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J C Stoof

Publications and source records attributed to J C Stoof.

At least 19 recordsLinked to original sources
PubMed1999

Leads for the development of neuroprotective treatment in Parkinson's disease and brain imaging methods for estimating treatment efficacy.

Patients suffering from Parkinson's disease display severe and progressive deficits in motor behavior, predominantly as a consequence of the degeneration of dopaminergic neurons, located in the mesencephalon and projecting to striatal regions. The cause of Parkinson's disease is still an enigma. Consequently, the pharmacotherapy of Parkinson's disease consists of symptomatic treatment, with in particular L-dihydroxyphenylalanine (L-DOPA) and/or dopamine receptor agonists. These induce a dramatic initial improvement. However, serious problems gradually develop during long-term treatment. Therefore, a more rational, c.q. causal treatment is needed which requires the introduction of compounds ameliorating the disease process itself. The development of such compounds necessitates (1) more information on the etiopathogenesis, i.e., the cascade of events that ultimately leads to degeneration of the dopaminergic neurons, and (2) brain imaging methods, to estimate the extent of the degeneration of the dopaminergic neurons in the living patient. This is not only important for the early diagnosis, but will also allow to monitor the effectiveness of alleged neuroprotective compounds on a longitudinal base. In this paper, etiopathogenic mechanisms are highlighted along the line of the oxidative stress hypothesis and within this framework, attention is mainly focused on the putative role of glutathione, dopamine auto-oxidation and phase II biotransformation enzymes. Especially, drugs able to increase the activity of phase II biotransformation enzymes seem to elicit a broad-spectrum (neuro)protective response and look very promising leads for the development of neuroprotective treatment strategies in Parkinson's disease. New developments in brain imaging methods (single photon emission computed tomography (SPECT) and positron emission tomography (PET)) to visualize the integrity of the striatal dopaminergic neurons in humans are highlighted as well. Especially, the introduction of radioligands that bind selectively to the dopamine transporter seems to be a significant step forward for the early diagnosis of Parkinson's disease. Performing these brain imaging studies with fixed time intervals does not only create the possibility to follow the degeneration rate of the dopaminergic neurons in Parkinson's disease but also provides the opportunity to estimate therapeutic effects of putative neuroprotective agents in the individual patient.

Brain↗
PubMed1999

The alleged dopamine D1 receptor agonist SKF 83959 is a dopamine D1 receptor antagonist in primate cells and interacts with other receptors.

So far, no clear correlation has been found between the effects of dopamine D1 receptor agonists on motor behavior in primate models of Parkinson's disease and their ability to stimulate adenylate cyclase in rats, the benzazepine SKF 83959 (3-methyl-6-chloro-7,8-hydroxy-1-[3-methylphenyl]-2,3,4,5-tetrahydro-]H- 3-benzazepine) being the most striking example. Since this discrepancy might be attributed to: (A) the different species used to study these effects or (B) the interaction of SKF 83959 with other catecholamine receptors, the aims of this study were: (1) to study the ability of SKF 83959 to stimulate adenylate cyclase in cultured human and monkey glial cells equipped with dopamine D1 receptors and (2) to evaluate the affinity for and the functional interaction of SKF 83959 with other catecholamine receptors. Binding studies revealed that SKF 83959 displayed the highest affinity for the dopamine D1 receptor (pKi=6.72) and the alpha2-adrenoceptor (pKi=6.41) and moderate affinity for the dopamine D2 receptor and the noradrenaline transporter. In monkey and human cells, SKF 83959 did not stimulate cyclic adenosine monophosphate (cAMP) formation to a significant extent, but antagonized very potently the dopamine-induced stimulation of cAMP formation in both cell types. The compound stimulated basal dopamine outflow and inhibited depolarization-induced acetylcholine release only at concentrations > 10 microM. Finally, SKF 83959 concentration dependently increased electrically evoked noradrenaline release, indicating that it had alpha2-adrenoceptor blocking activity and interfered with the noradrenaline transporter. In conclusion, SKF 83959 is a potent dopamine D1 receptor and alpha2-adrenoceptor antagonist. Thus, the anti-parkinsonian effects of SKF 83959 in primates are not mediated by striatal dopamine D1 receptors coupled to adenylate cyclase in a stimulatory way.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1999

Comparative in vivo study of iodine-123-labeled beta-CIT and nor-beta-CIT binding to serotonin transporters in rat brain.

