Browsing by Author "Wurtman, Richard J."
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Item Caffeine potentiates the enhancement by choline of striatal acetylcholine release(Pergamon-Elsevier Science, 1992) Johnson, David A.; Wurtman, Richard J.; Ulus, İsmail Hakkı; Uludağ Üniversitesi/Tıp Fakültesi/Farmakoloji Anabilim Dalı.; D-5340-2015We investigated the effect of peripherally administered caffeine (50 mg/kg), choline (30, 60, or 120 mg/kg) or combinations of both drugs on the spontaneous release of acetylcholine (ACh) from the corpus striatum of anesthetized rats using in vivo microdialysis. Caffeine alone or choline in the 30 or 60 mg/kg dose failed to increase ACh in microdialysis samples; the 120 mg/kg choline dose significantly enhanced ACh during the 80 min following drug administration. Coadministration of caffeine with choline significantly increased ACh release after each of the choline doses tested. Peak microdialysate levels with the 120 mg/kg dose were increased 112% when caffeine was additionally administered, as compared with 54% without caffeine. These results indicate that choline administration can enhance spontaneous ACh release from neurons, and that caffeine, a drug known to block adenosine receptors on these neurons, can amplify the choline effect.Item Characterization of phentermine and related compounds as monoamine oxidase (MAO) inhibitors(Pergamon-Elsevier Science Ltd, 2000-06-15) Maher, Timothy J.; Wurtman, Richard J.; Ulus, İsmail H.; Uludağ Üniversitesi/Tıp Fakültesi/Farmakoloji ve Klinik Farmakolojisi Bölümü.; D-5340-2015Phentermine was shown in the 1970s to inhibit the metabolism of serotonin by monoamine oxidase (MAO), but never was labeled as an MAO inhibitor; hence, it was widely used in combination with fenfluramine, and continues to be used, in violation of their labels, with other serotonin uptake blockers. We examined the effects of phentermine and several other unlabeled MAO inhibitors on MAO activities in rat lung, brain, and liver, and also the interactions of such drugs when administered together. Rat tissues were assayed for MAO-A and -B, using serotonin and beta-phenylethylamine as substrates. Phentermine inhibited serotonin-metabolizing (MAO-A activity in all three tissues with K-i values of 85-88 mu M. These potencies were similar to those of the antidepressant MAO inhibitors iproniazid and moclobemide. When phentermine was mixed with other unlabeled reversible MAO inhibitors (e.g. pseudoephedrine, ephedrine, norephedrine; estradiol benzoate), the degree of MAO inhibition was additive. The cardiac valvular lesions and primary pulmonary hypertension that have been reported to be associated with fenfluramine-phentermine use may have resulted from the intermittent concurrent blockage of both serotonin uptake and metabolism.Item Choline increases acetylcholine release and protects against the stimulation-induced decrease in phosphatide levels within membranes of rat corpus striatum(Elsevier, 1988-04-10) Wurtman, Richard J.; Mauron, Charlotte; Blusztajn, Jan Krzysztof; Ulus, İsmail Hakkı; Uludağ Üniversitesi/Tıp Fakültesi/Farmakoloji Anabilim Dalı.; 0000-0001-8438-3122; D-5340-2015This study examined the possibility that membrane phospholipids might be a source of choline used for acetylcholine (ACh) synthesis. Slices of rat striatum or cerebellum were superfused with a choline-free or choline-containing (10, 20 or 40 μM) physiological solution with eserine, for alternating 20 min periods of rest or electrical stimulation. Superfusion media were assayed for choline and ACh, and slice samples taken before and after stimulation were assayed for choline, ACh, various phospholipids, protein and DNA. The striatal slices were able to sustain the stimulation-induced release of ACh, releasing a total of about 3 times their initial ACh contents during the 8 periods of stimulation and rest. During these 8 cycles, 885 pmol/μg DNA free choline was released from the slices into the medium, an amount about 45-fold higher than the initial or final free choline levels in the slices. Although repeated stimulation of the striatal slices failed to affect tissue levels of free choline or ACh, this treatment did cause significant, dose-related (i.e., number of stimulation periods) stoichiometric decreases in tissue levels of phosphatidylcholine (PC) and of the other major phospholipids; tissue