Correction: Thrombospondin-targeting TAX2 peptide impairs tumor growth in preclinical mouse models of childhood neuroblastoma.

The authors "Revital Rattenbach", "ltschak Lamensdorf", and "Celine Martin" were not included in the author list of this published article however should be considered to be authors since they contributed substantially to the work. The updated author list of this article can be found in the associated correction.

A novel potential therapy for vascular diseases: blood-derived stem/progenitor cells specifically activated by dendritic cells.

Background: Vascular diseases are a major cause of morbidity and mortality, particularly in diabetic patients. Stem/progenitor cell treatments with bone marrow-derived cells show safety and promising outcomes, albeit not without some preprocedural adverse events related to cell collection and mobilization. We describe a novel technology for generating a therapeutic population (BGC101) of enriched endothelial progenitor cells (EPCs) from non-mobilized blood, using dendritic cells to specifically direct stem/progenitor cell activity in vitro.

THR-18, a 18-mer peptide derived from PAI-1, is neuroprotective and improves thrombolysis by tPA in rat stroke models.

Objective: The thrombolytic treatment of stroke is limited by a narrow therapeutic time window and is associated with significant adverse side effects. To improve this situation, the modulation of tissue-type plasminogen activator (tPA) activity by a synthetic plasminogen activator inhibitor-1-derived 18-mer peptide (THR-18) was examined in two models of stroke in rats.

Methods: In the first model (thromboembolic), stroke was induced by intra-carotid injection of micro-clots to rats, and tPA (6 mg/kg) was intravenously infused for 30 minutes with or without THR-18 (1 mg/kg) at 4 hours post-induction.

Blood-brain barrier permeability and tPA-mediated neurotoxicity.

Tissue type plasminogen activator (tPA) can induce neuronal apoptosis, disrupt the blood-brain barrier (BBB), and promote dilation of the cerebral vasculature. The timing, sequence and contributions of these and other deleterious effects of tPA and their contribution to post-ischemic brain damage after stroke, have not been fully elucidated. To dissociate the effects of tPA on BBB permeability, cerebral vasodilation and protease-dependent pathways, we developed several tPA mutants and PAI-1 derived peptides constructed by computerized homology modeling of tPA.

Spontaneous aortitis in the Balb/c mouse.

We examined whether high incidence rates (18%-56%) of inflammation in the root of the aorta detected in a Balb/c mouse model for hind limb ischemia were related to the surgical procedure. Twenty mice underwent ligation of the femoral artery; incidences of aortic root inflammation were compared to those observed in controls. We used a multiple-section sampling method to increase the sensitivity of the diagnostic rates.

Blood-brain barrier opened by stimulation of the parasympathetic sphenopalatine ganglion: a new method for macromolecule delivery to the brain.

Object: Drug delivery across the blood-brain barrier remains a significant challenge. Based on earlier findings, the authors hypothesized that parasympathetic innervation of the brain vasculature could be used to augment drug delivery to the brain.

Methods: Using a craniotomy-cerebrospinal fluid superfusate paradigm in rats with an intravenous injection of tracer the authors demonstrated that stimulation of the postganglionic parasympathetic fibers of the sphenopalatine ganglion (SPG) increased the concentration of fluorescein isothiocyanate-dextran (4-250 kD) in the superfusate by two- to sixfold.

Attenuation of methamphetamine induced dopaminergic neurotoxicity by flupirtine: microdialysis study on dopamine release and free radical generation.

Flupirtine is a triaminopyridine derived centrally acting analgetic, which has been found to display neuroprotective effects in models of excitotoxic cell damage, global, and focal ischemia, but no direct interaction with any component of the N-methyl-D-aspartate (NMDA) and glutamate triggered Ca(2+)-channel. Additionally flupirtine shows potent antioxidant effects in isolated mitochondria and cell culture. Work in models of monoamine depletion and neuroleptic induced catalepsy in rats suggests a interaction of flupirtine with the dopaminergic neurotransmitter system as well.

The nitroxide antioxidant tempol is cerebroprotective against focal cerebral ischemia in spontaneously hypertensive rats.

Free radicals appear to participate in the final common pathway of neuronal death in ischemia and may therefore be an adequate target for therapy. Tempol is a nitroxide antioxidant with proven protective efficacy in several animal models, including myocardial ischemia, that has not been previously tested in models of permanent cerebral ischemia. Spontaneously hypertensive rats underwent permanent middle cerebral artery occlusion (PMCAO).

Bax and Bak coalesce into novel mitochondria-associated clusters during apoptosis.

Bax is a member of the Bcl-2 family of proteins known to regulate mitochondria-dependent programmed cell death. Early in apoptosis, Bax translocates from the cytosol to the mitochondrial membrane. We have identified by confocal and electron microscopy a novel step in the Bax proapoptotic mechanism immediately subsequent to mitochondrial translocation.

Modification of dopamine release by selective inhibitors of MAO-B.

Chronic low dose deprenyl treatment in rats causes an increase in striatal extracellular dopamine level, without significant reduction in deaminated metabolite formation. This effect could be the result of increased endogenous levels of the MAO-B substrate beta-phenylethylamine, which is both a releaser of dopamine as well as an inhibitor of the neuronal membrane active dopamine uptake. In guinea pigs, however, striatal extracellular dopamine was not increased either by deprenyl or by clorgyline.

Selective monoamine oxidase subtype inhibition and striatal extracellular dopamine in the guinea-pig.

Striatal microdialysate levels of dopamine (DA) in conscious guinea-pigs were measured following acute (1 day) and chronic (21 days) treatment with deprenyl (2 and 0.25 mg kg(-1) s.c.

