, 28-week ovariectomized (OVX) animals, and E2-replaced OVX animals. Twenty-eight weeks after OVX, there were significant reductions in two of the three cerebral cortical regions analyzed [frontal (35%) and temporal (39%) cortexes], but E2 replacement was without effect. Twenty-eight weeks after OVX, there were also reductions in BDNF mRNA in all subregions of the hippocampus except CA1 (CA2 by 38%, CA3 by 44%, CA4 by 39%, and dentate gyrus by 37%), whereas E2 replacement was effective in elevating BDNF mRNA levels in the CA3, CA4, and dentate gyrus subregions. Collectively, the data demonstrate that E2 deprivation leads to a reduction in BDNF mRNA. Further, at the time point studied, E2 replacement is more effective in maintaining BDNF mRNA in the hippocampus than in the cortex, suggesting a regional difference in the ovarian steroid requirement for expression of BDNF.

Analysis of Variance↗
PubMed1994

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.c. implantation of a Silastic pellet containing 17-beta E2 (E2 pellet), resulting in a replacement of E2 to physiological levels. Ovary-intact (INTACT) animals served as our positive control. Active avoidance behavior and choline acetyltransferase (ChAT) activity in the frontal cortex and hippocampus were assessed at 5 and 28 weeks postovariectomy while performance on the Morris water task and high-affinity choline uptake (HACU) were measured only at the 5-week time point. At the 5-week time point, E2 replacement caused a significant elevation in the level of active avoidance performance relative to OVX animals. At the 28-week time point, OVX animals demonstrated a significantly lower number of avoidances relative to controls (61%) whereas E2-pellet animals not only demonstrated superior performance relative to OVX animals but also showed an accelerated rate of learning. Morris water task performance, on the other hand, was not significantly affected by estrogenic milieu despite a trend towards better performance in the E2-pellet group. Neurochemical analyses revealed that 5 weeks of ovariectomy was sufficient to reduce HACU in both the frontal cortex and hippocampus by 24 and 34%, respectively, while E2 replacement was successful in elevating HACU relative to OVX animals in both regions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

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. The addition of E2 to SK-N-SH cells in serum free media maintained both total and live cell number at a level comparable to the fetal bovine serum (FBS) treated cells at both 24 and 48 h. At 96 h after treatment with E2, total and live cell numbers were diminished relative to the 48-h sample and the 96-h FBS group, but were still more than twice the number observed in serum free media. Associated with the reduced effects of E2 at 96 h was an increase in the ratio of dead to total cells, although it remained about 50% less than the serum free group. Through 48 h, E2 exposure did not increase thymidine uptake in SK-N-SH cells, indicating that the effect of E2 on SK-N-SH cells was cytoprotective rather than mitogenic. Collectively, these data support a cytoprotective action of E2 on neuronal or glial cell types in vitro.

Animals↗
PubMed1993

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 0.5 mg/kg). Animals were killed 7 or 14 days after the initiation of treatments. Blood and tissue samples were collected for subsequent analysis. Plasma T levels were suppressed by 98% and 97% through 14 days after CAST or E2-CDS treatment. CAST increased plasma gonadotropin (LH) concentrations, while E2-CDS reduced LH compared to intact control levels. E2-CDS treatment increased plasma E2 levels to 24 (one injection) or 75 pg/ml (two injections) at 7 or 14 days, respectively. E2-CDS, given once a week for 2 consecutive weeks, resulted in a decreased growth of the prostate tumor by 61%, while CAST reduced the weights of these tumors by only 20%. In response to E2-CDS (one or two injections), weights of the in situ ventral prostate and seminal vesicles were significantly reduced by 70% and 50%, respectively, in tumor-bearing rats. Similarly, CAST reduced the weights of these tissues by 80% (prostate) or 52% (seminal vesicle) at 7 or 14 days after treatment. Pituitary weight increased, while testes weight decreased by 20% with two injections of E2-CDS, compared with intact control rats. Collectively, these data indicate that E2-CDS is effective in reducing the growth rate of prostatic tumors in the rat.

Animals↗
PubMed1993

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. These two changes resulted in a 3-fold increase in both mean GH concentration and total GH secretion over 6 h. In female rats, chronic morphine reduced GH pulse amplitudes but did not significantly affect other parameters of GH secretion. By contrast, chronic naloxone treatment of female rats reduced basal GH levels by 64% without affecting GH pulse amplitudes or pulse frequency. These data suggest that endogenous opioid systems are involved in the regulation of the basal GH secretion in both male and female rats.

Animals↗
PubMed1993

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. Semiempirical MO calculations (at the AM-1 level) were performed on 1 and 2 in order to understand the structural and electronic features as compared to dopamine.

Animals↗
PubMed1992

Effects of advancing age on cerebrospinal fluid concentrations of prolactin in the female rat.

