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Biomedical subjects

P S Green

Publications and source records attributed to P S Green.

At least 19 recordsLinked to original sources
PubMed2006

Differential modulation of plasma beta-amyloid by insulin in patients with Alzheimer disease.

BACKGROUND: Hyperinsulinemia and insulin resistance are risk factors for memory impairment and Alzheimer disease (AD). Insulin regulates levels of the amyloid beta-peptide (Abeta) in vitro in neuronal cultures and in vivo in the CSF of normal older adults. OBJECTIVE: To determine whether insulin affected plasma Abeta levels and whether such effects differed for patients with AD compared with normal older adults. METHODS: Fifty-nine patients with AD and 50 healthy older adults each received infusions of saline and of insulin (1.0 mU.kg(-1).min(-1)) with accompanying dextrose to maintain euglycemia. A subset of participants (19 AD, 12 normal) received two additional conditions, in which insulin was infused at a lower (0.33 mU.kg(-1).min(-1)) and higher (1.67 mU.kg(-1).min(-1)) rate. Plasma insulin and Abeta were measured after 120 minutes of infusion. RESULTS: Adults with AD had higher plasma insulin vs normal adults at the two higher infusion rates, despite receiving comparable amounts of insulin. For normal adults, insulin reduced plasma Abeta levels at the middle (1.0 mU.kg(-1).min(-1)) dose, with attenuated effects at lower and higher doses. In contrast, for patients with AD, insulin raised plasma Abeta levels at the two higher doses (1.0 and 1.67 mU.kg(-1).min(-1)). CONCLUSIONS: These results suggest that patients with Alzheimer disease (AD) have reduced insulin clearance and insulin-provoked plasma amyloid beta-peptide (Abeta) elevation. Abnormal regulation of peripheral Abeta by insulin may contribute to AD risk.

Aged↗
PubMed2001

Estradiol protects against ATP depletion, mitochondrial membrane potential decline and the generation of reactive oxygen species induced by 3-nitroproprionic acid in SK-N-SH human neuroblastoma cells.

Mitochondria are recognized as modulators of neuronal viability during ischemia, hypoxia and toxic chemical exposure, wherein mitochondria dysfunction leading to ATP depletion may be a common pathway of cell death. Estrogens have been reported to be neuroprotective and proposed to play a role in the modulation of cerebral energy/glucose metabolism. To address the involvement of 17beta-estradiol preservation of mitochondrial function, we examined various markers of mitochondrial activity in human SK-N-SH neuroblastoma cells exposed to 3-nitroproprionic acid (3-NPA), a succinate dehydrogenase inhibitor which uncouples oxidative phosphorylation. 3-NPA (10 mM) significantly increased ATP levels at 2 h then caused a 40% and a 50% decrease in ATP levels from baseline when treated for 12 h and 24 h, respectively. 3-NPA also induced significant increases in levels of cellular hydrogen peroxide and peroxynitrite at 2 h and a 60% decrease in mitochondrial membrane potential (MMP) at 12 h exposure. 17beta-Estradiol (17beta-E(2)) pretreatment restored the ATP level back to 80% at 12 h of that in control cells treated with 3-NPA but without E(2), blunted the effect of 3-NPA on MMP and reactive oxygen species levels. The present study indicates that 17beta-E(2) can preserve mitochondrial function in the face of inhibition of oxidative phosphorylation.

Adenosine Triphosphate↗
PubMed2001

The nonfeminizing enantiomer of 17beta-estradiol exerts protective effects in neuronal cultures and a rat model of cerebral ischemia.

Estrogens are potent neuroprotective compounds in a variety of animal and cell culture models, and data indicate that estrogen receptor (ER)-mediated gene transcription is not required for some of these effects. To further address the requirement for an ER in estrogen enhancement of neuronal survival, we assessed the enantiomer of 17beta-estradiol (ENT-E(2)), which has identical chemical properties but interacts only weakly with known ERs, for neuroprotective efficacy. ENT-E(2) was both as potent and efficacious as 17beta-estradiol in attenuating oxidative stress-induced death in HT-22 cells, a murine hippocampal cell line. Further, ENT-E(2) completely attenuated H(2)O(2) toxicity in human SK-N-SH neuroblastoma cells at a 10 nM concentration. In a rodent model of focal ischemia, 17beta-estradiol (100 microgram/kg) or ENT-E(2) (100 microgram/kg), injected 2 h before middle cerebral artery occlusion, resulted in a 60 and 61% reduction in lesion volume, respectively. ENT-E(2), at the doses effective in this study, did not stimulate uterine growth or vaginal opening in juvenile female rats when administered daily for 3 days. These data indicate that the neuroprotective effects of estrogens, both in vitro and in vivo, can be disassociated from the peripheral estrogenic actions.

