Biomedical subjects

P Cumming

Publications and source records attributed to P Cumming.

65 records · Page 4Linked to original sources

PubMed1991

Interstitial 3-methoxytyramine reflects striatal dopamine release: an in vivo microdialysis study.

Previous ex vivo studies have provided indirect evidence that the dopamine (DA) metabolite 3-methoxytyramine (3-MT) may be a useful index of DA release in vivo. In the present study, in vivo microdialysis was utilized to assess directly the relationship between extracellular DA and 3-MT in the striatum of rats following a variety of pharmacological manipulations. Apomorphine, a DA receptor agonist, produced a rapid, transient decrease in both DA and 3-MT. Conversely, the DA receptor antagonist haloperidol produced a concomitant increase in extracellular DA and 3-MT. Increases in DA and 3-MT were also noted following the administration of the DA uptake inhibitor, bupropion. Local application of tetrodotoxin resulted in the complete elimination of measurable amounts of DA and 3-MT in the dialysate, gamma-Butyrolactone also greatly decreased DA and 3-MT. Finally, d-amphetamine produced a large increase in DA and 3-MT in animals that had been treated previously with gamma-butyrolactone. The Pearson correlation coefficients for DA and 3-MT following these manipulations ranged from 0.87 to 0.97. These data indicate that interstitial 3-MT is an accurate index of DA release. However, when compared with previous ex vivo findings, the present results also suggest that changes in tissue concentrations of 3-MT may not reliably reflect DA release following certain pharmacological manipulations.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1990

Inhibition of rat brain histamine-N-methyltransferase by 9-amino-1,2,3,4-tetrahydroacridine (THA).

9-Amino-1,2,3,4-tetrahydroacridine (THA), an inhibitor of acetylcholinesterase, has been proposed as a treatment for Alzheimer's disease on the basis of its ability to increase cerebral levels of acetylcholine. THA shares structural features with aminoquinoline compounds known to be inhibitors of histamine-N-methyltransferase (HNMT). THA was found to be a potent competitive inhibitor of rat brain HNMT in vitro, with a Ki of 35 nM with respect to both histamine and S-adenosyl-L-methionine, the co-substrate. Two hours after systemic administration of THA (5 and 10 mg/kg, i.p.), HNMT from rat brain was largely inhibited. The levels of histamine in striatum and cerebral cortex were elevated by this treatment. Thus, THA at moderate doses is able to alter histamine metabolism in the central nervous system.

4-Aminopyridine↗

PubMed1989

Cerebral histamine levels are unaffected by MPTP administration in the mouse.

The mechanism by which 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) depletes forebrain dopamine is not fully understood, but a necessary step involves the formation of neurotoxic MPP+ by monoamine oxidase type B (MAO-B). The histamine neurons in the brain contain MAO-B and are a possible site for the production of MPP+. Two weeks after MPTP injections (2 X 50 mg/kg i.p.) in C-57 mice, striatal dopamine was reduced by more than 70%. However, histamine levels in neocortex, hippocampus and hypothalamus were unaffected by this neurotoxic dose of MPTP. Thus, as in Parkinson's disease, central histaminergic systems appear to be spared in the MPTP model.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1988

Kinetics of in vitro decarboxylation and the in vivo metabolism of 2-18F- and 6-18F-fluorodopa in the hooded rat.

The metabolisms of L-18F-2-fluoro-DOPA (L-2-18F-DOPA) and L-18F-6-fluoro-DOPA (L-6-18F-DOPA) were compared in vitro and in vivo in the carbidopa-pretreated male hooded rat. In vivo, the sole metabolites in plasma were O-methylated derivatives. The peripheral formation of the O-methylated derivative of L-2-18F-DOPA was approximately twice as great as that for the 6-isomer. Animals were killed at 10 and 60 min after administration of the 18F-DOPAs, and samples of striatum and vermis were analyzed by HPLC. L-2-18F-DOPA passed less readily into brain than did L-6-18F-DOPA. Whereas significant amounts of 6-18F-fluorodopamine and metabolites were formed in the striatum, no decarboxylated derivatives of L-2-18F-DOPA were found. Determination of the Michaelis-Menten kinetic constants for aromatic amino acid decarboxylase AADC, EC 4.1.1.26) indicated that the Km for L-2-18F-DOPA (982 +/- 115 microM) was considerably higher than that for L-6-18F-DOPA (101 +/- 22 microM). The low substrate affinity for AADC and the relatively more rapid rate of O-methylation in the periphery account for the lack of formation of 2-18F-fluorodopamine in vivo. The ratio of total radioactivity between striatum and other brain regions is related to the decarboxylation of radiolabeled tracer and the relative persistence of the decarboxylated derivatives in the striatum. Since L-2-18F-DOPA is not decarboxylated in rat striatum, it is not a promising agent for the study of cerebral DOPA metabolism in humans by means of positron emission tomography.