protein levels also declined significantly. Addition of exogenous choline to the superfusion medium produced dose-related increases in resting and evoked ACh release. The choline also fully protected the striatal slices from phospholipid depletion for as many as 6 stimulation periods. Cerebellar slices liberated large amounts of free choline into the medium but did not release measurable quantities of ACh; their phospholipid and protein levels did not decline with electrical stimulation. These data show that membrane phospholipids constitute a reservoir of free choline that can be used for ACh synthesis. When free choline is in short supply, ACh synthesis and release are sustained at the expense of this reservoir. The consequent reduction in membrane PC apparently is associated with a depletion of cellular membrane. The use of free choline by cholinergic neurons for two purposes, the syntheses of both ACh and membrane phospholipids, may thus impart vulnerability to them in situations where the supply of free choline is less than that needed for acetylation.Item Cytidine and uridine increase striatal CDP-choline levels without decreasing acetylcholine synthesis or release(Springer/Plenum Publishers, 2006) Watkins, Carol J.; Wurtman, Richard J.; Ulus, İsmail Hakkı; Cansev, Mehmet; Uludağ Üniversitesi/Tıp Fakültesi/Farmakoloji ve Klinik Farmakoloji Anabilim Dalı.; 0000-0003-2918-5064; M-9071-2019; D-5340-2015; 7004271086; 8872816100Aims: Treatments that increase acetylcholine release from brain slices decrease the synthesis of phosphatidylcholine by, and its levels in, the slices. We examined whether adding cytidine or uridine to the slice medium, which increases the utilization of choline to form phospholipids, also decreases acetylcholine levels and release. Methods: We incubated rat brain slices with or without cytidine or uridine (both 25400 mu M), and with or without choline (20-40 mu M), and measured the spontaneous and potassium-evoked release of acetylcholine. Results: Striatal slices stimulated for 2 h released 2650 +/- 365 pmol of acetylcholine per mg protein when incubated without choline, or 4600 +/- 450 pmol/mg protein acetylcholine when incubated with choline (20 mu M). Adding cytidine or uridine (both 25-400 mu M) to the media failed to affect acetylcholine release whether or not choline was also added, even though the pyrimidines (400 mu M) did enhance choline's utilization to form CDP-choline by 89 or 61%, respectively. The pyrimidines also had no effect on acetylcholine release from hippocampal and cortical slices. Cytidine or uridine also failed to affect acetylcholine levels in striatal slices, nor choline transport into striatal synaptosomes. Conclusion: These data show that cytidine and uridine can stimulate brain phosphatide synthesis without diminishing acetylcholine synthesis or release.Item Does phentermine inhibit monoamine oxidase? Reply(Elsevier, 1999-04-17) Maher, Timothy J.; Wurtman, Richard J.; Ulus, İsmail Hakkı; Uludağ Üniversitesi/Tıp Fakültesi/Farmakoloji Anabilim Dalı.; D-5340-2015; 7004271086Item Evidence for the existence of pyrimidinergic transmission in rat brain(Pergamon-Elsevier Science, 2015-04) Ulus, İsmail H.; Wurtman, Richard J.; Cansev, Mehmet; Orhan, Fulya; Yaylagül, Esra O.; Işık, Esra; Türkyılmaz, Mesut; Aydın, Sami; Gümüş, Abdullah; Sevinç, Cansu; Coşkun, Necdet; Uludağ Üniversitesi/Tıp Fakültesi/Tıbbi Farmakoloji Anabilim Dalı.; Uludağ Üniversitesi/Fen Edebiyat Fakültesi/Biyoloji Bölümü.; Uludağ Üniversitesi/Fen Edebiyat Fakültesi/Kimya Bölümü.; Uludağ Üniversitesi/Tıp Fakültesi.; 0000-0002-5206-1185; 0000-0002-4101-8448; M-9071-2019; FRQ-5179-2022; GWJ-0755-2022; EBA-0754-2022; HUU-9736-2023; AAL-1786-2020; B-1200-2012; ABH-4915-2020; CCT-7508-2022; 8872816100; 55866311800; 55618956600; 50761143600; 56320252500; 7005387015; 56473463900; 56473593500; 7004177880The uridine nucleotides uridine-5'-triphosphate (UTP) and uridine-5'-diphosphate (UDP) have previously been identified in media from cultured cells. However, no study to date has demonstrated their presence in brain extracellular fluid (ECF) obtained in vivo. Using a novel method, we now show that UTP and UDP, as well as uridine, are detectable in dialysates of striatal ECF obtained from freely-moving rats. Intraperitoneal (i.p.) administration of uridine or exposure of striatum to depolarizing concentrations of