Studies were conducted to determine the effects of advancing age on serum and cerebrospinal fluid (CSF) prolactin (PRL) concentrations in the female rat. In young rats with basal serum PRL levels, CSF PRL was maintained at 1.1-2.1% of serum PRL levels. In middle-aged rats, CSF PRL levels and the ratio of CSF to serum PRL was low in rats which maintained estrous cycles, but was increased 4- to 10-fold in rats which were in constant estrus. In aged constant estrous rats, CSF PRL concentrations were increased markedly and the CSF to serum PRL ratio increased to 31%. Collectively, these data indicate that (i) in young female rats, only a fraction of serum PRL reaches the CSF; (ii) that CSF PRL concentrations are low in middle-aged rats which exhibit estrous cycles and (iii) that aging and the constant estrous state are associated with elevated CSF PRL concentrations. As such, the age-related elevation in serum PRL levels and the fraction of PRL which accumulates in the CSF may contribute to the age-related dysfunction in brain PRL-responsive neurons.

Aging↗
PubMed1992

Effects of haloperidol and prolactin secreting tumors on cerebrospinal fluid concentrations of prolactin in the female rat.

Studies were conducted to determine the effects of acute and chronic elevations in prolactin (PRL) secretion on serum and cerebrospinal fluid (CSF) PRL concentrations in the female rat. Young female rats showed a dose-dependent increase in serum and CSF PRL in response to haloperidol. A time-course evaluation of serum and CSF PRL levels after haloperidol indicated that serum PRL concentrations increased markedly by 30 min and declined thereafter; while CSF PRL increased more slowly, peaking at 2 to 8 h. In young rats with basal serum PRL levels, CSF PRL was maintained at 0.8 to 2.1% of serum PRL levels. During acute hyperprolactinemia, the CSF to serum PRL ratio increased to about 4%. During chronic severe hyperprolactinemia, induced by the growth of a MtT.W15 tumor, CSF PRL concentrations increased to 75 ng/ml, but this represented only 1.5% of serum PRL concentrations. Collectively, these data indicate that the blood-brain barrier effectively limits access to the brain of circulating PRL.

Analysis of Variance↗
PubMed1992

Opiate modulation of growth hormone secretion is compromised during the steroid-induced luteinizing hormone surge.

Earlier studies from our laboratory have shown that treatments with gonadal steroids which cause a surge of luteinizing hormone (LH) blunt the effects of morphine on LH secretion, locomotor activity, nociception and temperature regulation. The present study was conducted to determine if the growth hormone (GH) response to morphine sulfate (MS) was also affected during steroid-induced LH surges. Adult ovariectomized female rats were primed with estradiol benzoate (EB: -49 h prior to P4 or oil injection) and/or progesterone (P4; 10.00 h). Seven and one half hours after P4 treatment, at the time of the steroid-induced LH surge, the GH response to an intravenous dose of 0.5, 2.0 or 5.0 mg/kg MS was determined. A GH peak response occurred at 15 min after drug administration and was maximal at the dose of 2 mg/kg MS in all groups. Although the timing of the GH rise was not altered in either EB/oil- or EB/P4-treated animals, a significant blunting of MS-induced GH secretion was observed across all doses of MS with a greater reduction being observed in EB/P4-treated animals. In a second study the GH response to opiates was investigated prior to and following the steroid-induced LH surge to determine if the suppression of opiate-induced GH secretion was confined to the time of the preovulatory LH surge. Before the LH surge (2.5 h), a mild suppression of opiate-induced GH secretion was observed only in EB/oil-treated animals. After the LH surge (13 h after P4 administration), morphine-induced GH secretion was similar in all groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Opiate stimulation of prolactin secretion is reversed by ovarian hormone treatment.

Previous studies have indicated that during the estradiol- and progesterone (P4)-induced surge in luteinizing hormone (LH), the effects of opiates on behavioral, autonomic and neuroendocrine functions are altered. In the present study, we further evaluated the apparent universality of alterations in opiate-mediated function during the LH surge by investigating the effects of morphine sulfate (MS) on prolactin (PRL) secretion during both the estradiol benzoate (EB) and the EB + P4-induced LH surges. All doses of MS tested (0.5, 2.0 and 5.0 mg/kg) resulted in significant increases in PRL secretion in nonestrogen-treated animals which did not show LH/PRL surges. During the LH/PRL surge induced by EB/P4 treatment, MS caused no change in the PRL secretion, while in EB/oil treated animals, a paradoxical and dose-dependent decrease in PRL secretion was observed. The suppression of PRL was 52, 68 and 80% of baseline respectively for the 3 doses of MS. Evaluation of the time dependence of MS on PRL secretion showed that the paradoxical suppression in EB/oil-treated animals was seen only during the LH/PRL surge, occurring at 17.30 h (7.5 h post P4 injection), and not before (12.30 h) or after (23.00 h) the steroid-induced LH/PRL surge. Finally, we assessed the role of pituitary dopamine receptors on the phenomenon of MS-induced PRL suppression in EB/oil rats. Domperidone (1mg/kg), a peripherally active D2 receptor antagonist, administered prior to the morphine challenge, attenuated the opiate-induced PRL suppression in EB/oil-treated animals suggesting that a dopaminergic mechanism is involved in this paradoxical response to morphine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Estradiol enhances behavioral sensitization to cocaine and amphetamine-stimulated striatal [3H]dopamine release.

