Modulation of pro-survival Akt/protein kinase B and ERK1/2 signaling cascades by quercetin and its in vivo metabolites underlie their action on neuronal viability.

Much recent interest has focused on the potential of flavonoids to interact with intracellular signaling pathways such as with the mitogen-activated protein kinase cascade. We have investigated whether the observed strong neurotoxic potential of quercetin in primary cortical neurons may occur via specific and sensitive interactions within neuronal mitogen-activated protein kinase and Akt/protein kinase B (PKB) signaling cascades, both implicated in neuronal apoptosis. Quercetin induced potent inhibition of both Akt/PKB and ERK phosphorylation, resulting in reduced phosphorylation of BAD and a strong activation of caspase-3.

Effects of heparin and related molecules upon neutrophil aggregation and elastase release in vitro.

1 Neutrophil-derived elastase is an enzyme implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Heparin inhibits the enzymatic activity of elastase and here we provide evidence for the first time that heparin can inhibit the release of elastase from human neutrophils. 2 Unfractionated and low molecular weight heparins (UH and LMWH, 0.

Protein kinase C beta2-dependent phosphorylation of core 2 GlcNAc-T promotes leukocyte-endothelial cell adhesion: a mechanism underlying capillary occlusion in diabetic retinopathy.

Increased leukocyte-endothelial cell adhesion is a key early event in the development of retinopathy and atherogenesis in diabetic patients. We recently reported that raised activity of glycosylating enzyme [beta]1,6 acetylglucosaminyltransferase (core 2 GlcNAc-T) is responsible for increased leukocyte-endothelial cell adhesion and capillary occlusion in retinopathy. Here, we demonstrate that elevated glucose increases the activity of core 2 GlcNAc-T and adhesion of human leukocytes to retinal capillary endothelial cells, in a dose-dependent manner, through diabetes-activated serine/threonine protein kinase C beta2 (PKCbeta2)-dependent phosphorylation.

Alterations in m-RNA expression for Cu,Zn-superoxide dismutase and glutathione peroxidase in the basal ganglia of MPTP-treated marmosets and patients with Parkinson's disease.

Alterations occurring in the antioxidant enzymes, copper, zinc-dependent superoxide dismutase (Cu,Zn-SOD) and glutathione peroxidase (GPX) following nigral dopaminergic denervation are unclear. We now report on the distribution and levels of m-RNA for Cu,Zn-SOD and GPX in basal ganglia of normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets, and in normal individuals and patients with Parkinson's disease (PD) using in situ hybridization histochemistry and oligodeoxynucleotide (single-stranded DNA) probes. Cu,Zn-SOD and GPX m-RNA was present throughout basal ganglia (nucleus accumbens, caudate-putamen, globus pallidus, substantia nigra) in the common marmoset, with the highest levels being in substantia nigra (SN).

Commonly used L-amino acid decarboxylase inhibitors block monoamine oxidase activity in the rat.

The effects of the peripheral aromatic amino acid decarboxylase (AADC) inhibitors, carbidopa and benserazide, and the central AADC inhibitor, 3-hydroxybenzylhydrazine (NSD-1015) on peripheral and brain monoamine oxidase (MAO) A and B activity were investigated in the rat. In vitro, carbidopa, benserazide and NSD-1015 all potently inhibited hepatic MAO A and B activity (IC(50) 10-50 micro M). In ex vivo studies following systemic drug administration, NSD-1015 (100 mg/kg ip) produced 88% and 96% inhibition of hepatic and striatal MAO A and B activity respectively.

Overview of neural pathways in allergy and asthma.

Three groups of airway sensory nervous receptor may be involved in the pathophysiological changes in asthma and allergy. Those most active will be the C-fibre receptors, the rapidly adapting receptors, and A delta-nociceptive receptors. All are stimulated or sensitised by the inflammatory and immunological changes.

Both short- and long-acting D-1/D-2 dopamine agonists induce less dyskinesia than L-DOPA in the MPTP-lesioned common marmoset (Callithrix jacchus).

The current concept of dyskinesia is that pulsatile stimulation of D-1 or D-2 receptors by L-DOPA or short-acting dopamine agonists is more likely to induce dyskinesia compared to long-acting drugs producing more continuous receptor stimulation. We now investigate the ability of two mixed D-1/D-2 agonists, namely pergolide (long-acting) and apomorphine (short-acting), to induce dyskinesia in drug-nai;ve MPTP-lesioned primates, compared to L-DOPA. Adult common marmosets (Callithrix jacchus) were lesioned with MPTP (2 mg/kg/day sc for 5 days) and subsequently treated with equieffective antiparkinsonian doses of L-DOPA, apomorphine, or pergolide for 28 days.

Noxious stimulation induces Trk receptor and downstream ERK phosphorylation in spinal dorsal horn.

