Presynaptic dopamine DA2-receptors in rabbit jejunal arteries

Summary Excitatory junction potentials (e.j.ps) evoked by nerve stimulation with 15 pulses at 1 Hz were recorded from muscle cells of rabbit isolated jejunal arteries. LY 171555 1 mol/l, SKF 38393 10 mol/l, dopamine 10 ol/l and clonidine 0.1 mol/l depressed all e j.ps in the train. The percentage inhibition was inversely related to the number of pulses. S- and R-sulpiride, 10 mol/l, domperidone 1 mol/l, SCH 23390 1 mol/l and rauwolscine 1 mol/l did not change, or even depressed the first e j.ps. Of these compounds only S- and R-sulpiride, 10 mol/l and rauwolscine 1 mol/l facilitated the late e.j.ps. The percentage facilitation increased with the number of pulses until a maximum was reached; rauwolscine 1 ol/l had the largest effect. S- and R-sulpiride, 10 mol/l, as well as domperidone 1 ol/l antagonized the action of LY 171555 1 mol/l. S-Sulpiride was more potent than its R-isomer. SCH 23390 1 mol/l and rauwolscine 1 mol/l blunted the effect of SKF 38393 10 mol/l. Rauwolscine 1 mol/l slightly reduced the inhibition by dopamine 10 mol/l; S-sulpiride 10 mol/l was antagonistic only in the presence of rauwolscine 1 mol/l. When rauwolscine 1 mol/l, prazosin 0.1 mol/l, propranolol 1 mol/l and cocaine 10 mol/l was added to the medium, dopamine 10 mol/l continued to produce the same depression of e j.ps, as in the absence of these compounds. Under such conditions S-sulpiride 10 mol/l also counteracted dopamine 10 gmol/l. Rauwolscine 1 mol/l prevented the effect of clonidine 0.1 mol/l. The antagonists were not absolutely selective against only one type of agonist. We suggest that both presynaptic DA₂- and postsynaptic DA₁-receptors are present in rabbit jejunal arteries. The activation of either receptor-type may depress the e j.ps. Dopamine interferes with neuroeffector transmission due to ₂-adrenoceptor agonist properties; its DA₂-effect is unmasked only after ₂-adrenoceptor blockade. There was no evidence for a co-transmitter function of dopamine. Send offprint requests to P. Illes at the above address     

Morphometric changes of gray matter in Parkinson's disease with depression: A voxel‐based morphometry study

The origin of the high rate of depression in idiopathic Parkinson's disease (PD) is unknown. We applied voxel‐based morphometry (VBM), as a sensitive tool in detection of gray matter MR density alterations, to find differences in depressed and nondepressed PD patients. Patients with idiopathic PD were classified into depressed (DPD) and nondepressed (NDPD) groups based on the Montgomery‐Åsberg Depression Rating Scale (MADRS). Subsequently, a group comparisons were performed between depressed PD (n = 23), nondepressed PD (n = 27) and normal healthy controls (NC, n = 16). There was no difference in gray matter density comparing healthy controls to any PD groups. However, when NDPD and DPD cohorts were compared, density alteration of the bilateral orbitofrontal, bilateral rectal gyrus, and also the right superior temporal pole was detected in the depressed subgroup. Exploratory analyses revealed an inverse correlation of MADRS scores and severity of VBM alteration in these regions beside the right medial temporal gyrus, anterior and medial cingular gyrus, and parahippocampal gyrus. These results suggest that depression in PD is related to gray matter decrease in the bilateral orbitofrontal and right temporal regions as well as the limbic system. © 2007 Movement Disorder Society     

Dasatinib inhibits coated-platelet generation in patients with chronic myeloid leukemia

