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R P Ebstein

Publications and source records attributed to R P Ebstein.

At least 19 recordsLinked to original sources
PubMed1992

Iron accumulation in the rat basal ganglia after excitatory amino acid injections--dissociation from neuronal loss.

The current study examines in an animal model the relation of excessive iron accumulation in the basal ganglia to the pathology of Parkinsonism and Hallervoden-Spatz disease. Following a unilateral microinjection of excitatory amino acids, kainate, or quinolinate to the anterior olfactory nucleus/ventral striatal region, an increase in histochemical iron concentration was observed in the ipsilateral ventral pallidum, the islands of calleja, the globus pallidus, the entopeduncular nucleus, the ventral thalamus, and the substantia nigra pars reticulata. The iron was observed both in glia and as intensification of patches in the neuropil. In a second group of rats, after microinjection of ibotenate or quisqualate to the nucleus basalis of Meynert, iron accumulated in the ipsilateral entopeduncular nucleus and pars reticulata of substantia nigra. Increased iron accumulation, compared to that in the contralateral side, was stable for months after a single microinjection. In the basal ganglia distal from the site of EAA injection, no gross morphological changes were associated with the increased iron accumulation. The implications of these findings to the pathology of Parkinson's and Hallervorden-Spatz diseases are discussed.

Animals↗
PubMed1991

Phospholipase A2 activity in Epstein-Barr virus-transformed lymphoblast cells from schizophrenic patients.

We examined the activity of phospholipase A2 in Epstein-Barr virus-transformed lymphoblast cell lines established from ten schizophrenic patients and ten controls. A novel method for determination of enzyme activity in whole cells was employed, by measuring the hydrolysis of a fluorescent analogue of phosphatidylcholine. No significant difference in phospholipase A2 activity was found between the groups. These results suggest that the previously reported changes in phospholipase A2 activity in plasma and in fresh peripheral cells are indicative of environmental influences and not of "trait" characteristics intrinsic to schizophrenia.

Adult↗
PubMed1990

Platelet adenylate cyclase and phospholipase C activity in posttraumatic stress disorder.

Adenylate cyclase and phospholipase C activity were examined in platelet membranes obtained from 19 male subjects with combat-related posttraumatic stress disorder (PTSD) and 35 age- and gender-matched healthy controls. Basal and forskolin-stimulated adenylate cyclase activity were significantly lower in the PTSD group whereas aluminum chloride plus sodium fluoride (AlCl3/NaF)- and prostaglandin E1 (PGE1)-stimulated responses were normal. There was no difference in phospholipase C activity between the two groups. The lower basal and forskolin-stimulated adenylate cyclase responses replicate a previous report and suggest that PTSD may be associated with an abnormality of the catalytic subunit of the receptor-adenylate cyclase complex.

Adenylyl Cyclases↗
PubMed1990

Cyclic AMP second messenger signal generation in EBV-transformed lymphoblastoid cells from schizophrenic patients.

Several aspects of cyclic AMP second messenger signal generation were examined in EBV-transformed cell lines from 12 schizophrenic patients and 12 age- and sex-matched controls. No evidence was obtained suggesting a heritable abnormality in cyclic AMP synthesis in schizophrenia. Basal, forskolin, A1/NaF- and GppNHp-stimulated cyclic AMP synthesis in membranes from transformed cell lines was identical for schizophrenic and control subjects. In addition, no significant differences were observed for basal, forskolin-, isoproterenol- and prostaglandin E1-stimulated cyclic AMP accumulation in intact cell lines derived from ten of the schizophrenic patients compared with cell lines derived from ten of the control subjects.

Adenylyl Cyclases↗
PubMed1990

Cortical second messengers after NBM damage: no change in responses to cholinergic agonists.

Damage to the nucleus basalis of Meynert (NBM) decreases acetylcholine (ACh) innervation of cortex. We explored transmission of cholinergic messages in cortex 2-3 weeks after such damage. The NBM damage was unilateral and the ipsilateral denervated cortex was compared to the contralateral nondenervated cortex. The response to carbachol, a muscarinic ACh receptor-agonist, was measured by inhibition of forskolin-induced cAMP accumulation in cortical membranes and by formation of inositol phosphate (IP) in cortical slices. No difference was found in the carbachol effects between ipsi- and contralateral cortices. Thus, we find no evidence of either receptor loss or receptor supersensitivity. There was, however, a significant decrease in K(+)-stimulated IP formation in the cortex ipsilateral to the damage which probably reflected loss of cholinergic terminals. When comparing the cortex contralateral to NBM damage with the cortex contralateral to sham damage in control rats, no difference was found in any of the above parameters. When severe cognitive deficits are observed, 2-3 weeks after NBM damage, loss of presynaptic ACh is the main change in cortical cholinergic transmission.