Both iodine-123-labeled beta-CIT (2beta-carbomethoxy-3beta-(4-iodophenyl)tropane) and nor-beta-CIT (2beta-carbomethoxy-3beta-(4-iodophenyl)nortropane) have shown to be suitable radioligands for imaging serotonin (5-HT) transporters. [(123)I]nor-beta-CIT has the highest in vitro affinity for 5-HT transporters among beta-CIT analogs reported so far. However, no direct comparison-studies of these two radiotracers as to their in vivo binding to 5-HT transporters have been reported so far. Therefore, it is still unclear which of the two radiotracers is more suitable for single photon emission computed tomography (SPECT) imaging of 5-HT transporters. The purpose of this study was to compare directly in a controlled design the in vivo [(123)I]beta-CIT and [(123)I]nor-beta-CIT binding to 5-HT transporters under the same conditions in rats with the focus on brain kinetic characteristics by means of a two-compartment analysis. We observed that [(123)I]beta-CIT has a higher binding potential and faster kinetics for 5-HT transporters than [(123)I]nor-beta-CIT, suggesting that [(123)I]beta-CIT may be a more suitable radioligand than [(123)I]nor-beta-CIT for imaging 5-HT transporters with SPECT.

Animals↗
PubMed1999

Sub-chronic administration of the dopamine D(1) antagonist SKF 83959 in bilaterally MPTP-treated rhesus monkeys: stable therapeutic effects and wearing-off dyskinesia.

RATIONALE: SKF 83959 acts as a D(1) antagonist in vitro but has been claimed to induce anti-parkinsonian effects after acute administration in MPTP-treated marmosets. OBJECTIVE: The aim of the present study was to evaluate the therapeutic and undesired effects of sub-chronic administration of SKF 83959 in bilaterally MPTP-treated rhesus monkeys and to compare these effects with the effects of l-dopa and the dopamine agonist SKF 82958. METHODS: MPTP was given in the left carotid artery (2.5 mg) and 6 weeks later, the right carotid artery (1.25 mg). The monkeys (n = 4) had previously been treated chronically with l-dopa (22 days, 10 mg/kg) and SKF 82958 (22 days, 1 mg/kg). Three months after the last administration of SKF 82958, SKF 83959 was given in a dose of 0.5 mg/kg from day 1 to day 15 and in a dose of 1.0 mg/kg from day 16 to day 18. RESULTS: SKF 83959 increased goal-directed limb movements in all animals, including those unresponsive to l-dopa. This therapeutic effect did not diminish during treatment. With respect to body displacement and undesired effects, a large variation in the response to SKF 83959 was found: a large increase in body displacement co-occurred with oro-facial dyskinesia (n = 2), whereas a small increase in body displacement co-occurred with dystonia (n = 2). In contrast to the undesired effects of l-dopa, the dyskinetic effects of SKF 83959 were primarily limited to the first treatment day. Unlike l-dopa and SKF 82958, SKF 83959 did not induce epileptoid behaviour. CONCLUSION: Sub-chronic administration of SKF 83959 induced both clear-cut therapeutic effects that remained stable in time, and a limited number of dyskinetic effects that wore off during the treatment. The dopamine D(1) antagonist SKF 83959 may be considered as an alternative treatment in Parkinson's disease, especially in those patients who do not respond to L-dopa.

Animals↗
PubMed1999

The validity of the pretreated, unilaterally MPTP-treated monkeys as a model of Parkinson's disease: a detailed behavioural analysis of the therapeutic and undesired effects of the D2 agonist quinpirole and the D1 agonist SKF 81297.