potassium chloride increases extracellular uridine, UTP and UDP, while tetrodotoxin (TTX) decreases their ECF levels. Uridine administration also enhances cholinergic neurotransmission which is accompanied by enhanced brain levels of diacylglycerol (DAG) and inositol trisphosphate (IP3) and blocked by suramin, but not by PPADS (pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid) or MRS2578 suggesting a possible mediation of P2Y2 receptors activated by UTP. These observations suggest that uridine, UTP and UDP may function as pyrimidinergic neurotransmitters, and that enhancement of such neurotransmission underlies pharmacologic effects of exogenous uridine on the brain.Item Exogenous cytidine-5'-diphosphocholine increases brain cytidine-5'-diphosphocholine levels in gerbils(Wiley, 2005-08) Wurtman, Richard J.; Cansev, Mehmet; Uludağ Üniversitesi/Tıp Fakültesi.; M-9071-2019Item Giving uridine and/or docosahexaenoic acid orally to rat dams during gestation and nursing increases synaptic elements in brains of weanling pups(Karger, 2009-04) Marzloff, George; Sakamoto, Toshimasa; Wurtman, Richard J.; Cansev, Mehmet; Ulus, İsmail Hakkı; Uludağ Üniversitesi/Tıp Fakültesi/Farmakoloji ve Klinik Farmakoloji Anabilim Dalı.; 8872816100; 7004271086Developing neurons synthesize substantial quantities of membrane phospholipids in producing new synapses. We investigated the effects of maternal uridine (as uridine-5′-monophosphate) and docosahexaenoic acid supplementation on pups' brain phospholipids, synaptic proteins and dendritic spine densities. Dams consumed neither, 1 or both compounds for 10 days before parturition and 20 days while nursing. By day 21, brains of weanlings receiving both exhibited significant increases in membrane phosphatides, various pre- and postsynaptic proteins (synapsin-1, mGluR1, PSD-95), and in hippocampal dendritic spine densities. Administering these phosphatide precursors to lactating mothers or infants could be useful for treating developmental disorders characterized by deficient synapses.Item Nutritional modifiers of aging brain function: Use of uridine and other phosphatide precursors to increase formation of brain synapses(Oxford University Press, 2010-12) Wurtman, Richard J.; Sakamoto, Toshimasa; Ulus, İsmael; Cansev, Mehmet; Uludağ Üniversitesi/Tıp Fakültesi/Tıbbi Farmakoloji Anabilim Dalı.; 0000-0003-2918-5064; M-9071-2019; 8872816100Brain phosphatide synthesis requires three circulating compounds: docosahexaenoic acid (DHA), uridine, and choline. Oral administration of these phosphatide precursors to experimental animals increases the levels of phosphatides and synaptic proteins in the brain and per brain cell as well as the numbers of dendritic spines on hippocampal neurons. Arachidonic acid fails to reproduce these effects of DHA. If similar increases occur in human brain, administration of these compounds to patients with diseases that cause loss of brain synapses, such as Alzheimer's disease, could be beneficial.Item Oral uridine-5 '-monophosphate (UMP) increases brain CDP-choline levels in gerbils(Elsevier Science BV, 2005-10-05) Watkins, Carol J.; Beek, Eline M.van der; Wurtman, Richard J.; Cansev, Mehmet; Uludağ Üniversitesi/Tıp Fakültesi/Farmakoloji ve Klinik Farmakoloji Anabilim Dalı.; 0000-0003-2918-5064; M-9071-2019We examined the biochemical pathways whereby oral uridine-5'-monophosphate (UMP) increases membrane phosphatide synthesis in brains of gerbils. We previously showed that supplementing PC12 cells with uridine caused concentration-related increases in CDP-choline levels, and that this effect was mediated by elevations in intracellular uridine triphosphate (UTP) and cytidine triphosphate (CTP). In the present study, adult gerbils received UMP (1 mmol/kg), a constituent of human breast milk and infant formulas, by gavage, and plasma samples and brains were collected for assay between 5 min and 8 It thereafter. Thirty minutes after gavage, plasma uridine levels were increased from 6.6 +/- 0.58 to 32.7 +/- 1.85 pM (P < 0.001), and brain uridine from 22.6 +/- 2.9 to 89.1 +/- 8.82 pmol/mg tissue (P < 0.001). UMP also significantly increased plasma and brain cytidine levels; however, both basally and following UMP, these levels were much lower than those of uridine. Brain UTP, CTP, and CDP-choline were all elevated 15 min after UMP (from 254 +/- 31.9 to 417 +/- 50.2, [ P < 0.05]; 