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Biomedical subjects

R J Wurtman

Publications and source records attributed to R J Wurtman.

At least 73 records · Page 4Linked to original sources
PubMed1995

Cerebrospinal fluid levels of amyloid beta-protein in Alzheimer's disease: inverse correlation with severity of dementia and effect of apolipoprotein E genotype.

Alzheimer's disease (AD) is characterized by formation in brain of neurofibrillary tangles and of amyloid deposits. The major protein component of the former is tau, while the latter are composed of amyloid beta-peptides (A beta), which are derived by proteolytic cleavage of the amyloid beta-protein precursor (APP). Both tau and various secretory APP derivatives including A beta and APPS are present in human cerebrospinal fluid (CSF). To investigate whether clinical signs of AD are paralleled by changes in CSF levels of these proteins, we correlated quantitative measures of dementia severity with CSF concentrations of A beta, of APPS, and of tau. We found that levels of A beta in CSF of AD patients were inversely correlated both to cognitive and to functional measures of dementia severity. In contrast, levels of APPS and of tau did not correlate with dementia severity. Apolipoprotein E (apoE) genotype did not influence CSF levels of A beta, APPS, or tau, which were similar among AD patients with Apo E epsilon 3/3, epsilon 3/4, and epsilon 4/4 alleles. These data indicate that CSF levels of A beta decrease with advancing severity of dementia in AD and suggest that they are independent of a patient's Apo E genotype.

Aged↗
PubMed1995

Brain serotonin, carbohydrate-craving, obesity and depression.

Serotonin-releasing brain neurons are unique in that the amount of neurotransmitter they release is normally controlled by food intake: Carbohydrate consumption--acting via insulin secretion and the "plasma tryptophan ratio"--increases serotonin release; protein intake lacks this effect. This ability of neurons to couple neuronal signaling properties to food consumption is a link in the feedback mechanism that normally keeps carbohydrate and protein intakes more or less constant. However, serotonin release is also involved in such functions as sleep onset, pain sensitivity, blood pressure regulation, and control of the mood. Hence many patients learn to overeat carbohydrates (particularly snack foods, like potato chips or pastries, which are rich in carbohydrates and fats) to make themselves feel better. This tendency to use certain foods as though they were drugs is a frequent cause of weight gain, and can also be seen in patients who become fat when exposed to stress, or in women with premenstrual syndrome, or in patients with "winter depression," or in people who are attempting to give up smoking. (Nicotine, like dietary carbohydrates, increases brain serotonin secretion; nicotine withdrawal has the opposite effect.) It also occurs in patients with normal-weight bulimia. Dexfenfluramine constitutes a highly effective treatment for such patients. In addition to producing its general satiety-promoting effect, it specifically reduces their overconsumption of carbohydrate-rich (or carbohydrate-and fat-rich) foods.

Animals↗
PubMed1995

Sleep-inducing effects of low doses of melatonin ingested in the evening.

We previously observed tht low oral doses of melatonin given at noon increase blood melatonin concentrations to those normally occurring nocturnally and facilitate sleep onset, as assessed using and involuntary muscle relaxation test. In this study we examined the induction of polysomnographically recorded sleep by similar doses given later in the evening, close to the times of endogenous melatonin release and habitual sleep onset. Volunteers received the hormone (oral doses of 0.3 or 1.0 mg) or placebo at 6, 8, or 9 PM. Latencies to sleep onset, to stage 2 sleep, and to rapid eye movement (REM) sleep were measured polysomnographically. Either dose given at any of the three time points decreased sleep onset latency and latency to stage 2 sleep. Melatonin did not suppress REM sleep or delay its onset. Most volunteers could clearly distinguish between the effects of melatonin and those of placebo when the hormone was tested at 6 or 8 PM. Neither melatonin dose induced "hangover" effects, as assessed with mood and performance tests administered on the morning after treatment. These data provide new evidence that nocturnal melatonin secretion may be involved in physiologic sleep onset and that exogenous melatonin may be useful in treating insomnia.