Several lines of evidence suggest that the brain-derived neurotrophic factor (BDNF) acts as central pain neuromodulator. We examined the ability of different types of peripheral stimulation to activate the BDNF high-affinity receptor, TrkB, in the spinal cord. We found that noxious chemical, mechanical, or thermal stimuli, but not innocuous stimuli, caused Trk phosphorylation in the spinal cord.

Functional morphology and physiology of pulmonary rapidly adapting receptors (RARs).

Rapidly adapting receptors (RARs) in the airway mucosa are found from the nasopharynx to the bronchi. They have thin (Adelta) vagal afferent fibres and lie in and under the epithelium, but their morphology has not been defined. They are very sensitive to mechanical stimuli, and have a rapidly adapting irregular discharge.

Alterations in striatal neuropeptide mRNA produced by repeated administration of L-DOPA, ropinirole or bromocriptine correlate with dyskinesia induction in MPTP-treated common marmosets.

Chronic administration of L-DOPA to MPTP-treated common marmosets induces marked dyskinesia while repeated administration of equivalent antiparkisonian doses of ropinirole and bromocriptine produces only mild involuntary movements. The occurrence of dyskinesia has been associated with an altered balance between the direct and indirect striatal output pathways. Using in situ hybridisation histochemistry, we now compare the effects of these drug treatments on striatal preproenkephalin-A (PPE-A) and adenosine A(2a) receptor mRNA expression as markers of the indirect pathway and striatal preprotachykinin (PPT) mRNA and preproenkephalin-B (PPE-B, prodynorphin) mRNA expression as markers of the direct pathway.

Effects of short- and long-term (--)-deprenyl administration on mRNA for copper, zinc- and manganese-superoxide dismutase and glutathione peroxidase in rat brain.

The effect of short-term (3 weeks, 2 mg/kg day) and long-term (12 and 20 months, 0.5 mg/kg day) administration of (-)-deprenyl on the mRNA expression of three neuroprotective enzymes in subdivisions of rat basal ganglia was investigated. In situ hybridisation histochemistry with oligodeoxynucleotide probes was used to measure levels of copper, zinc superoxide dismutase (Cu,Zn-SOD), manganese superoxide dismutase (Mn-SOD), and glutathione peroxidase (GPX) mRNA.

Repeated administration of piribedil induces less dyskinesia than L-dopa in MPTP-treated common marmosets: a behavioural and biochemical investigation.

Piribedil ([1-(3,4-methylenedioxybenzyl)-4-(2-pyrimidinyl)piperazine]; S 4200) is a dopamine agonist with equal affinity for D(2)/D(3) dopamine receptors effective in treating Parkinson's disease as monotherapy or as an adjunct to levodopa (L-dopa). However, its ability to prime basal ganglia for the appearance of dyskinesia is unknown. We now report on the ability of repeated administration of piribedil to induce dyskinesia in drug naïve 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) -lesioned common marmosets compared with L-dopa and its actions on the direct and indirect striatal outflow pathways.

The monoamine reuptake blocker brasofensine reverses akinesia without dyskinesia in MPTP-treated and levodopa-primed common marmosets.

The common marmoset develops motor deficits after MPTP treatment and exhibits dyskinesia after chronic levodopa (L-dopa) dosing and subsequent re-challenge with L-dopa and other dopaminergic agents. We report on the actions of the potent monoamine reuptake blocker brasofensine on motor disability, locomotor activity, and dyskinesia in the 1-methyl-4-1, 2,3,6-tetrahydropyridine (MPTP) -treated marmoset model of Parkinson's disease. Oral administration of brasofensine (0.

BDNF modulates sensory neuron synaptic activity by a facilitation of GABA transmission in the dorsal horn.

Topical application of brain-derived neurotrophic factor (BDNF) to the adult rat isolated dorsal horn with dorsal root attached preparation inhibited the electrically evoked release of substance P (SP) from sensory neurons. This effect of BDNF was dose dependent (EC(50) 250 pM) and reversed by the tyrosine kinase inhibitor, K-252a. BDNF-induced inhibition of SP release was blocked by the GABA(B) receptor antagonist CGP 55485 but not by naloxone.

Dopamine reuptake inhibition and failure to evoke dyskinesia in MPTP-treated primates.

Nonspecific monoamine reuptake inhibitors reverse motor abnormalities in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated marmosets without evoking established dyskinesia. However, it is not known whether dopamine reuptake inhibition alone explains these actions or whether noradrenaline and/or serotonin reuptake blockade also contributes. L-DOPA (12.

Effects of food processing on flavonoids and lycopene status in a Mediterranean tomato variety.

