Biomedical subjects

Richard J Wurtman

Publications and source records attributed to Richard J Wurtman.

9 recordsLinked to original sources

PubMed2003

Stimulation of CDP-choline synthesis by uridine or cytidine in PC12 rat pheochromocytoma cells.

Oral administration of CDP-choline to rats raises plasma and brain cytidine levels and increases brain levels of phosphatidylcholine (PC). In contrast, in humans oral CDP-choline increases plasma levels of uridine. To determine whether uridine can also enhance PC synthesis, we developed an assay for CDP-choline, an immediate and rate-limiting precursor in PC synthesis, and measured this intermediate in clonal PC12 rat pheochromocytoma cells incubated with various concentrations of uridine or cytidine. Addition of uridine (50-100 microM) to the incubation medium caused significant elevations in UTP, CT, USAP and CDP-choline levels in PC12 cells. Uridine had no effect on the synthesis of diacylglycerol (DAG) or the activity of the phosphotransferase which catalyzes the synthesis of PC from DAG and CDP-choline. Hence uridine treatment was unlikely to inhibit the conversion of endogenous CDP-choline to PC. These results suggest the possibility that uridine may also enhance PC synthesis in intact brain.

Animals↗

PubMed2003

Cyclooxygenase-2 mediates platelet-activating factor-induced prostaglandin E2 release from rat primary astrocytes.

The phospholipid mediator platelet-activating factor (PAF), and its non-hydrolyzable analog methylcarbamyl-PAF (mc-PAF) increase prostaglandin E(2) (PGE(2)) release from astrocyte-enriched cortical cell cultures. Cyclooxygenase (COX) enzymes--of which there are two known isoforms--convert arachidonic acid to prostaglandin (PG) H(2) (PGH(2)), which is further metabolized to various PGs, including PGE(2). COX-1 is generally considered to contribute to cell homeostasis, whereas COX-2 is thought to mediate inflammatory/immune PG formation. In this study we examined the involvement of the COX isoforms in PAF-induced PGE(2) release. Treatment of cells with the non-specific COX inhibitor indomethacin, or the specific COX-2 inhibitor NS-398, prior to mc-PAF stimulation completely blocked the PAF-induced release of PGE(2); treatment with more selective COX-1 inhibitors (i.e. piroxicam and SC-560) failed to significantly do so. These data suggest that COX-2 is responsible for PAF-mediated PGE(2) release in primary astrocytes.

Animals↗

PubMed2003

Dietary cytidine (5')-diphosphocholine supplementation protects against development of memory deficits in aging rats.

The present study was designed to assess the effect of supplementation with dietary cytidine (5')-diphosphocholine (CDP-choline), a source of cytidine and choline, on memory in young and older rats. Although the hippocampal-dependent memory deficits in aged rats are well documented, cognitive functioning in early aging has not been as thoroughly evaluated. Female Sprague-Dawley rats (3 or 15 months of age) consumed either a control diet or a diet supplemented with CDP-choline (approximately 500 mg/kg/day) for 8 weeks, after which they were trained to perform spatial and cued versions of the Morris water maze. Compared with young rats, aged rats exhibited a selective deficit in spatial memory tasks that required rats to retain information for 24 h or longer. CDP-choline supplementation protected against the development of this deficit, but had no memory-enhancing effect in normal young rats. These findings suggest that early-aged rats display a selective impairment in hippocampal-dependent long-term memory, and that dietary CDP-choline supplementation can protect against this deficit.

Administration, Oral↗

PubMed2003

Effects of normal meals rich in carbohydrates or proteins on plasma tryptophan and tyrosine ratios.

BACKGROUND: The delivery of circulating tryptophan to the brain and its conversion to serotonin vary directly with plasma concentrations of tryptophan and inversely with those of other large neutral amino acids (LNAAs). Although carbohydrate-rich, protein-free formula diets have been shown to elevate, and high-protein diets to depress, the tryptophan-LNAA ratio, few data are available about this ratio's responses to actual meals. OBJECTIVE: We determined whether carbohydrate-rich or protein-rich breakfasts, such as those Americans normally eat, produce substantial differences in the plasma tryptophan-LNAA ratio and in the corresponding ratio for tyrosine, the precursor of brain dopamine and norepinephrine. DESIGN: Nine overnight-fasted subjects consumed, 3-7 d apart, a carbohydrate-rich (69.9 g carbohydrate and 5.2 g protein) and a protein-rich (15.4 g carbohydrate and 46.8 g protein) breakfast. Blood samples collected at baseline and after 40, 80, 120, and 240 min were assayed for tryptophan, tyrosine, the 5 other LNAAs, and insulin. RESULTS: The carbohydrate-rich and protein-rich breakfasts had significantly different effects on both the plasma tryptophan-LNAA and tyrosine-LNAA ratios (each P < 0.01). Among the 8 subjects who consumed both breakfasts, the median difference for tryptophan:LNAA was 54% (range: 36-88%) and for tyrosine:LNAA was 28% (range: 10-64%). Insulin concentrations rose significantly after the carbohydrate but not after the protein meal. CONCLUSIONS: High-carbohydrate and high-protein breakfasts similar to those Americans normally eat can cause substantial differences in the plasma tryptophan ratio and thus, probably, in brain tryptophan concentrations and serotonin synthesis. Such meals also change the plasma tyrosine ratio and may thereby modify catecholamine synthesis.