Administration, Oral↗
PubMed1995

Choline enhances scopolamine-induced acetylcholine release in dorsal hippocampus of conscious, freely-moving rats.

We examined the effects of exogenous choline (30, 60, 120 mg/kg, i.p.) on basal and scopolamine-evoked acetylcholine (ACh) release in awake animals, using in vivo microdialysis. After collection of 3-4 baseline dialysate samples (15 min each), rats received either saline or choline chloride and 4 additional samples were collected. All animals then received scopolamine hydrochloride (0.5 mg/kg, i.p.) and 6 additional samples were collected. Basal ACh release in animals receiving choline did not differ from that in rats given saline, nor from ACh release prior to choline administration. Scopolamine alone increased average ACh levels in dialysates from 1.22 +/- 0.54 to 11.18 +/- 3.07 pmol/15 min (mean +/- SD; p = 0.001); administration of 60 mg/kg or 120 mg/kg of choline chloride significantly enhanced maximal scopolamine responses by about 55%. These results suggest that supplemental choline enhances evoked ACh release in hippocampus of freely-moving rats.

Acetylcholine↗
PubMed1995

L-tyrosine ameliorates some effects of lower body negative pressure stress.

Tyrosine, a large neutral amino acid normally present in protein foods, is the precursor of the catecholamine neurotransmitters dopamine, norepinephrine, and epinephrine. Animal studies indicate that systemic administration of tyrosine in pharmacological quantities can reduce physiological and behavioral decrements induced by highly stressful conditions. The current study was designed to test the effects of tyrosine (100 mg/kg of body weight) on humans exposed to cardiovascular stress. Twenty participants were exposed to two Lower Body Negative Pressure (LBNP) sessions (-50 mm Hg for a maximum of 30 min) during each of two testing sessions of a repeated measure double-blind placebo-controlled study. The detected effects of tyrosine include an overall increase in pulse pressure (LBNP typically reduces pulse pressure) and an increase in auditory event related potential amplitude (P300-N300), an electro-physiological correlate of attention which may indicate enhanced cognitive activation.

Adult↗
PubMed1995

Effect of cytidine on membrane phospholipid synthesis in rat striatal slices.

Using rat striatal slices, we examined the effect of cytidine on the conversion of [3H]choline to [3H]-phosphatidylcholine ([3H]PC), and on net syntheses of PC, phosphatidylethanolamine (PE), and phosphatidylserine, when media did or did not also contain choline, ethanolamine, or serine. Incubation of striatal slices with cytidine (50-500 microM) caused dose-dependent increases in intracellular cytidine and cytidine triphosphate (CTP) levels and in the rate of incorporation of [3H] choline into membrane [3H]PC. In pulse-chase experiments, cytidine (200 microM) also increased significantly the conversion of [3H]choline to [3H]PC during the chase period. When slices were incubated with this concentration of cytidine for 1 h, small (7%) but significant elevations were observed in the absolute contents (nmol/mg of protein) of membrane PC and PE (p < 0.05), but not phosphatidylserine, the synthesis of which is independent of cytidine-containing CTP. Concurrent exposure to cytidine (200 microM) and choline (10 microM) caused an additional significant increase (p < 0.05) in tissue PC levels beyond that produced by cytidine alone. Exposure to choline alone at a higher concentration (40 microM) increased the levels of all three membrane phospholipids (p < 0.01); the addition of cytidine, however, did not cause further increases. Concurrent exposure to cytidine (200 microM) and ethanolamine (20 microM) also caused significantly greater elevations (p < 0.05) in tissue PE levels than those caused by cytidine alone. In contrast, the addition of serine (500 microM) did not enhance cytidine's effects on any membrane phospholipid. Exposure to serine alone, however, like exposure to sufficient choline, increased levels of all three membrane phospholipids significantly (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Evidence that 5'-cytidinediphosphocholine can affect brain phospholipid composition by increasing choline and cytidine plasma levels.