The goal of this study was to evaluate the validity of the pretreated, unilaterally MPTP-treated monkey as an animal model of Parkinson's disease (PD). For that purpose, a detailed ethogram was developed and assessed in four male rhesus monkeys that had received MPTP (2.5 mg) in the carotid artery contralateral to the dominant limb. Subsequently, the behavioural effects of the dopamine D2 agonist quinpirole and the dopamine D1 agonist SKF 81297 were studied. The ethogram was found to allow a clear-cut and objective separation of drug-induced behaviours into therapeutic and undesired effects in the MPTP-treated monkeys. Saline-treated monkeys predominantly displayed ipsilateral goal-directed fore-limb movements, and distinct types of ipsilaterally directed rotations. Although quinpirole and SKF 81297 increased motor behaviours, such as body displacement, contralateral fore-limb movements and contralateral rotational behaviours, assessment of the new detailed ethogram revealed that this increase was completely due to the activation of abnormal, non-goal-directed behaviours, such as dyskinetic fore-limb movements, pivoting and shuffling. Moreover, the new ethogram made clear that the drug treatments induced not only dyskinesia and dystonia, but also epileptoid behaviour, which was confirmed by EEG analysis. In summary, the detailed behavioural analysis showed that this model does not adequately predict the clinical effects of the D2 agonist. It is concluded that the pretreated, unilaterally MPTP-treated monkey is not a valid model to predict the therapeutic and undesired effects of dopaminergic drugs in humans.

Animals↗
PubMed1999

The predictive validity of the drug-naive bilaterally MPTP-treated monkey as a model of Parkinson's disease: effects of L-DOPA and the D1 agonist SKF 82958.

The aim of this study was twofold: (1) to study the predictive validity of the drug-naive, bilaterally MPTP-treated monkey as an animal model of Parkinson's disease (PD), and (2) to investigate the therapeutic and undesired effects of the D1 agonist SKF 82958 as compared to L-DOPA treatment, in drug-naive and L-DOPA pretreated monkeys. A detailed ethogram was used, allowing the separation of therapeutic and undesired effects. Eight weeks after bilateral intracarotid MPTP administration, SKF 82958 (1 mg/kg, n = 4, SKF 82958, naive group) or methyl-L-DOPA + carbi-dopa (10 + 2.5 mg/kg, n = 4, L-DOPA group) was administered intramuscularly for 22 days. After a drug-free period of eight weeks, the L-DOPA group was treated with SKF 82958 for 22 days (SKF 82959, 1 mg/kg, n=4, pretreated). All drug treatments increased the parameters used classically to evaluate dopaminergic drugs, namely body displacement, dyskinesia and dystonia. However, the new detailed analysis revealed that L-DOPA, but not SKF 82958, had therapeutic effects, reflected by an increase in goal-directed fore-limb use. SKF 82958, but not L-DOPA, induced additional undesired effects; including epileptoid behaviours in both drug-naive and drug-pretreated monkeys. In one L-DOPA-unresponsive monkey, SKF 82958 did induce minor therapeutic effects, as well as undesired effects. Although the effects of SKF 82958 on fore-limb movements, rotational behaviours and body displacement were comparable in the naive and pretreated group, SKF 82958 re-initiated undesired effects in the L-DOPA pretreated group from day one. It is concluded that the bilaterally MPTP-treated monkey is an animal model with predictive validity for PD: it adequately predicts the therapeutic effects and undesired effects of L-DOPA. Furthermore, it is concluded that SKF 82958 is less effective than L-DOPA in the treatment of PD, because it did not induce therapeutic effects, but instead elicited several undesired effects.

Animals↗
PubMed1998

Priming with L-DOPA differently affects dynorphin and substance P mRNA levels in the striatum of 6-hydroxydopamine-lesioned rats after challenge with dopamine D1-receptor agonist.