Adult↗

PubMed2002

Effect of a 5-HT(2C) serotonin agonist, dexnorfenfluramine, on amyloid precursor protein metabolism in guinea pigs.

Stimulation of serotonin receptor subtypes 5-HT(2A) or 5-HT(2C) in stably transfected 3T3 cells by dexnorfenfluramine (DEXNOR) or serotonin increases secretion of the APP metabolite APP(s). It is not known whether activation of these receptors can also affect APP metabolism in vivo. We examined the effects of a single intraperitoneal (i.p.) injection of DEXNOR on APP(s) levels in cerebrospinal fluid (CSF) of guinea pigs. These levels were significantly (P<0.05) increased by a single dose of DEXNOR (1-4 mg/kg); those of the APP metabolites Abeta(1-40) and Abeta(1-42) were unaffected. The DEXNOR-induced (1 mg/kg) increases in CSF APP(s) were suppressed by ritanserin (1 mg/kg) but not by ketanserin (2 mg/kg). When given alone, ritanserin did not affect CSF levels of APP(s), Abeta(1-40), or Abeta(1-42). Chronic treatment with DEXNOR for 9 days (1 mg/kg bid, i.p.) increased CSF APP(s) levels, measured 2 h after the last injection (P<0.05), and decreased those of CSF Abeta(1-42) (P<0.05). Neither hippocampal nor cortical levels of the APP holoprotein (APP(h)), nor body weight, were affected by DEXNOR. Chronic administration of mCPP (1-(m-chlorophenyl)piperazine) (2 mg/kg bid, i.p.), a 5-HT(2B/2C) agonist, for 9 days also increased CSF APP(s) levels (P<0.5) when measured 2 h after the drug's last administration; hippocampal and cortical APP(h) levels were unaffected. However, mCPP also caused a significant decrease in body weight gain. These data indicate that the pharmacological activation of 5-HT(2C) receptors can stimulate CSF APP(s) secretion and reduce Abeta production in vivo. Hence 5-HT(2C) receptors, which apparently are localized to the brain, may represent useful targets for the development of treatments for Alzheimer's disease.

Alzheimer Disease↗

PubMed2002

Platelet-activating factor increases prostaglandin E(2) release from astrocyte-enriched cortical cell cultures.

The phospholipid mediator platelet-activating factor (PAF) increased the release of prostaglandin E(2) (PGE(2)) from astrocyte-enriched cortical cell cultures in a concentration- and time-dependent manner. The nonhydrolyzable PAF analog methylcarbamyl-PAF (mc-PAF), the PAF intermediate lyso-PAF, and arachidonic acid (AA) also produced this effect. In contrast, phosphatidlycholine (PC) and lyso-PC, lipids that are structurally similar to PAF and lyso-PAF, had no effect on PGE(2) production, suggesting that PAF-induced PGE(2) release is not the consequence of nonspecific phospholipid-induced membrane perturbation. Antagonism of intracellular PAF binding sites completely abolished the ability of mc-PAF and lyso-PAF to mobilize PGE(2,) and attenuated the AA effect. Antagonism of the G-protein-coupled PAF receptor in plasma membranes had no significant effect on mc-PAF, lyso-PAF or AA-induced PGE(2) release. Based on the present findings, we hypothesize that intracellular PAF is a physiologic stimulus of PGE(2) production in astrocytes.

Animals↗

PubMed2002

Platelet-activating factor antagonists decrease the inflammatory nociceptive response in rats.