We examined the effects of orally administered 5'-cytidinediphosphocholine (CDP-choline) on arterial plasma choline and cytidine levels and on brain phospholipid composition in rats. Animals receiving a single oral dose of 100, 250, or 500 mg/kg showed peak plasma choline levels 6-8 h after drug administration (from 12 +/- 1 to 17 +/- 2, 19 +/- 2, and 24 +/- 2 microM, respectively). The area under the plasma choline curve at > 14 microM, i.e., at a concentration that induces a net influx of choline into the brain, was significantly correlated with CDP-choline dose. In rats receiving 500 mg/kg this area was 2.3 times that of animals consuming 250 mg/kg, which in turn was 1.8 times that of rats receiving 100 mg/kg. Plasma cytidine concentrations increased 5.4, 6.5, and 15.1 times baseline levels, respectively, 8 h after each of the three doses. When the oral CDP-choline treatment was prolonged for 42 and 90 days, brain phosphatidylcholine concentrations increased significantly (by 22-25%; p < 0.05) in rats consuming 500 mg/kg/day. Brain phosphatidylethanolamine and phosphatidylserine concentrations also increased significantly under some experimental conditions; levels of other phospholipids were unchanged.

Animals↗
PubMed1995

Regulated secretion of beta-amyloid precursor protein in rat brain.

The beta-amyloid precursor protein (APP) is a ubiquitous, highly conserved secretory glycoprotein that is expressed at high levels in mammalian brain by neurons, astrocytes, and activated microglia. Secreted APP (APPs) is generated by the cleavage of APP within the beta-amyloid (A beta) portion of its ectodomain. The formation and secretion of APPs can be increased by activation of particular neurotransmitter receptors and subsequent protein phosphorylation. We found that tissue slices from rat cortex, hippocampus, striatum, and cerebellum secrete APPs in vitro. APPs secretion was enhanced by electrical stimulation, but was not associated with a general increase in the release of total protein, lactate dehydrogenase (LDH) activity, or neuronal cell adhesion molecules. The pharmacological profile of stimulation-induced APPs secretion suggests complex interactions between muscarinic receptor subtypes in the tissue slices: in the unstimulated state, activation of Muscarinic M1 receptors increased APPs release while nonspecific activation of multiple muscarinic receptors had little effect on APPs release; in electrically stimulated slices, nonspecific inhibition of muscarinic receptors blunted the increase in APPs secretion. The nonspecific muscarinic agonist carbachol increased APPs secretion only in the presence of an M2 receptor antagonist, suggesting that activation of M2 receptors suppresses APPs formation. These data indicate that secretory APP processing in brain includes depolarization-enhanced cleavage of the cell-associated holoprotein within its ectodomain, and that the net effect of depolorization involves several subtypes of acetylcholine receptors.

Amyloid beta-Protein Precursor↗
PubMed1995

Regulation of proteolytic processing of the amyloid beta-protein precursor by first messengers. A novel potential approach for the treatment of Alzheimer's disease.

Amyloid deposits in Alzheimer's disease brains consist of aggregated amyloid beta-peptides (A beta) which are derived by proteolytic processing of the amyloid beta-protein precursor (APP). Proteolytic APP processing can be regulated by the activity of neuronal cell surface receptors including the muscarinic m1 and m3, the serotoninergic 5-HT2 and 5-HT1C, vasopressin and bradykinin receptor subtypes. Receptor stimulation with appropriate agonists rapidly increases the rates of release of the alpha-secretase processing product APPs which is cleaved within the A beta domain and thus is a non-amyloidogenic derivative. Moreover, stimulation of m1 receptors also decreases the formation of A beta, a secreted potentially amyloidogenic and possibly neurotoxic APP fragment. Similar biochemical events occur in stimulation experiments of fresh rat brain slices suggesting that neuronal activity may be involved in regulating APP processing in mammalian brain. Activation of non-amyloidogenic APP processing and inhibition of amyloidogenic processing pathways by subtype-specific agonists of muscarinic, serotoninergic or peptidergic receptors provides a novel approach for the pharmacological modulation of APP processing in Alzheimer's disease.