In unilaterally 6-hydroxydopamine-lesioned rats, potentiation of D1-agonist-induced turning behavior by priming with l-DOPA was correlated with changes in striatal neuropeptide mRNA levels. In non-primed rats, administration of the D1-agonist SKF-38393 markedly increased dynorphin and substance P mRNA levels in the lesioned striatum. Priming with l-DOPA dissociated the response of the two neuropeptides to the D1-agonist, with higher dynorphin and reduced substance P mRNA levels.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1998

Astrocyte-enhanced neuronal survival is mediated by scavenging of extracellular reactive oxygen species.

The survival of cultured neurons is promoted by the presence of antioxidants or astrocytes. This indicates that extracellular reactive oxygen species (ROS) impair neuronal survival and suggests that astrocytes exert their survival-enhancing effect through inactivation of these toxicants. However, to our knowledge, data supporting this hypothesis are lacking. Previously, we showed that loss of the antioxidant glutathione abolishes the neuronal survival-stimulating action of astrocytes in cocultures, consisting of rat striatal astrocytes and mesencephalic, dopaminergic neurons. Using uptake of [3H]dopamine as marker of neuronal survival, we presently investigated whether this effect of glutathione depletion is mediated by extracellular ROS. For this purpose, we incubated glutathione-depleted cocultures with superoxide dismutase, catalase or both. Whereas superoxide dismutase had no effect and catalase only partially protected, addition of the enzymes together completely prevented the impairment of neuronal survival caused by glutathione loss. No change in neuronal survival occurred upon exposure of control cocultures to superoxide dismutase and/or catalase. These data strongly implicate scavenging of extracellular ROS in astrocyte-stimulated neuronal survival and moreover suggest a crucial role for glutathione in this process.

Animals↗
PubMed1998

Drug-naive patients with Parkinson's disease in Hoehn and Yahr stages I and II show a bilateral decrease in striatal dopamine transporters as revealed by [123I]beta-CIT SPECT.

Ten healthy subjects and 16 patients with early Parkinson's disease (PD) were examined with single photon emission computed tomography (SPECT) and [123I]beta-CIT, a ligand for the dopamine (DA) transporter. Only drug-naive patients were examined since the expression of and binding to DA transporters may be influenced by dopaminergic medication. The main finding was a significant reduction in [123I]beta-CIT binding in the ipsi- and contralateral striatal regions, especially in the putamen, which showed a mean reduction of 65% of the control mean. Discriminant function analysis of the putaminal [123I]beta-CIT binding measures classified 100% of the cases in the correct group. Disease severity correlated negatively and highly significantly with the binding measures. Tremor ratings did not correlate with the SPECT measures, whereas rigidity, and to a lesser extent bradykinesia, did. Patients with unilateral PD showed a bilateral loss of striatal DA transporters. Our findings indicate that with [123I]beta-CIT SPECT it is possible to diagnose PD in subjects with very mild symptoms and signs. Moreover, finding a bilateral loss of striatal DA transporters in patients with unilateral PD also suggests that it may be possible to identify subjects in the preclinical phase of the disease.

Adult↗
PubMed1998

Iodine-123-N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-iod ophenyl)tropane SPECT in healthy controls and early-stage, drug-naive Parkinson's disease.