Animals↗

PubMed1987

Altered metabolism of [18F]-6-fluorodopa in the hooded rat following inhibition of catechol-O-methyltransferase with U-0521.

[18F]-6-Fluoro-L-DOPA ([18F]DOPA), a tracer for cerebral dopamine in studies utilizing positron emission tomography (PET), is rapidly metabolized by catechol-O-methyltransferase (COMT) in the periphery following intravenous injection to carbidopa-pretreated humans and rats. Experiments were performed to determine the effect of pretreatment with 3',4'-dihydroxy-2-methyl-propiophenone (U-0521), a competitive inhibitor of COMT, on [18F]DOPA metabolism in the carbidopa-pretreated hooded rat. U-0521 (25 mg/kg, i.p.), administered 10 min prior to the [18F]DOPA, served to increase the persistence of [18F]DOPA in plasma over a 2-hr period by decreasing the rate of formation of the peripheral metabolite 3-O-methyl-6-fluorotyrosine (Me[18F]DOPA). This compound passes readily into brain and was the sole [18F]DOPA metabolite observed in cortex and cerebellum. U-0521 produced a short-lasting decrease in Me[18F]DOPA levels in these two tissues. In striatum, decreases in Me[18F]DOPA were found to last at least 90 min. Associated with the elevated availability of [18F]DOPA in plasma produced by U-0521 were 50% increases in striatal [18F]dopamine ([18F]DA) levels and 40% increases in the levels of [18F]dihydroxyphenylacetic acid ([18F]DOPAC) at times between 30 and 90 min following [18F]DOPA injection. Increased decarboxylation of [18F]DOPA in the striatum of U-0521-treated rats resulted in heightened radiocontrast between striatum and other cerebral tissues.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1987

Effects of MPTP poisoning on central somatostatin and substance P levels in the mouse.

The effects of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) on the levels of the neuropeptides somatostatin and substance P, were examined in various brain regions of C57 mice. Two weeks after injections of MPTP (2 X 30, 2 X 40 and 2 X 50 mg/kg i.p.) a dose-dependent decrease in striatal catecholamine levels was observed. There was also a dose-dependent increase in nigral somatostatin immunoreactivity and no reduction in striatonigral substance P levels. These results are in contrast with the changes observed in peptide levels in post-mortem Parkinson's brains.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1987

Toxicity of p-methoxyphenol to dopamine neurons in the rat substantia nigra.

Local injections of p-methoxyphenol into the substantia nigra of rats led to a mildly dose-related destruction of dopamine neurons as indicated by reductions of dopamine and its metabolites in the ipsilateral striatum and by loss of tyrosine hydroxylase immunoreactivity in the injected substantia nigra. Both Nissl staining of the injected nucleus and measurement of noradrenaline and serotonin in the ipsilateral striatum indicated some selectivity of the toxic action.

Animals↗

PubMed1987

The metabolism of [18F]6-fluoro-L-3,4-dihydroxyphenylalanine in the hooded rat.

The metabolism of the positron-emitting compound [18F]6-fluoro-L-3,4-dihydroxyphenylalanine (*F-DOPA) was studied in carbidopa-pretreated male hooded rats. Thirty minutes following carbidopa administration (5 mg/kg i.p.), animals received *F-DOPA (500 micrograms/kg; specific activity, 175-230 Ci/mol) as an intrajugular bolus. Blood samples were taken at various times between 5 and 90 min, and the plasma was analyzed by HPLC with gamma counting of fractions. *F-DOPA disappeared rapidly from plasma in concert with the formation of the 3-O-methylated metabolite, Me-*F-DOPA. Animals were killed from 5 to 120 min after injection, and the brains were rapidly dissected. The disappearance of *F-DOPA from both vermis and striatal samples was rapid. Me-*F-DOPA, the sole metabolite observed in the vermis, was the major labeled material in the striatum at greater than or equal to 20 min after injection. Fluorodopamine was an important metabolite in the striatum, making up 25% of total radioactivity at early intervals. Striatal samples also contained fluoro-3,4-dihydroxyphenylacetic acid, which constituted approximately 10% of the total radioactivity, and traces of two radiolabeled compounds, tentatively identified as fluorohomovanillic acid and fluoro-3-methoxytyramine.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1986

Determination of plasma [18F]-6-fluorodopa during positron emission tomography: elimination and metabolism in carbidopa treated subjects.