Animals↗
PubMed2000

Neuroprotective effects of phenolic A ring oestrogens.

We have formulated the 'phenolic A ring hypothesis' for the neuroprotective effects of oestrogens based upon several observations: (i) structure-activity relationships show that a phenolic A ring and at least two additional rings are required for neuroprotection while oestrogenicity requirements are more stringent; (ii) neuroprotection with phenolic A ring compounds occurs in cells that lack oestrogen receptors and are not antagonized by anti-oestrogens; (iii) phenolic A ring compounds rapidly activate a variety of signal transduction pathways that are known to be involved in cell homeostasis; and (iv) in vivo, treatment with oestrogens results in a neuronal type-independent neuronal protection from ischaemic insult. Potential mechanisms of actions that may be involved in the neuroprotective effects of phenolic A ring compounds are: (i) oestrogen redox cycling that potently inhibits oxidative stress; (ii) interactions with signal transduction pathways including the transcription factor cAMP response element binding protein; and (iii) induction of anti-apoptotic proteins. These signalling pathways may individually or collectively contribute to the plethora of neuronal cell types that are protected from a variety of insults by oestrogen-like compounds.

Animals↗
PubMed2000

Protective effect of estrogens against oxidative damage to heart and skeletal muscle in vivo and in vitro.

Estrogen has been shown to protect skeletal muscle from damage and to exert antioxidant properties. The purpose of the present study was to investigate the antioxidant and protective properties of estrogens in rodent cardiac and skeletal muscle and H9c2 cells. Female Sprague-Dawley rats were separated into three groups, ovariectomized (OVX), ovariectomized with estrogen replacement (OVX + E2), and intact control (SHAM), and were assessed at two time periods, 4 and 8 weeks. Rodents hearts were analyzed for basal and iron-stimulated lipid peroxidation in the absence and presence of beta-estradiol (betaE2) by measuring thiobarbituric acid reactive species (TBARS). Isolated soleus (SOL) and extensor digitorum longus (EDL) were analyzed for creatine kinase (CK) efflux. Using H9c2 cells, the in vitro effects of betaE2 and its isomer alpha-estradiol were investigated under glucose-free/hypoxic conditions. TBARS assay was also performed on the H9c2 in the presence or absence of betaE2. The results indicate that OVX rodent hearts are more susceptible to lipid peroxidation than OVX + E2 hearts. OVX soleus showed higher cumulative efflux of CK than OVX + E2. Furthermore, H9c2 survival during oxidative stress was enhanced when estrogen was present, and both OVX hearts at 4 weeks and H9c2 cells particularly were protected from oxidative damage by estrogens. We conclude that estrogen protects both skeletal and cardiac muscle from damage, and its antioxidant activity can contribute to this protection.

Animals↗
PubMed2000

Estrogens and estrogen-like non-feminizing compounds. Their role in the prevention and treatment of Alzheimer's disease.

The present position paper is intended to provide evidence that estrogen deprivation contributes to the occurrence and course of Alzheimer's disease (AD) and that currently available estrogen preparations may be useful in the prevention and treatment of AD in women. Additionally, there is now substantial preclinical evidence to support the development of novel non-feminizing estrogens for use in male and female subjects for the protection of neurons from damage and death that underlies the neuropathology of AD. Estrogens and non-feminizing estrogen-like compounds may exert their beneficial effects in AD through a variety of mechanisms, directly through their neuroprotective actions and indirectly through their neurotrophic effects. Inasmuch as estrogens are comparatively free of both acute and chronic toxicities, and non-feminizing estrogens are expected to be even safer, their use for years to decades for the prevention or treatment of AD is possible.

Alzheimer Disease↗
PubMed1999

Glutamate receptor requirement for neuronal death from anoxia-reoxygenation: an in Vitro model for assessment of the neuroprotective effects of estrogens.