Alzheimer Disease↗
PubMed1994

Effects of subchronic pretreatment with D-fenfluramine or p-chloroamphetamine on [3H]inositolmonophosphate accumulation in rat cortical miniprisms.

Phosphatidylinositol (PI) breakdown in rat cerebral cortex is stimulated by serotonin (5-HT), acting via 5-HT2 and possibly 5-HT3 receptors and by acetylcholine or carbachol, acting via muscarinic M1 and M3 receptors. Serotoninergic neurons have been described as tonically inhibiting cortical acetylcholine release. We studied the effects of subchronic pretreatment with high doses of D-fenfluramine (10 mg/kg, i.p., daily for 4 days), which releases 5-HT and blocks its reuptake, on 5-HT-and carbachol-stimulated PI breakdown, as measured by [3H]inositolmonophosphate ([3H]IP1) accumulation in cortical miniprisms. This pretreatment decreased 5-HT-stimulated [3H]IP1 accumulation, suggesting that a prolonged increase of 5-HT in the synaptic cleft reduces the activity of the transducing system used by postsynaptic 5-HT receptors. Carbachol-stimulated PI breakdown was unaltered by pretreatment with D-fenfluramine. Pretreatment with a single dose of p-chloroamphetamine (5 mg/kg), a serotoninergic neurotoxin, which depleted cortical 5-HT by 85%, did not change [3H]IP1 accumulation after stimulation by 5-HT or by the muscarinic agonist carbachol. Subchronic pretreatment, which depleted cortical 5-HT by 90%, decreased both 5-HT- and carbachol-stimulated [3H]IP1 accumulation. The mechanism by which p-chloroamphetamine, but not D-fenfluramine, diminishes the PI response to carbachol might involve impairment of the tonic serotoninergic inhibition of acetylcholine release.

Animals↗
PubMed1994

Effects of systemic or oral ad libitum monosodium glutamate administration on striatal glutamate release, as measured using microdialysis in freely moving rats.

We examined effects of high doses of monosodium glutamate (MSG) on extracellular glutamate levels in rat striata, using in vivo microdialysis. Parenteral doses (0.5, 1.0 and 2.0, but not 0.25, g/kg, i.p.) caused dose- and time-dependent increases, peaking after 40 min (at 174 +/- 47%, 485 +/- 99% and 1021 +/- 301% of basal levels, respectively). In contrast, dietary MSG (1.49 +/- 0.10 g/kg/h) was ineffective.

Administration, Oral↗
PubMed1994

Effect of inducing nocturnal serum melatonin concentrations in daytime on sleep, mood, body temperature, and performance.

We examined effects of very low doses of melatonin (0.1-10 mg, orally) or placebo, administered at 1145 h, on sleep latency and duration, mood, performance, oral temperature, and changes in serum melatonin levels in 20 healthy male volunteers. A repeated-measure double-blind Latin square design was used. Subjects completed a battery of tests designed to assess mood and performance between 0930 and 1730 h. The sedative-like effects of melatonin were assessed by a simple sleep test: at 1330 h subjects were asked to hold a positive pressure switch in each hand and to relax with eyes closed while reclining in a quiet darkened room. Latency and duration of switch release, indicators of sleep, were measured. Areas under the time-melatonin concentration curve varied in proportion to the different melatonin doses ingested, and the 0.1- and 0.3-mg doses generated peak serum melatonin levels that were within the normal range of nocturnal melatonin levels in untreated people. All melatonin doses tested significantly increased sleep duration, as well as self-reported sleepiness and fatigue, relative to placebo. Moreover, all of the doses significantly decreased sleep-onset latency, oral temperature, and the number of correct responses on the Wilkinson auditory vigilance task. These data indicate that orally administered melatonin can be a highly potent hypnotic agent; they also suggest that the physiological increase in serum melatonin levels, which occurs around 2100 h daily, may constitute a signal initiating normal sleep onset.