UNLABELLED: The aims of this study were to investigate whether the loss of striatal dopamine transporters in early and drug-naive patients with Parkinson's disease could be demonstrated by means of 123I-N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodoph enyl)tropane (123I-FP-CIT) SPECT in a 1-day protocol and whether the SPECT measures were correlated with disease severity. METHODS: Twenty-one early-stage and drug-naive Parkinson's disease patients (age range 42-73 yr; mean age 55.5 yr) and 14 healthy controls (age range 28-83 yr; mean age 53.6 yr) were examined. SPECT image acquisition was always performed at 3 hr postinjection. The ratio of specific to nonspecific striatal 123I-FP-CIT binding was used as the outcome measure. RESULTS: All striatal 123I-FP-CIT ratios were significantly lower in the Parkinson's disease group compared to those in the control group. The mean reduction in the putamen was 57% of the control mean, and that in the caudate nucleus was 29% of the control mean. Patients with unilateral Parkinson's disease showed a bilateral loss of striatal 123I-FP-CIT binding. Discriminant function analysis, using the 123I-FP-CIT SPECT data of the ipsilateral and contralateral putamen, predicted group membership in all cases; the contralateral putamen accounted for the greatest difference between the Parkinson's disease patients and the controls. In the control group, a clear decline in 123I-FP-CIT binding was found with aging, amounting to 9.6%/decade. Unexpectedly, in the Parkinson's disease group, regression analysis revealed that neither severity of disease nor age accounted for a significant part of the variance in striatal SPECT measures. CONCLUSION: Our findings indicate that 123I-FP-CIT SPECT is a reliable method to discriminate between early, drug-naive Parkinson's disease patients and healthy controls and to identify patients in the preclinical phase of Parkinson's disease. Possibly due to the relatively homogeneous group of Parkinson's disease patients and the use of a suboptimal outcome measure, no significant correlations were found between striatal 123I-FP-CIT binding ratios and disease severity, such as were established earlier with 123I-beta-CIT. Further research is necessary to interpret these findings.

Adult↗
PubMed1998

Imaging of dopamine transporters with iodine-123-FP-CIT SPECT in healthy controls and patients with Parkinson's disease.

UNLABELLED: Several SPECT studies reported decreased striatal 123I-N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodoph enyl)nortropane ([123I]FP-CIT) binding in patients with Parkinson's disease. For application in routine clinical studies, information on the reliability and reproducibility of the [123I]FP-CIT SPECT technique is critical. This study reports on the reliability and reproducibility of [I23I]FP-CIT SPECT in healthy control subjects and patients with Parkinson's disease using two different analysis protocols: the conventional region of interest (ROI) protocol and a newly developed, fully automatic, operator-independent volume of interest (VOI) protocol. METHODS: We performed repeated [123I]FP-CIT SPECT scans in 6 healthy control subjects and 10 patients with Parkinson's disease to measure scan-to-scan variations. Scintigraphic data were analyzed 3 hr after injection of the radiotracer. RESULTS: In controls, the mean test/retest for the ratio of the striatal-to-nonspecific [123I]FP-CIT uptake were (3.79 +/- 0.67/3.82 +/- 0.74) and (4.16 +/- 0.70/4.08 +/- 0.97) for the ROI and VOI technique, respectively. No significant differences were measured between test/retest studies. The mean test/retest variability for the ROI technique was low (7.25%) with excellent reliability (rho = 0.99). In addition, the mean test/retest variability for the VOI technique was also low (7.47%) with very high reliability (rho = 0.95). In Parkinson's disease patients, we found mean test/retest for the striatal-to-nonspecific [123I]FP-CIT ratio of (1.78 +/- 0.23/1.79 +/- 0.25) and (1.83 +/- 0.31/1.85 +/- 0.35) using the ROI and VOI technique, respectively. Also in patients, these results did not differ significantly between test/retest studies. The mean test/retest variability for the ROI technique was low (7.90%) with excellent reliability (rho = 1.00). In addition, the mean test/retest variability for the VOI technique was also low (7.36%) with high reliability (rho = 0.96). CONCLUSION: Reliable and reproducible results were obtained with the ROI, as well as the VOI technique, for the analysis of striatal dopamine transporters with [123I]FP-CIT SPECT in healthy controls and Parkinson's disease patients. The use of an operator-independent method will be a great advantage in routine clinical studies.

Aged↗
PubMed1997

Vesamicol and some of its derivatives: questionable ligands for selectively labelling acetylcholine transporters in rat brain.