56.8 +/- 1.8 to 71.7 +/- 1.8, [P < 0.001]; and 11.3 +/- 0.5 to 16.4 1, [P < 0.001] pmol/rng tissue, respectively), returning to basal levels after 20 and 30 min. The smallest UMP dose that significantly increased brain CDP-choline was 0.05 inmol/kg. These results show that oral UMP, a uridine source, enhances the synthesis of CDP-choline, the immediate precursor of PC, in gerbil brain. (c) 2005 Elsevier B.V All rights reserved.Item Phentermine and other monoamine-oxidase inhibitors may increase plasma serotonin when given with fenfluramines(Lancet, 1999-01-02) Maher, Timothy J.; Wurtman, Richard J.; Ulus, İsmail Hakkı; Uludağ Üniversitesi/Tıp Fakültesi/Farmakoloji Anabilim Dalı.; D-5340-2015Item Stimulation of CDP-choline synthesis by uridine or cytidine in PC12 rat pheochromocytoma cells(Elsevier, 2003-05-09) Richardson, U.Ingrid; Watkins, Carol J.; Pierre, Celine; Wurtman, Richard J.; Ulus, İsmail Hakkı; Uludağ Üniversitesi/Tıp Fakültesi/Tıbbi Farmakoloji Anabilim Dalı.; D-5340-2015; 7004271086Oral 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 muM) 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.Item Synaptic proteins and phospholipids are increased in gerbil brain by administering uridine plus docosahexaenoic acid orally(Elsevier Science, 2006-05-09) Wurtman, Richard J.; Watkins, Carol J.; Wang, Lei; Marzloff, George; Ulus, İsmail Hakkı; Cansev, Mehmet; Uludağ Üniversitesi/Tıp Fakültesi/Farmakoloji Anabilim Dalı.; 0000-0003-2918-5064; D-5340-2015; 7004271086; 8872816100The synthesis of brain phosphatidy1choline may utilize three circulating precursors: choline; a pyrimidine (e.g., uridine, converted via UTP to brain CTP); and a PUFA (e.g., docosahexaenoic acid); phosphatidylethanolamine may utilize two of these, a pyrimidine and a PUFA. We observe that consuming these precursors can substantially increase membrane phosphatide and synaptic protein levels in gerbil brains. (Pyrimidine metabolism in gerbils, but not rats, resembles that in humans.) Animals received, daily for 4 weeks, a diet containing choline chloride and UMP (a uridine source) and/or DHA by gavage. Brain phosphatidy1choline rose by 13-22% with uridine and choline alone, or DHA alone, or by 45% with the combination, phosphatidylethanolamine and the other phosphatides increasing by 39-74%. Smaller elevations occurred after 1-3 weeks. The combination also increased the vesicular protein Synapsin-1 by 41%, the postsynaptic protein PSD-95 by 38% and the neurite neurofibrillar proteins NF-70 and NF-M by up to 102% and 48%, respectively. However, it had no effect on the cytoskeletal protein beta-tubulin. Hence, the quantity of synaptic membrane probably increased. The precursors act by enhancing the substrate saturation of enzymes that initiate their incorporation into phosphatidylcholine and phosphatidylethanolamine and by UTP-mediated activation of P2Y receptors. Alzheimer's disease brains contain fewer and smaller synapses and reduced levels of synaptic proteins, membrane phosphatides, choline and DHA. The three phosphatide precursors might thus be useful in treating this disease..Item Use of phosphatide precursors to promote synaptogenesis(Annual Reviews, 2009) Wurtman, Richard J.; Sakamoto, Toshimasa; Cansev, Mehmet; Ulus, İsmail Hakkı; Uludağ Üniversitesi/Tıp Fakültesi.; 0000-0003-2918-5064; D-5340-2015; M-9071-2019; 8872816100; 7004271086New brain synapses form when a postsynaptic structure, the dendritic spine, interacts with a presynaptic terminal. Brain synapses and dendritic spines, membrane-rich structures, are depleted in Alzheimer's disease,as are some circulating compounds needed for synthesizing phosphatides, the major constituents of synaptic membranes. Animals given three of these compounds, all nutrients-uridine, the omega-3 polyunsaturated fatty acid docosahexaenoic acid, and choline-develop increased levels of brain phosphatides and of proteins that are concentrated within synaptic membranes (e.g., PSD-95, synapsin-1), improved cognition, and enhanced neurotransmitter release. The nutrients work by increasing the substrate-saturation of low-affinity enzymes that synthesize the phosphatides. Moreover, uridine and its nucleotide metabolites activate brain P2Y receptors, which control neuronal differentiation and synaptic protein synthesis. A preparation containing these compounds is being tested for treating Alzheimer's disease.