RATIONALE: Platelet-activating factor (PAF) is a membrane-derived phospholipid mediator that has biological effects on a variety of cells and tissues. A variety of stimuli, including those producing inflammation, promote the synthesis and release of PAF from various cell types. Evidence suggests that PAF exerts cellular actions through a plasma membrane receptor as well as via intracellular (microsomal) PAF binding sites. OBJECTIVE: The present study was designed to: 1) investigate the role of PAF in a model of inflammatory nociception in rats (i.e. the formalin test), and 2) localize PAF's site(s) of action in nociception. To do this, we assessed the effect of administering two PAF antagonists (BN 52021 and BN 50730, which are selective for cell surface and intracellular PAF binding sites, respectively) on formalin-induced nociceptive responses. METHODS: Forty minutes prior to formalin injection into the rat hindpaw, male Sprague-Dawley rats received systemic injections of BN 52021 (10, 1, or 0.1 mg/kg), BN 50730 (10, 1, or 0.1 mg/kg), or vehicle (45% 2-hydroxypropyl-beta-cyclodextrin in distilled water, HBC) and the effects of the drugs on nociceptive behavioral responses were measured. RESULTS: Rats receiving systemic BN 52021 or BN 50730 displayed a significant reduction of nociceptive responses in the late, but not early, phase of formalin-induced nociception. CONCLUSIONS: These findings suggest a role for endogenous PAF in nociceptive transmission, especially for persistent pain such as that which occurs in the late phase of the formalin test. The findings also indicate that both intracellular and cell surface PAF binding sites are involved in nociceptive modulation in rats, and that PAF antagonists might be useful for treating some patients with acute or chronic pain.

Animals↗

PubMed2002

Environmental conditions influence hippocampus-dependent behaviours and brain levels of amyloid precursor protein in rats.

Sprague-Dawley rats were reared in enriched (EC; group housing, exposure to stimulating objects, frequent handling) or restricted (RC; individual housing, no exposure to stimulating objects, minimal handling) environments starting on day 23 of life. At six months of age, they underwent behavioural tests to assess 'cognitive' and 'stimulus-response' memory, selective attention, and inflammatory pain processing. Alterations in synapses and cell survival may occur as a result of environment differences; therefore we assessed the brain levels of several proteins implicated in neurite outgrowth, synaptogenesis, and cell survival. Brains were dissected and analysed for amyloid precursor protein (APP) and other synaptic and cytoskeletal proteins using Western blotting. The performance of EC animals in a hidden platform water maze task, and in a test of selective attention (both of which are thought to involve the hippocampus) was superior to that of RC animals. In contrast, performance of RC animals on two stimulus-response tasks, the visible platform water maze test and simple visual discrimination (both of which are thought to be hippocampal independent) was indistinguishable from that of EC animals. Male EC rats displayed a different behavioural response to formalin during the inflammatory phase of nociception--the phase affected by hippocampal processing; a similar trend was observed in females. Female but not male RC rats exhibited elevated plasma corticosterone levels; adrenal weights were unaffected by environmental conditions. Region-specific increases in brain levels of APP, neurofilament-70 (NF-70), and platelet-activating factor receptor (PAF-R) were found in EC rats. These data suggest that enriched animals manifest enhanced functioning of certain hippocampus-mediated behaviours when compared with that of their restricted counterparts; and that brain levels of various synaptic and structural proteins involved in neurite outgrowth, cell survival, and synaptogenesis, are affected by environmental factors.

Amyloid beta-Protein Precursor↗

PubMed2002

Stress and the adrenocortical control of epinephrine synthesis.

Psychologic states produced by environmental or physiologic stresses are usually associated with hypersecretion of adrenal hormones, particularly epinephrine and the glucocorticoids (hydrocortisone in humans or corticosterone in rats). A common mechanism links the secretion of these hormones, even though the adrenal medulla and cortex have different embryologic origins and biochemical properties and very different mechanisms controlling their secretory activities, ie, a cholinergic nervous input stimulates medullary secretion while a hormone, corticotropin (ACTH), activates secretion from the cortex. This mechanism is made possible by an intra-adrenal portal vascular system, which provides the medulla with uniquely high concentrations of glucocorticoids. These high concentrations are needed to induce the medullary enzyme, phenylethanolamine-N-methyltransferase (PNMT), which controls the synthesis of epinephrine from norepinephrine. By suppressing glucocorticoid secretion, pituitary failure compromises epinephrine synthesis and decreases the rate at which epinephrine is secreted; in contrast, prolonged chronic stress can enhance epinephrine synthesis and secretion within the adrenal, the brain, or both organs. This control mechanism could be involved in the long-term consequences of stress.

Adrenal Cortex↗