Acidic dopamine metabolites are actively extruded from PC12 cells by a novel sulfonylurea-sensitive transporter.

Incubation of PC 12 cells with the sulfonylurea drug, glipizide (1-100 microM), increased intracellular levels of the acidic metabolites of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). The levels of these acids in the medium were decreased, indicating the presence of a sulfonylurea-sensitive organic anion transporter. In the present study, we demonstrate that the sulfonylurea-sensitive transport of acidic dopamine metabolites is unidirectional, ATP dependent, unaffected by ouabain or by tetrodotoxin and blocked by drugs that interact with the multidrug-resistance protein-1 (MRP1).

3,4-Dihydroxyphenylacetaldehyde potentiates the toxic effects of metabolic stress in PC12 cells.

3,4-Dihydroxyphenylacetaldehyde (DOPAL) is a toxic metabolite formed by the oxidative deamination of dopamine. This aldehyde is mainly oxidized to 3,4-dihydroxyphenylacetic acid (DOPAC) by aldehyde dehydrogenase (ALDH), but is also partly reduced to 3, 4-dihydroxyphenylethanol (DOPET) by aldehyde or aldose reductase (ARs). In a previous study, we found that rotenone, a complex I inhibitor, induced a rapid accumulation of DOPAL and DOPET in the medium of cultured PC12 cells.

Metabolic stress in PC12 cells induces the formation of the endogenous dopaminergic neurotoxin, 3,4-dihydroxyphenylacetaldehyde.

3,4-Dihydroxyphenylacetaldehyde (DOPAL) has been reported to be a toxic metabolite formed by the oxidative-deamination of dopamine (DA) catalyzed by monoamine oxidase. This aldehyde is either oxidized to 3,4-dihydroxyphenylacetic acid (DOPAC) by aldehyde dehydrogenase, an NAD-dependent enzyme or reduced to 3, 4-dihydroxyphenylethanol (DOPET) by aldehyde or aldose reductase. In the present study we examined whether levels of DOPAL are elevated by inhibition of the mitochondrial respiratory chain.

Effect of glipizide on dopamine synthesis, release and metabolism in PC12 cells.

Sulfonylureas block ATP-dependent K(+) channels (K/ATP channels) in pancreatic beta cells and brain gamma-aminobutyric acid (GABA) containing neurons causing depolarization-evoked insulin or GABA release. In high concentrations, sulfonylureas also inhibit catecholamine release from bovine adrenal chromaffin cells and isolated guinea pig aorta. In this study, we examined the effect of glipizide, a sulfonylurea, on dopamine release from PC12 cells and found that neither basal nor K(+)-stimulated dopamine release was affected.

Sources and physiological significance of plasma dopamine sulfate.

Dopamine in the circulation occurs mainly as dopamine sulfate, the sources and physiological significance of which have been obscure. In this study, plasma concentrations of dopamine sulfate were measured after a meal, after fasting for 4 days, and during i.v.

Effect of low-dose treatment with selegiline on dopamine transporter (DAT) expression and amphetamine-induced dopamine release in vivo.

1. Chronic treatment with low doses of the selective monoamine oxidase (MAO) type B inhibitors selegiline [(-)-deprenyl] and rasagiline, causes elevation in extracellular level of 3,4-dihydroxyphenylethylamine (dopamine) in the rat striatum in vivo (Lamensdorf et al., 1996).

Kir6.2 oligoantisense administered into the globus pallidus reduces apomorphine-induced turning in 6-OHDA hemiparkinsonian rats.

ATP-sensitive inwardly rectifying potassium channels (KATPs) couple cell metabolism with its membrane potential. The best characterized KATP is the pancreatic KATP which is an heteromultimer of Kir6.2 and SUR1 protein subunits.

Reduced striatal tyrosine hydroxylase activity is not accompanied by change in responsiveness of dopaminergic receptors following chronic treatment with deprenyl.

Deprenyl is the only selective monoamine oxidase B (MAO-B) inhibitor that is in clinical use for the treatment of Parkinson's disease. Our previous studies showed that chronic treatment of rats with low (MAO-B selective) doses of deprenyl inhibited dopamine (DA) re-uptake and enhanced DA release in the striatum. These changes could affect DA synthesis rate by activation of negative feedback loops.

Effect of long-term treatment with selective monoamine oxidase A and B inhibitors on dopamine release from rat striatum in vivo.

Acute inhibition of monoamine oxidase B (MAO-B) in the rat does not affect striatal dopamine (DA) metabolism, but chronic MAO-B inhibition with deprenyl has been reported to increase the release of striatal DA, as shown using in vitro techniques. To see whether chronic MAO-B inhibition also causes an increase in DA release in vivo, rats were treated for 21 days with either deprenyl (0.25 mg/kg), TVP-1012 [R(+)-N-propargyl-1-aminoindan mesylate; 0.

Pharmacology and neuroprotective properties of rasagiline.

Rasagiline [R(+)-N-propargyl-1-aminoindane] is a selective irreversible inhibitor of MAO-B which is not metabolised to amphetamine-like derivatives. Like deprenyl, when given to rats in a dose selective for inhibition of MAO-B, it does not affect striatal extracellular fluid dopamine levels, but when administered chronically (21 days) it increased striatal microdialysate dopamine without reduction in deaminated metabolites. Similarly to deprenyl, rasagiline (10(-6)M) increased the percentage of tyrosine hydroxylase positive cells in a primary culture of rat fetal mesencephalic cells (6 days in culture).