1. Previous studies demonstrated that estrogens, specifically 17 beta-estradiol, the potent, naturally occurring estrogen, are neuroprotective in a variety of models including glutamate toxicity. The aim of the present study is twofold: (1) to assess the requirement for glutamate receptors in neuronal cell death associated with anoxia-reoxygenation in three cell types, SK-N-SH and HT-22 neuronal cell lines and primary rat cortical neuronal cultures, and (2) to evaluate the neuroprotective activity of both 17 beta-estradiol and its weaker isomer, 17 alpha-estradiol, in both anoxia-reoxygenation and glutamate toxicity. 2. SK-N-SH and HT-22 cell lines, both of which lack NMDA receptors as assessed by MK-801 binding assays, were resistant to both anoxia-reoxygenation and glutamate-induced cell death. In contrast, primary rat cortical neurons, which exhibit both NMDA and AMPA receptors, were sensitive to brief periods of exposure to anoxia-reoxygenation or glutamate. As such, there appears to be an obligatory requirement for NMDA and/or AMPA receptors in neuronal cell death resulting from brief periods of anoxia followed by reoxygenation. 3. Using primary rat cortical neuronal cultures, we evaluated the neuroprotective activity of 17 beta-estradiol (1.3 or 133 nM) and 17 alpha-estradiol (133 nM) in both anoxia-reoxygenation and excitotoxicity models of cell death. We found that the 133 nM but not the 1.3 nM dose of the potent estrogen, 17 beta-estradiol, protected 58.0, 57.5, and 85.3% of the primary rat cortical neurons from anoxia-reoxygenation, glutamate, or AMPA toxicity, respectively, and the 133 nM dose of the weak estrogen, 17 alpha-estradiol, protected 74.6, 81.7, and 85.8% of cells from anoxia-reoxygenation, glutamate, or AMPA toxicity, respectively. These data demonstrate that pretreatment with estrogens can attenuate glutamate excitotoxicity and that this protection is independent of the ability of the steroid to bind the estrogen receptor.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1999

Executive function in depression: the role of performance strategies in aiding depressed and non-depressed participants.

OBJECTIVES: Depression has been found to be associated with dysfunction in executive processes, whereas relatively automatic processes are thought to remain intact. Failure to generate or implement adequate performance strategies has been postulated in depressed participants. The present study investigated spontaneous strategy usage in depressed and control participants, and the effectiveness of providing a hint about performance strategies. METHODS: Unipolar depressed participants were compared with matched healthy controls on three tasks sensitive to executive function: memory for categorised words, response suppression, and multiple scheduling. Participants in each group were randomly allocated to strategy aid and no strategy aid conditions. Those in the strategy aid condition were given a hint about the use of an appropriate performance strategy for each task, in addition to the standard instructions given to those in the no strategy aid condition. RESULTS: Depressed participants performed worse than controls on each of the three tasks, and were found to use appropriate performance strategies less often. Provision of strategy hints increased the use of performance strategies in two of the three tasks, memory for categorised words, and response suppression, but did not significantly improve overall performance for either group. CONCLUSIONS: The findings were consistent with the view that depressed participants fail to use appropriate performance strategies spontaneously to the same extent as controls. However, provision of information alone does not seem to be an adequate means of enhancing performance. The role of performance strategies in cognitive impairment in depression is discussed, both in terms of initiating use of such strategies and carrying these out efficiently.

Adult↗
PubMed1998

Nuclear estrogen receptor-independent neuroprotection by estratrienes: a novel interaction with glutathione.

Post-menopausal estrogen replacement therapy is associated with a reduction in the risk of Alzheimer's disease and has been reported to improve cognitive functioning in several small clinical trials. The present study evaluates the dependence of estrogenic neuroprotection on the presence of estrogen receptors using the murine neuronal cell line, HT-22, exposed to the neurotoxic beta-amyloid peptide. These cells lack functional estrogen receptors. The amyloid peptide killed 50-60% of these cells and concurrent treatment with either of three estratrienes, beta-estradiol, alpha-estradiol, or estratrien-3-ol, resulted in a dose-dependent protection. The potency of this estrogen neuroprotection was dependent on the presence of glutathione in the culture media. The presence of reduced glutathione in the media increases the neuroprotective potency of estrogens by an average of 400-fold. These results demonstrate that a nuclear estrogen receptor is not necessary for the neuroprotective actions of estrogens; however, the presence of an appropriate antioxidant in the extracellular milieu is needed for estratriene neuroprotection at physiologically and pharmacologically relevant doses. These data suggest the possibility of combined estrogen-antioxidant therapy for neurodegenerative diseases such as Alzheimer's disease.

Amyloid beta-Peptides↗
PubMed1998

A novel, synergistic interaction between 17 beta-estradiol and glutathione in the protection of neurons against beta-amyloid 25-35-induced toxicity in vitro.