Locomotor activity and stereotypy induced by cocaine is increased or 'sensitized' after repeated cocaine administration. This behavioral sensitization may be mediated by a persistent increase in dopamine (DA) transmission in mesolimbic and nigrostriatal pathways. Since the female estrous cycle and ovarian steroid hormones appear to affect both cocaine sensitization and DA transmission, studies were undertaken to determine the effects of ovarian steroids on sensitization of the behavioral responses to repeated cocaine injections and any concomitant effects on striatal DA release. Young female adult rats were ovariectomized and 2 weeks later were implanted with chronic release forms of estradiol (E), progesterone (P), both (EP) or vehicle (V). Locomotor and stereotypic behavior were rated after an initial injection of either saline or cocaine (10 mg/kg, i.p.) and after the 8th daily injection of saline or cocaine. A significant increase in both locomotor and stereotypic behaviors was seen after the first cocaine injection relative to saline-injected animals and this response was not affected by steroid treatment. Repeated injections of cocaine caused sensitization of the initial behavioral response to cocaine (i.e. an increase in stereotypic and locomotor behavior) and the degree of cocaine sensitization was greatest in group E. Steroid treatment did not affect behavior in saline-treated rats. When striatal [3H]DA release was measured in vitro 1 or 7 days after the last injection, amphetamine-stimulated release was greater in vehicle-treated rats 7 days after cocaine injections but not 1 day after injections. In contrast, release was enhanced in group E both 1 and 7 days after cocaine.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphetamine↗
PubMed1991

Effects of estradiol and progesterone on the sensitivity to pain and on morphine-induced antinociception in female rats.

Long-term ovariectomized (OVX) rats were exposed to 2- or 14-day replacement with pellets made of cholesterol (CHOL), estradiol (E2), progesterone (P4), or a combination of E2 and P4. Following the treatment with steroids the antinociceptive effect of morphine (5 mg/kg,sc) was measured by a hot-plate method. Pellets of E2 (0.5 and 5%) caused dose- and time-dependent reductions of morphine-induced antinociception as compared with OVX rats treated with CHOL pellets. Moreover, OVX rats pretreated with E2 pellets had decreased basic sensitivity to nociceptive stimulus (hyperalgesia). Treatment for 2 and 14 days with 75% P4 pellets produced significant reduction of MOR antinociception. The low dose of P4 (10% pellet) did not change the effect of MOR on Day 2 but significantly increased the antinociceptive effect of MOR on Day 14. Replacement of OVX rats with one 0.5% E2 pellet plus one 10% P4 pellet resulted in marked inhibition of the antinociceptive effect of MOR on Day 2 as well as on Day 14. Central injection 30 min before MOR of either LHRH antagonist or the antiserum against LHRH into OVX rats pretreated for 14 days with both steroids had no effect on the degree of the antinociception. The results suggest that the effects which ovarian steroids exert on opioid systems vary according to the dose, the duration of treatment, and the type of steroid administered.

Animals↗
PubMed1991

Conditioned taste aversion induced by estradiol pellets.

In two experiments, ovariectomized rats were given a novel diet prior to the implantation of a fused pellet of estradiol (E2 pellet). In short-term (3 weeks) ovariectomized rats, the suppression of food intake induced by estrogen was not affected by the introduction of the novel diet. However, a sensitive two-choice preference test revealed that subjects implanted with the E2 pellet had a lesser preference for the novel diet than controls implanted with the vehicle pellet. In long-term (18 weeks) ovariectomized rats, implantation of the E2 pellet had a large effect on the consumption of the novel diet. Intake was reduced to less than 1 g in all subjects on Days 3-7 after E2 pellet implantation. A subsequent two-choice preference test indicated the presence of a strong aversion to the novel diet in the estradiol-treated rats relative to the controls. These experiments show that estradiol can induce conditioned taste aversions that have either no effect on intake or totally suppress food intake, depending upon postovariectomy time.

Animals↗
PubMed1991

Comparison of morphine tolerance in body temperature and luteinizing hormone secretion.

Small doses of morphine induce a hyperthermic response that does not change with repeated injections, whereas higher doses induce a hypothermia that changes to hyperthermia with repeated treatment. Experiment 1 confirmed these results in ovariectomized rats, using 6 repeated injections of morphine at 5 or 30 mg/kg. Using the same treatment regimen. Experiment 2 showed that the low dose of morphine induced a transient suppression of LH levels followed by a hypersecretion, and that repeated injections did not affect this response. The high dose (30 mg/kg) of morphine initially induced a sustained suppression of LH. Following the sixth injection of the high dose, subjects showed an intact or exaggerated suppression of LH, but an accelerated recovery to control levels. Experiment 3 extended the phase of repeated treatment of the high dose to 12 days and replicated the results of Experiment 2.

Animals↗