Acetylcholine↗
PubMed1989

Uptake of 3H-spiperone by lymphocytes in schizophrenia.

Uptake of 3H-spiperone into lymphocytes obtained from control subjects (N = 22), chronic schizophrenics (N = 20), relatives with psychiatric disorder (N = 11) and unaffected relatives (N = 17) was studied. No differences were observed in spiperone uptake among any of the groups examined. Although previous investigations reported marked differences in 3H-spiperone uptake between schizophrenic and control subjects, we were unable to replicate their findings: the failure to replicate those of Bondy and colleagues may well be due to our inability to duplicate in our laboratory the exact biochemical methodology described by these investigators. Saturation curves could not be determined for most subjects. In addition, chronicity of illness and long-term exposure to neuroleptic medication among the schizophrenic subjects may partially account for the contradictory results reported by different investigators.

Adult↗
PubMed1988

Lithium modulation of second messenger signal amplification in man: inhibition of phosphatidylinositol-specific phospholipase C and adenylate cyclase activity.

The activity of phosphatidylinositol-specific phospholipase C was significantly reduced in platelets obtained from 20 euthymic manic-depressive patients on therapeutic lithium doses (mean blood level 0.85 mEq/l) compared to an age- and sex-matched group of 36 control subjects. The activities of prostaglandin E1-, aluminum/NaF-, and forskolin-stimulated platelet adenylate cyclase activity were also measured in a similar group of 16 lithium-treated and 22 control subjects. A marked reduction in both postreceptor (aluminum/NaF and forskolin) and receptor-stimulated (prostaglandin E1) platelet adenylate cyclase activity was observed in the lithium-treated group (mean blood level 0.81 mEq/l). These findings support the hypothesis that lithium's therapeutic mode of action in manic-depressive psychosis is mediated by the combined down-regulation of both principal second messenger systems, inositol phosphates and cyclic adenosine monophosphate, by reducing the activity of phosphatidylinositol-specific phospholipase C and adenylate cyclase.

Adenylyl Cyclase Inhibitors↗
PubMed1988

Cyclic AMP second-messenger signal amplification in depression.

Beta-adrenergic-mediated cyclic AMP accumulation was reduced in lymphocytes obtained from depressed patients from that observed in an age- and sex-matched group of control subjects. Among the depressed patients, those not responding to treatment showed significantly lower pretreatment responses to isoproterenol compared with patients who exhibited significant clinical improvement during antidepressant treatment. Late-night (terminal) insomnia was significantly associated with the blunted response to beta-adrenergic stimulation. In depressed patients with the lowest isoproterenol response, the effect of forskolin (which acts distal to the receptor and directly stimulates the catalytic subunit) on cyclic AMP accumulation was also significantly decreased. This suggests that post-receptor modulations of signal amplification also play a role in the reduced response to beta-adrenergic stimulation in depression.

Adult↗
PubMed1987

Isoelectric focusing of human platelet phospholipase C: evidence for multimolecular forms.

Polyacrylamide gel isoelectric focusing was employed to characterize phospholipase C activity in the supernatant fraction after disruption of human platelets. Three bands of enzyme activity were detected on focused gels: a major band of activity (B) and two additional bands (A,C) were consistently identified. The isoelectric points of the three bands were in the range of pH 7.5-8.0. Phospholipase C activity was assayed using both phosphatidylinositol and phosphatidylinositol-4-monophosphate. The prominent B band was active against both substrates and no evidence for substrate preference towards phosphoinositides was obtained. These data suggest that isozyme forms of cystolic phospholipase C are present in human platelet supernatant and suggest the possibility of functional and structural differentiation of the various forms of the enzyme.

Animals↗
PubMed1987

Effect of lithium in vitro and after chronic treatment on human platelet adenylate cyclase activity: postreceptor modification of second messenger signal amplification.