The present studies were undertaken to investigate the possibility of an interaction between 17 beta-estradiol (E2) and glutathione in protecting cells against the presence of beta-amyloid 25-35 (betaAP 25-35). We demonstrate that when evaluated individually, supraphysiological concentrations of either E2 (200 nM) or of reduced glutathione (GSH; 325 microM) can protect SK-N-SH human neuroblastoma cells from betaAP 25-35 (20 microM) toxicity. This dose of betaAP 25-35 was chosen based on the LD50 (28.9 microM) obtained in our earlier work. However, in the presence of 3.25 microM GSH, the neuroprotective EC50 of E2 was shifted from 126 +/- 89 nM to 0.033 +/- 0.031 nM, approximately 4000-fold. Similarly, in primary rat cortical neurons, the addition of GSH (3.25 microM) increased the potency of E2 against betaAP 25-35 (10 microM) toxicity, as evidenced by a shift in the EC50 values of E2 from 68 +/- 79 nM in the absence of GSH to 4 +/- 6 nM in its presence. The synergy between E2 and GSH was not antagonized by the addition of the estrogen receptor antagonist, ICI 182,780. Other thiol-containing compounds did not interact synergistically with E2, nor were any synergistic interactions observed between E2 and ascorbic acid or alpha-tocopherol. Based on these data, we propose an estrogen-receptor independent synergistic interaction between glutathione and E2 that dramatically increases the neuroprotective potency of the steroid and may provide insight for the development of new treatment strategies for neurodegenerative diseases.

Amyloid beta-Peptides↗
PubMed1997

Low concentrations of estradiol reduce beta-amyloid (25-35)-induced toxicity, lipid peroxidation and glucose utilization in human SK-N-SH neuroblastoma cells.

The present studies were undertaken to determine the role of physiologically relevant concentrations of estrogens on amyloid-induced changes in cell viability, metabolic demands, and lipid peroxidation in response to the toxic fragment of beta-amyloid (betaAP 25-35). To this end, SK-N-SH human neuroblastoma cells were exposed to betaAP 25-35 or betaAP 25-35 plus 17beta-estradiol, and cell viability, media glucose use and lactate production were measured at time points ranging from 3 to 15 h for examination of acute effects, or at 48 and 72 h time points for chronic effects. Addition of betaAP 25-35 to SK-N-SH cells decreased the number of viable cells from 5% at 3 h to 35% at 15 h when compared to vehicle controls. Chronic treatment for 48 and 72 h caused decreases in viable cell number of 70% and 65%, respectively. Paradoxically, both glucose utilization and lactate production were found to be increased for the betaAP-treated cells. Concomitant estrogen treatment was found to be neuroprotective, as the severity of the insult on cell viability was decreased by 40% at 15 h and up to 71% at 72 h. Likewise, the addition of 17beta-estradiol decreased both the glucose use and lactate production of the cells. Chronic treatment with betaAP caused increases in lipid peroxidation over vehicle treated controls of 82% and 78% at 48 and 72 h, respectively, while decreases in peroxidation of 48% were seen with simultaneous estrogen treatment. These results indicate that the neuroprotective effects of estrogens against betaAP-induced toxicity are due in part to their capability to decrease lipid peroxidation and may additionally be attributable to decreasing the metabolic load of the cell.

Amyloid beta-Peptides↗
PubMed1997

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. Using an active-avoidance paradigm and a spatial memory task, the effects of estrogen deprivation were tested on memory-related behaviors. OVX caused a decline in avoidance behavior, and estrogen replacement normalized the response. In the Morris water task of spatial memory, OVX animals showed normal spatial learning but were deficient in spatial memory, an effect that was prevented by estrogen treatment. Together these data indicate that OVX in rats results in an estrogen-reversible impairment of learning/memory behavior. Because a plethora of information has been generated that links decline in memory-related behavior to dysfunction of cholinergic neurons, the effects of estrogens on cholinergic neurons were tested. We demonstrated that OVX causes a decrease in high affinity choline uptake and choline acetyltransferase activity in the hippocampus and frontal cortex; ERT reverses this effect. Further, we showed that estrogens promote the expression of mRNA for brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), 2 neurotrophic substances that have been shown to ameliorate the effects of age and injury on cholinergic neurons. Tissue culture models were used to evaluate whether estrogen treatment increases the survival of neurons when exposed to a variety of insults. 17-beta-Estradiol (beta-E2) protects cells from the neurotoxic effects of serum deprivation and hypoglycemia in human neuroblastoma cell lines. We have also observed that 17-alpha-estradiol (alpha-E2), a weak estrogen, shows neuroprotective efficacy in the SK-N-SH cell line at concentrations equivalent to beta-E2. Finally, we have observed that tamoxifen, a classic estrogen antagonist, blocks only one-third of the neuroprotective effects of either alpha-E2 or beta-E2. Collectively, these results indicate that estrogen is behaviorally active in tests of learning/ memory; activates basal forebrain cholinergic neurons and neurotrophin expression; and is neuroprotective for human neuronal cultures. We conclude that estrogen may be a useful therapy for AD and other neurodegenerative diseases.