Since the introduction of tyrosine kinase inhibitors, the overall survival of patients with chronic myeloid leukemia has markedly improved. However long term use of these drugs results in various adverse events. Treatment with second generation dasatinib is often complicated by hemorrhagic events. Previous lumi-aggregometry studies have shown impaired platelet function in patients on dasatinib therapy. Dual agonist activated platelets (coated-platelets) are also sensitive indicators of platelet function. We hypothesized that dual activation with convulxin and thrombin of platelets in a flow cytometric assay could be a more sensitive method for detecting platelet dysfunction as compared to single agonist studies used in lumi-aggregometer. Platelets of healthy volunteers incubated with dasatinib as well as platelets from patients on dasatinib therapy were investigated. Low therapeutic plasma level dasatinib concentrations at which a considerable reduction in coated-platelet generation was observed in vitro, did not cause detectable change in platelet aggregation response. Coated-platelet assay and lumi-aggregometry were also investigated at 0, 1 and 4 hours after drug administration in dasatinib treated CML patients. Significant decrease was observed at 1 hour in maximal aggregation by collagen. Although the aggregation curves became normalized by 4 hours, coated-platelet generation was still inhibited in dasatinib treated patients. Nilotinib, another second generation tyrosine kinase inhibitor, had no effect on aggregation and on coated-platelet formation neither in vitro nor in ex vivo samples. At therapeutic plasma levels coated-platelet assay is more sensitive than lumi-aggregometry studies for the demonstration of the inhibitory effect of dasatinib on platelet function.     

The Stem Cell Research Environment: A Patchwork of Patchworks

Few areas of recent research have received as much focus or generated as much excitement and debate as stem cell research. Hope for the therapeutic promise of this field has been matched by social concern associated largely with the sources of stem cells and their uses. This interplay between promise and controversy has contributed to the enormous variation that exists among the environments in which stem cell research is conducted throughout the world. This variation is layered upon intra-jurisdictional policies that are also often complex and in flux, resulting in what we term a ‘patchwork of patchworks’. This patchwork of patchworks and its implications will become increasingly important as we enter this new era of stem cell research. The current progression towards translational and clinical research among international collaborators serves as a catalyst for identifying potential policy conflict and makes it imperative to address jurisdictional variability in stem cell research environments. The existing patchworks seen in contemporary stem cell research environments provide a valuable opportunity to consider how variations in regulations and policies across and within jurisdictions influence research efficiencies and directions. In one sense, the stem cell research context can be viewed as a living experiment occurring across the globe. The lessons to be gleaned from examining this field have great potential for broad-ranging general science policy application.

Decrease of current responses at human recombinant P2X3 receptors after substitution by Asp of Ser/Thr residues in protein kinase C phosphorylation sites of their ecto-domains

The whole-cell patch-clamp technique was used to record current responses to nucleotides in HEK 293 cells transiently transfected with the human (h) P2X(3) receptor. When GDP-beta-S was included into the pipette solution, UTP at concentrations which did not alter the holding current, facilitated the alpha,beta-methylene ATP (alpha,beta-meATP)-induced current. The substitution of Ser/Thr residues situated within protein kinase C (PKC) consensus phosphorylation sites of the P2X(3) receptor ecto-domain by the neutral amino acid Ala either abolished (T134A, S178A) or did not alter (T196A, S269A) the UTP-induced potentiation of the alpha,beta-meATP current. The substitution of the same Ser/Thr residues in all four PKC sites by the negatively charged Asp prevented the potentiation by UTP. The Asp mutations abolished the first, fast offset time-constant, but did not alter, or in the case of S269D even increased, the second, slow offset time-constant; at the same time such mutations invariably increased the onset time-constant and massively depressed the peak current amplitude. None of the Ala mutations (with the exception of S269A) influenced the time-course of desensitisation or the peak current amplitude. It is concluded that constitutive activation of PKC sites at the ecto-domain of the hP2X(3) receptor both abolishes the UTP-induced potentiation of the alpha,beta-meATP current and accelerates its rate of desensitisation.     

P2X7 receptors in the nervous system

P2X₇ receptors are ligand-gated ion channels, expressed as homo-oligomeric assemblies of individual subunits. They are widely distributed at immunocompetent cells of the central and peripheral nervous system and are believed to be primarily involved in host-defense reaction. However, a growing amount of evidence indicates that their signaling role in the brain is more widespread than previously anticipated. In this paper, we review the present knowledge on the structural and pharmacological features of the P2X₇ receptor, as well as its cell-type specific localization in the nervous system. Subsequently, the participation of P2X₇ receptors in distinct neuronal, astroglial and microglial functions are described. Finally, since they may play a prominent role in certain neurologic disorders, such as ischemia-reperfusion injury, Alzheimer's disease, spinal cord injury and sensory neuropathies, the pathological role and potential therapeutic exploitation of P2X₇ receptors are also discussed.