LiCl in vitro markedly inhibits forskolin-stimulated human platelet adenylate cyclase activity by competing competitively with Mg2+ for a site on the catalytic subunit. The sensitivity of platelet membrane adenylate cyclase to lithium inhibition for individual manic patients was determined by the Dixon plot procedure: marked individual differences in sensitivity to lithium were observed pretreatment (0.66 mM-3.15 mM LiCl). After 3 weeks of continuous treatment with lithium in vivo a significant decrease in adenylate cyclase affinity for lithium was observed (pretreatment average Ki = 1.38 +/- 0.92 mM vs. treatment average Ki = 2.98 +/- 1.35 mM LiCl, n = 10). The clinical implications of these findings relating to chronic lithium exposure are discussed.

Adenylyl Cyclase Inhibitors↗
PubMed1987

Cyclic AMP signal transduction in posttraumatic stress disorder.

Cyclic adenosine 3',5'-monophosphate (cAMP) signal transduction was examined in lymphocytes and platelets obtained from patients with posttraumatic stress disorder. Intact lymphocytes from the posttraumatic patients (N = 10) showed significantly lower basal, isoproterenol-, and forskolin-stimulated cAMP levels than those from 10 healthy control subjects. In platelet membrane preparations, basal, forskolin-, aluminum chloride plus sodium fluoride-, and prostaglandin E1-stimulated adenylate cyclase activity levels were all significantly lower in the posttraumatic group than in the control group. The authors discuss the potential role of their findings as a biological marker for posttraumatic stress disorder.

Adenylyl Cyclases↗
PubMed1986

Age related decline in aluminum-activated human platelet adenylate cyclase: post-receptor changes in cyclic AMP second messenger signal amplification in normal aging and dementia of the Alzheimer type.

Low, micromolar concentrations of aluminum (in the presence of NaF) were shown to strongly activate human platelet adenylate cyclase and provided a useful probe for evaluating cyclic AMP second messenger function distal to the receptor: The effect of normal aging and disease state on second messenger activity in man was studied by measurements of the aluminum-activated enzyme. A significant decline in aluminum-stimulated platelet adenylate cyclase activity in older, healthy subjects was observed. An age-associated decline in NaF-stimulated cyclic AMP synthesis was also demonstrated for normal, non-demented subjects. These findings suggest an age-associated lesion at the level of the guanine nucleotide regulatory protein/catalytic subunit of the adenylate cyclase complex. However, for patients with Alzheimer's disease no such decline in platelet adenylate cyclase activity was detected, and increased sensitivity to both aluminum and NaF was demonstrated.

Adenylyl Cyclases↗
PubMed1986

Hormone and forskolin-stimulated cyclic AMP accumulation in human lymphocytes: reliability of longitudinal time measurements.

Reliability of measurement of lymphocyte cyclic AMP synthesis in intact cells was estimated by taking 3 successive blood samples during a one-month period from 11 healthy volunteers. Isoproterenol and prostaglandin E1-stimulated cyclic AMP accumulation were used to evaluate the activity of these two receptor activities in human lymphocytes. Forskolin-stimulated cyclic AMP accumulation was used to evaluate the activity of the Ns/catalytic subunit. Only for forskolin was significant reliability observed. For isoproterenol and prostaglandin E1 significant reliability was observed only for male subjects.

Adult↗
PubMed1986

The cyclic AMP second messenger system in man: the effects of heredity, hormones, drugs, aluminum, age and disease on signal amplification.