Adolescent↗
PubMed1994

Regulation of proteolytic processing of the amyloid beta-protein precursor of Alzheimer's disease in transfected cell lines and in brain slices.

beta A4 is the principal component of Alzheimer's disease brain amyloid. It is derived from proteolytic processing of amyloid beta-protein precursors (APP), a family of transmembrane glycoproteins. Secretion of APPs, a secreted proteolytic derivative that is cleaved within the beta A4 domain of APP, is increased many-fold by the activation of cell-surface receptors, like the muscarinic m1 and m3 receptor subtypes, which are coupled to protein kinase C. Concomitantly, their activation decreases the formation of both secreted soluble beta A4 and of endosomal-lysosomal C-terminal APP derivatives. These data suggest that muscarinic m1 and m3 receptors accelerate non-amyloidogenic APP processing and depress the formation of potentially amyloidogenic derivatives. Other receptors that stimulate APPs secretion include those for bradykinin, vasopressin, and interleukin-1 receptors. A similar control mechanism is present in rat brain tissue slices, in which the release of both APPs and endogenous neurotransmitters is increased by electrical depolarization. This increase is tetrodotoxin-sensitive and frequency-dependent, suggesting that APPs release may normally depend on neuronal activity. Taken together, our findings suggest that specific receptor agonists might be effective in reducing the formation of potentially amyloidogenic APP derivatives in vivo.

Alzheimer Disease↗
PubMed1994

Aberrant snacking patterns and eating disorders in patients with obsessive compulsive disorder.

BACKGROUND: Appetitive symptoms, particularly carbohydrate craving, have been shown to occur in patients whose conditions responded to treatment with drugs that enhance serotonin-mediated neurotransmission. This suggested that patients with obsessive compulsive disorder (OCD) who also frequently respond to serotonergic drugs also might have similar distributions of appetitive and eating patterns. METHOD: A survey study of 170 OCD patients and 920 controls was conducted using a questionnaire that inquired about snacking behavior, including food preference, mood changes after eating, and previous diagnosis of eating disorders. The frequency responses in the two groups were tested for statistical significance. RESULTS: Significant differences were found between the OCD and control groups with respect to the reported incidence of eating disorders, snacking patterns, and mood response to food. CONCLUSION: This finding of different snacking patterns in OCD mirrors that found in other disorders that have been shown to be responsive to serotonergic drugs. The high incidence of carbohydrate snacking among OCD patients compared with the control group provides additional evidence that brain serotonin may be involved in this disorder.

Adult↗
PubMed1993

Effect of choline on basal and stimulated acetylcholine release: an in vivo microdialysis study using a low neostigmine concentration.

Using in vivo microdialysis, we examined the ability of choline (Ch) chloride (120 mg/kg i.p.) to amplify basal and stimulated acetylcholine (ACh) release from rat striatum in the presence of high (10(-5) M) and low (5 x 10(-8) M) neostigmine concentration. High concentrations might suppress ACh release, and thus Ch dependence, by excessively stimulating presynaptic cholinergic receptors; alternatively, they could enhance Ch dependence by depriving the cholinergic terminals of Ch that would otherwise be formed intrasynaptically from the hydrolysis of ACh. Both basal and stimulated ACh release were found to be tetrodotoxin (TTX) sensitive. The concentration of neostigmine in the microdialysis fluid positively affected basal ACh levels, but had no effect on Ch levels. Ch administration significantly increased ACh release (to 136% of basal values; P < 0.01) in the presence of the low neostigmine concentration, but failed to significantly increase ACh release following local electrical depolarization of striatal neurons. In contrast, Ch failed to affect basal ACh release in the presence of the high neostigmine concentration, but did increase electrically evoked release to 408% of basal values, as compared with 250% in rats receiving saline instead of the Ch (P < 0.05). Ch administration significantly increased microdialysate Ch levels in the presence of both of the neostigmine concentrations. Local administration of oxotremorine, a muscarinic agonist, to animals receiving the lower neostigmine concentration reduced basal ACh release and reduced the increase in basal release produced by Ch administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