Alzheimer Disease↗
PubMed1997

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. Then cells were exposed to 17 beta-E2 (0.2 or 2 nM), 17 alpha-E2 (0.2 or 2 nM), or cholesterol, testosterone, dihydrotestosterone, progesterone, or corticosterone (all at 2 nM). Cultures were insulted by serum deprivation, which caused a profound loss of cells. At 1 or 2 d of serum deprivation and steroid hormone replacement, the protection afforded cells by the steroid addition was assessed. Serum deprivation killed approximately 90% of cells cultured at both low and high plating density. Both 17 alpha- and 17 beta-E2 provided protection of SK-N-SH cells at either plating density. Further, a 10-fold molar excess of tamoxifen antagonized only approximately one-third of the neuroprotective effects of either isomer of estradiol, and a 100-fold excess of tamoxifen had no additional effect on the neuroprotection by 17 beta-E2. By contrast, none of the other steroids tested protected cells from the insult of serum deprivation. These results indicate that the neuroprotective effects of estrogens are not attributable to the general steroid structure, and the majority of the neuroprotection may not be mediated via a tamoxifenantagonized receptor mechanism.

Cholesterol↗
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↗
PubMed1996

Vascular applications of telepresence surgery: initial feasibility studies in swine.

PURPOSE: Telepresence surgery is a novel technology that will allow procedures to be performed on a patient at locations that are physically remote from the operating surgeon. This new method provides the sensory illusion that the surgeon's hands are in direct contact with the patient. We studied the feasibility of the use of telepresence surgery to perform basic operations in vascular surgery, including tissue dissection, vessel manipulation, and suturing. METHODS: A prototype telepresence surgery system with bimanual force-reflective manipulators, interchangeable surgical instruments, and stereoscopic video input was used. Arteriotomies created ex vivo in segments of bovine aortae or in vivo in femoral arteries of anesthetized swine were closed with telepresence surgery or by conventional techniques. Time required, technical quality (patency, integrity of suture line), and subjective difficulty were compared for the two methods. RESULTS: All attempted procedures were successfully completed with telepresence surgery. Arteriotomy closures were completed in 192+/-24 sec with conventional techniques and 483+/-118 sec with telepresence surgery, but the precision attained with telepresence surgery was equal to that of conventional techniques. Telepresence surgery was described as intuitive and natural by the surgeons who used the system. CONCLUSIONS: Blood-vessel manipulation and suturing with telepresence surgery are feasible. Further instrument development (to increase degrees of freedom) is required to achieve operating times comparable to conventional open surgery, but the system has great potential to extend the expertise of vascular surgeons to locations where specialty care is currently unavailable.

Animals↗
PubMed1992

Reflex transmission imaging improves ultrasonic visualization and characterization of calculi for lithotripsy applications.

A new ultrasound technique combining reflex transmission imaging (RTI) and integrated reflection C-scan (IRCS) imaging is being developed to enhance visualization of calculi for lithotripsy applications. Reflex transmission imaging/integrated reflection C-scan ultrasound produces orthographic images (similar to flat-field x-ray films) that improve the delineation of stone from soft tissue. Integrated reflection C-scan imaging is based on reflectivity while RTI is based on transmissivity of structures (stones) in the focal plane. Quantitative measurements of reflectance (IRCS) and attenuation (RTI) show potential for stone characterization and assessment of the degree of fragmentation. In vitro and in vivo images are presented.

Cholelithiasis↗
PubMed1991

Combined reflection and transmission ultrasound imaging.

Reflex transmission imaging (RTI) is a method for producing orthographic ultrasound transmission images, which depict focal-plane transmittance, by using a single transducer rather than an opposed transducer pair. RTI can be implemented using modified B-scan equipment, and a bidirectional scan probe. It has the further advantage of enabling simultaneous generation of integrated reflection C-scan (IRCS) images, which depict backscatter from the focal plane, in perfect registration with the transmission images. We describe these methods, demonstrate a new process by which the reflection and transmission images can be combined to produce a new image of superior quality, and demonstrate the applicability of this technique to improved visualization of kidney stones, with potential application to lithotripsy.

Humans↗