An investigation of the metabolism of [18F]-6-fluorodopa (FDOPA) given to carbidopa treated subjects for scanning by positron emission tomography (PET) has been carried out by analysis of plasma. Reverse phase ion pair HPLC and alumina extraction were employed to fractionate and identify the [18F]-labelled compounds of plasma over a two hour period. During this time, the plasma levels of both total 18F and FDOPA decreased as a bi-exponential function of time. The rates of 18F, but not FDOPA, elimination were observed to decrease with age. In addition to FDOPA, only one other major peak of radioactivity was resolved by HPLC. Identification of this compound as the O-methylated derivative of FDOPA (MeFDOPA) is based on its shared HPLC elution time with in vitro synthesized O-[methyl-14C]-FDOPA. The ratio of the concentration of MeFDOPA to FDOPA (MeFDOPA/FDOPA) in plasma increased linearly with time, and the slope of this linear relationship decreased with the age of the individual.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1986

Absence of adrenaline neurons in the guinea pig brain: a combined immunohistochemical and high-performance liquid chromatography study.

The distributions of catecholamine (CA) neurons in the medulla oblongata of the guinea pig and rat were compared using immunohistochemistry with rabbit antisera against the CA synthesizing enzymes, tyrosine hydroxylase (TH), dopamine-beta-hydroxylase (D beta H) and phenylethanolamine-N-methyltransferase (PNMT). TH and D beta H distributions were similar in the two species. In contrast, the central nervous systems of both normal and colchicine-treated guinea pigs failed to demonstrate immunoreactivity for PNMT, the synthetic enzyme for adrenaline. The concentrations of biogenic amines in the hypothalamus and medulla were determined in guinea pig and rat tissues by high-performance liquid chromatography with electrochemical detection. No adrenaline was detected in the guinea pig brain. Thus it appears that guinea pigs lack central neurons capable of synthesizing adrenaline.

Adrenergic Fibers↗

PubMedDate not supplied

The DaNeX study of embryonic mesencephalic, dopaminergic tissue grafted to a minipig model of Parkinson's disease: preliminary findings of effect of MPTP poisoning on striatal dopaminergic markers.

A multicenter study is under way to investigate the efficacy of allografting of embryonic mesencephalic neurons in a pig model of Parkinson's disease. We have first established that a stable parkinsonian syndrome can be established by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication of adult male Göttingen minipigs. We are now using positron emission tomography (PET) methods for testing the physiological responses to MPTP intoxication and the time course of the response to several treatment strategies. We now report preliminary results obtained in 11 pigs employed in the initial phase of the study; the completed study shall ultimately include 30 pigs. Animals were randomly assigned to one of five groups: 1) Control, 2) MPTP intoxication, 3) MPTP intoxication followed by allograft, 4) MPTP intoxication followed by allograft with immunosuppression, and 5) MPTP intoxication followed by allograft with immunosuppression and co-grafting of immortalized HiB5 cells, which had been manipulated to secrete glia cell line-derived neurotrophic factor (GDNF) (approximately 2 ng GDNF/h/10(5) cells). MPTP was administered (1 mg/kg/day, SC) for 7-10 days until the pigs had developed mild parkinsonian symptoms of muscle rigidity, hypokinesia, and impaired coordination, especially of the hind limbs. Approximately 2 weeks after the last MPTP dose, animals received a T1-weighted magnetic resonance imaging (MRI) scan, and a series of dynamic PET recordings. After the first series of PET scans, four grafts of porcine embryonic mesencephalic tissue (E28 days) were placed in each striatum of some MPTP-intoxicated pigs, using MRI-based stereotactic techniques. Immunosuppression of some animals with cyclosporin and prednisolone began just prior to surgery. Two more series of PET scans were performed at 4-month intervals after surgery. After the last scans, pigs were killed and the brains were perfused for unbiased stereological examination of cytological and histochemical markers in striatum and substantial nigra. The behavioral impairment of the animals (the "Parkinson's score") had been evaluated throughout the 8-month period. Kinetic analysis of the first set of PET scans has indicated that the rate constant for the decarboxylation of FDOPA in catecholamine fibers was reduced by 33% in striatum of the mildly parkinsonian pigs. The rate of association of [11C]NS-2214 to catecholamine uptake sites was reduced by 62% in the same groups of pigs. No significant difference was found in the binding potential of [11C]raclopride to the dopamine D2-like receptors in striatum of the MPTP-intoxicated versus control pigs. These preliminary results are suggestive that the activity of DOPA decarboxylase may be upregulated in the partially denervated pig striatum.

Animals↗