Presynaptic cholinergic markers could be used for estimating the integrity of the cholinergic systems in the human brain with brain imaging techniques such as Single-photon emission computed tomography (SPECT). Vesamicol, an inhibitor of the vesicular acetylcholine transporter, and some of its derivatives have been suggested as potential ligands for this purpose. However, vesamicol binds not only to acetylcholine transporters but also to sigma binding sites. In the present study, we estimated the contribution of sigma site labelling to [3H](-)-vesamicol binding in different rat brain regions by selectively labelling the acetylcholine transporter, using [3H](-)-vesamicol in the presence of the sigma-ligand 1,3-di(2-tolyl)guanidine to occlude the sigma binding sites. The contribution of sigma site labelling was substantial in all brain regions and ranged from 25% in the striatum to 60% in the medulla. In addition, we investigated, in various experimental set ups, the affinities of several vesamicol derivatives for acetylcholine transporters and sigma binding sites. All vesamicol derivatives used displayed a higher affinity for the sigma1 site than for the acetylcholine transporter and also displayed a high sigma2 site affinity. This poor selectivity limits the usefulness of these compounds as selective cholinergic markers for brain imaging studies.

Acetylcholine↗
PubMed1997

Astrocyte-mediated enhancement of neuronal survival is abolished by glutathione deficiency.

Astrocytes promote the survival of neurons. Conditions characterized by loss of neurons, such as aging and aging-related neurodegenerative disorders, are accompanied by both disturbances in astrocyte-neuron interactions and signs of oxidative damage. Neuronal glutathione, a major antioxidant in the brain, is maintained by astrocytes and brain levels of glutathione are reduced in named conditions. Therefore, we focused on a possible link between glutathione deficiency and loss of astrocyte-derived neuronal support. For this purpose, we used a coculture system consisting of rat striatal astrocytes and mesencephalic, dopaminergic (DAergic) neurons. Using tyrosine hydroxylase immunocytochemistry and radiolabeled dopamine uptake as parameters, an increase in the number and outgrowth of DAergic neurons was noted in cocultures as compared to cultures of mesencephalic neurons alone. This enhanced survival of DAergic neurons in cocultures was abolished following depletion of glutathione with buthionine sulfoximine. As demonstrated by glial fibrillary acidic protein immunocytochemistry and a microtiter tetrazolium assay, under these conditions no change in astrocyte survival occurred. However, glutathione depletion in cocultures was accompanied by loss of astrocyte-mediated neuroprotection against hydrogen peroxide toxicity. Thus, our results indicate that glutathione is important for the maintenance of the neuronal support function of astrocytes and that glutathione deficiency in the brain may lead to enhanced vulnerability of neurons to (oxidative) damage.

Animals↗
PubMed1997

Priming of 6-hydroxydopamine-lesioned rats with L-DOPA or quinpirole results in an increase in dopamine D1 receptor-dependent cyclic AMP production in striatal tissue.

Priming with a dopamine agonist greatly enhances the behavioral effectiveness of dopamine D1 receptor agonists in rats with 6-hydroxydopamine lesions of the nigrostriatal pathway. The present study investigated the influence of priming on cyclic AMP production in striatal slices. Stimulation of dopamine D1 receptors with dopamine or the dopamine D1 receptor agonist, 1-phenyl-6-Cl-7,8-diol-2,3,4,5-tetrahydro-(1H)-3-benzazepine (SKF 81297), increased cyclic AMP production in the lesioned striatum of rats primed with L-3,4-dihydroxyphenylalanine (L-DOPA) by 329% and 405%, respectively, whereas in drug-naive rats the increase was 183% and 187%, respectively. Priming with quinpirole produced similar results. It is suggested that priming with either L-DOPA or a dopamine D2 receptor agonist results in increased effectiveness of dopamine D1 signal transduction, apparently not only related to previous stimulation of D1 receptors.

Animals↗
PubMed1997

Anethole dithiolethione prevents oxidative damage in glutathione-depleted astrocytes.