The intracellular effects of a number of hormonal signals are mediated by the cyclic AMP second messenger system in man and the ubiquitous distribution of hormone-stimulated adenylate cyclase suggests the importance of this enzyme complex in normal aging and pathophysiological states. Various vectors including heredity, endogenous catecholamines, steroid hormones, and drugs affect the activity of hormone-stimulated adenylate cyclase in man. The effect of heredity was studied using lymphocytes obtained from monozygotic twin pairs and age and sex-matched sib pairs. Only for forskolin-stimulated activity is a significant proportion of individual variance attributable to heredity, suggesting the relative stability of the catalytic subunit. Beta-adrenergic and prostaglandin E-1 activity are "state" characteristics and their activities are controlled by environmental parameters. A significant reduction in isoproterenol-stimulated cyclic AMP accumulation between the menses and luteal phase of the menstrual cycle is observed in lymphocytes obtained from 11 female subjects. The lowest level of beta-adrenergic receptor activity is associated with the highest levels of progesterone and estradiol hormone levels in blood. Lithium at therapeutic concentrations markedly inhibits adenylate cyclase activity in platelet membranes. Moreover, marked individual differences are observed in sensitivity to lithium as determined by Dixon plot derived Ki values for 9 normal, healthy subjects. Human adenylate cyclase obtained from platelets and lymphocytes is activated by micromolar amounts of aluminum in the presence of NaF. Irreversible activation of adenylate cyclase by aluminum is suggested as a possible mechanism of this metal's neurotoxicity. The biochemical basis for the age-associated decline in beta-adrenergic responsiveness in man is discussed. Several investigations suggest a deficit at two levels in the adenylate cyclase complex: an impaired coupling of the receptor/N protein subunits and an additional lesion distal to the receptor at the level of N/C coupling. Perfusion studies with salbutamol suggest that the decline in beta-adrenergic sensitivity is general and not restricted to lymphocytes. Possible abnormalities in cyclic AMP signal amplification and recognition in various disease states is discussed. Increased prostaglandin E-1-stimulated cyclic AMP accumulation is observed in lymphocytes obtained from patients with Alzheimer's disease compared to age-matched controls and correlated with severity of the disease state.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenylyl Cyclases↗
PubMed1985

Beta-adrenergic-stimulated adenylate cyclase activity in normal and EBV-transformed lymphocytes.

Beta-adrenergic-associated cyclic AMP accumulation was studied in intact lymphocytes before and after transformation with Epstein-Barr virus into immortal cell lines. Although a marked reduction in isoproterenol-stimulated cyclic AMP synthesis was observed in transformed cells, forskolin-stimulated cyclic AMP accumulation was preserved. A parallel loss of 125-iodocyanopindolol binding sites suggests that the reduction in beta-adrenergic-stimulated AMP synthesis is due to receptor down-regulation.

Adenylyl Cyclases↗
PubMed1985

The effect of age on beta-adrenergic function in man: a review.

The structure and function of the beta-adrenergic adenylate cyclase complex in the elderly is reviewed. The function of the beta-adrenergic receptor in man is modulated by levels of circulating catecholamines, noncatecholamine hormones, drugs, disease, and age. Although a number of clinical observations demonstrate an age-related decrease in catecholamine responsiveness, the molecular basis of this phenomenon is unknown. Simple reduction in beta-receptor number does not appear to explain age-associated loss of catecholamine responsiveness. Recent investigations from our laboratory employed salbutamol-induced rise in plasma cyclic AMP (cAMP) levels to study the molecular basis for this phenomenon. In young individuals there was a threefold increase in plasma cAMP levels after salbutamol infusion. In older subjects only a 50% rise in plasma cAMP levels was observed. These results suggest that the basis for reduced catecholamine responsiveness in the elderly is due to a defect in the peripheral beta-receptor-linked adenylate cyclase complex. The finding of reduced beta-adrenergic-stimulated adenylate cyclase activity in the aged prompted us to determine the specificity of this decline by measuring the activity in older and younger individuals of another hormone-sensitive adenylate cyclase. However, no effect of subject age was observed on glucagon-sensitive adenylate cyclase activity, suggesting that the blunted response of the beta-receptor adenylate cyclase complex in the elderly represents a specific loss of function and is not due to a general age-associated decline in hormone-stimulated cyclase function. Specific molecular defects which could account for decline in beta-adrenergic responsiveness in the elderly are discussed.

Adenylyl Cyclases↗
PubMed1985

Heritability of forskolin and hormone-stimulated adenylate cyclase activity in human lymphocytes.

Isoproterenol, prostaglandin E1 and forskolin-stimulated cyclic AMP accumulation were compared in intact lymphocytes obtained from nine monozygotic and nine sib pairs matched for age and sex. Heritability was calculated by three different methods, two based on the intraclass correlation coefficients and one based directly on the variances. Only for forskolin is a significant proportion of variance (0.68-0.91) attributable to genetic factors, suggesting that forskolin-stimulated activity may prove to be a valuable genetic marker in studies of human pathology. Neither basal nor isoproterenol and prostaglandin E1-stimulated activity show significant heritability in intact human lymphocytes. The individual differences observed in levels of beta-adrenergic and prostaglandin stimulated receptor activity in human lymphocytes are, therefore, most likely due to environmental factors.

Adenylyl Cyclases↗