Astrocytes protect neurons against reactive oxygen species such as hydrogen peroxide, a capacity which reportedly is abolished following loss of the antioxidant glutathione. Anethole dithiolethione, a sulfur-containing compound which is used in humans, is known to increase cellular glutathione levels and thought thereby to protect against oxidative damage. In the present study we found that anethole dithiolethione increased the glutathione content of cultured rat striatal astrocytes. This effect was abolished by coincubation with the glutathione synthesis inhibitor buthionine sulfoximine. Nevertheless, in the presence of buthionine sulfoximine, despite the lack of an increase in the lowered glutathione level, anethole dithiolethione fully protected the astrocytes against the enhanced toxicity of hydrogen peroxide. Thus, apparently other mechanisms than stimulation of glutathione synthesis are involved in the compound's protective action in astrocytes. Considering the occurrence of lowered glutathione levels in neurodegenerative syndromes, we conclude that further evaluation of the therapeutic potential of anethole dithiolethione is warranted.

Anethole Trithione↗
PubMed1997

The antiproliferative effect of 8-chloro-adenosine, an active metabolite of 8-chloro-cyclic adenosine monophosphate, and disturbances in nucleic acid synthesis and cell cycle kinetics.

8-Chloro-adenosine, the dephosphorylated metabolite of the antineoplastic agent 8-chloro-cyclic AMP, has been proposed to act on the regulatory subunits of cyclic AMP-dependent protein kinase. 8-Chloro-adenosine has a growth-inhibitory effect, the mechanism of which is unclear. We investigated the effects of 8-chloro-cyclic AMP and 8-chloro-adenosine on nucleic acid synthesis and cell cycle kinetics in two human glioma cell lines. These effects were compared to those of the cyclic AMP analogue 8-(4-chlorophenyl)-thio-cyclic AMP (8-CPTcAMP), which is less susceptible to dephosphorylation. Whereas 8-CPTcAMP almost completely inhibited RNA and DNA synthesis, both 8-chloro-adenosine and 8-chloro-cyclic AMP only partly inhibited synthesis of RNA and DNA at growth-inhibitory concentrations, as demonstrated by using [5-1H] uridine and [14C]thymidine incorporation. Therefore, the growth-inhibitory effect of 8-chloro-cyclic AMP is not (or not completely) due to activation of cyclic AMP-dependent protein kinase nor to the inhibition of nucleic acid synthesis. Flow cytometric analysis revealed that 8-chloro-cyclic AMP and 8-chloro-adenosine probably block cell cycle progression at the G2M phase. The effects of 8-chloro-cyclic AMP on nucleic acid synthesis and cell cycle progression were largely prevented by adenosine deaminase, which inactivates 8-chloro-adenosine. This indicates that the effects of 8-chloro-cyclic AMP were at least in part due to its metabolite 8-chloro-adenosine. Incorporation of 8-chloro-adenosine into RNA and DNA might contribute to the disturbance of the cell cycle kinetics and growth-inhibitory effect of 8-chloro-adenosine.

2-Chloroadenosine↗
PubMed1997

[123I]beta-CIT single-photon emission tomography in Parkinson's disease reveals a smaller decline in dopamine transporters with age than in controls.

In vivo studies using single-photon emission tomography (SPET) and positron emission tomography have shown an age-related decline in the number of striatal dopamine transporters in healthy subjects. We examined ten healthy subjects and 33 de novo patients with Parkinson's disease (PD) using [123I]2beta-carbomethoxy-3beta-(4-iodophenyl)tropane ([123I]beta-CIT) SPET. A clear age-related loss of dopamine transporters was found in the healthy subjects. In the PD group, controlling for the contribution of disease severity, we found a small (compared with controls) but significant decrease with aging, though only in the ipsilateral regions. This aging effect was especially pronounced in younger patients. We conclude that the use of age-correct SPET data in PD, based on studies with healthy subjects, may lead to an under- or an overestimation of the striatal binding measures.

Adult↗