This research is focused on the antioxidant properties of dietary components, in particular phenolics and carotenoids and the assessment of the contribution of the combined antioxidants to the total antioxidant activity (TAA) of tomato fruit. The aim of this study was to analyse the effects of processing on the antioxidant properties of tomato. The effects of three different methods of processing fresh tomatoes into tomato sauce were investigated with respect to the antioxidant properties of the fruit.

Primary afferent input to and receptive field properties of cells in rat lumbar area X.

In this study we examined the primary afferent input to rat area X of Rexed, and characterized sensory receptive fields (RFs) of the cells therein. This poorly understood area contains primary afferent fibres, some of which are arranged into a compact bundle beneath the central canal. Anterograde transport of the B fragment of cholera toxin (CTB) from the sciatic nerve showed a strictly ipsilateral projection to segments in L4 and L5 but both ipsi- and contralateral projections in L6 and more caudal segments.

Instructing pelvic floor contraction facilitates transversus abdominis thickness increase during low-abdominal hollowing.

Background And Purpose: Low abdominal hollowing in four-point kneeling is used clinically to test and rehabilitate transversus abdominis (TrA) but many people find this exercise difficult to perform. Contracting pelvic floor muscles (PF) during low abdominal hollowing may facilitate contraction of TrA. Thickness increase in the abdominal muscles during low abdominal hollowing has been measured with real-time ultrasound scanning and may indicate muscle contraction.

The actions of a D-1 agonist in MPTP treated primates show dependence on both D-1 and D-2 receptor function and tolerance on repeated administration.

The potent and long acting D-1 receptor agonist, A-77636 reverses motor deficits in MPTP treated common marmosets following subcutaneous or oral administration. We now explore the effects of acute versus repeated administration of A-77636 and the relative roles of D-1 and D-2 receptor involvement in its antiparkinsonian actions. Acute oral administration (0.

Neuroregulation of cough: implications for drug therapy.

There have been remarkable advances recently in our understanding of the neuroregulation of cough in three areas: the properties of the sensory nerves, in particular their receptors and membrane channels; the plasticity of the pathways; and the central nervous mechanisms of cough. All these studies are relevant to our understanding of the pharmacology and therapy of cough.

Rapid cryofixation of rabbit muscle fibres after a temperature jump.

We describe a procedure whereby structural changes that occur in muscle fibres after a rapid temperature jump can be captured by cryofixation. In the thick filament from rabbit and other mammalian skeletal muscles there is a rapid transition from a non-helical to a helical structure as the temperature is raised from 273 K towards physiological levels. This transition is accompanied by characteristic intensity changes in the X-ray diffraction pattern of the muscle.

A novel control mechanism based on GDNF modulation of somatostatin release from sensory neurones.

Small-diameter sensory neurones found in the rat dorsal root ganglia (DRG) include cells sensitive to glial cell line-derived neurotrophic factor (GDNF), which express the inhibitory peptide somatostatin (SOM). Here we addressed the functional relationship between GDNF and sensory neurone-derived SOM. Topical application of GDNF through the rat isolated dorsal horn of the spinal cord promoted activity-induced release of SOM from central terminals of sensory neurones.

Vitamin C protects against hypochlorous Acid-induced glutathione depletion and DNA base and protein damage in human vascular smooth muscle cells.

Hypochlorous acid (HOCl), generated by myeloperoxidase released from activated macrophages, is thought to contribute to vascular dysfunction and oxidation of low density lipoproteins (LDLs) in atherogenesis. We have previously shown that HOCl exposure can cause chlorination and oxidation of isolated DNA and that vitamin C protects human arterial smooth muscle cells against oxidized LDL-mediated damage. We report in the present study that vitamin C attenuates HOCl-induced DNA base and protein damage and depletion of intracellular glutathione (GSH) and ATP in human arterial smooth muscle cells.

The distribution of copper, zinc- and manganese-superoxide dismutase, and glutathione peroxidase messenger ribonucleic acid in rat basal ganglia.

Oxidative stress may contribute to the progression of Parkinson's disease, and while the status of antioxidant enzymes is thus important, little data on their regional distribution in basal ganglia exist. We now report on the distribution and levels of messenger ribonucleic acid (m-RNA) for the antioxidant enzymes copper, zinc-superoxide dismutase (Cu,Zn-SOD), manganese-superoxide dismutase (Mn-SOD), and glutathione peroxidase in rat basal ganglia using in situ hybridisation histochemistry with complementary deoxyribonucleic acid probes specific for these enzymes. The m-RNA for Cu,Zn-SOD, Mn-SOD, and glutathione peroxidase was expressed throughout basal ganglia.

Phosphatidylinositol 3-kinase is a central mediator of NMDA receptor signalling to MAP kinase (Erk1/2), Akt/PKB and CREB in striatal neurones.

Ca2+ influx through NMDA receptors can initiate molecular changes in neurones which may underlie synaptic plasticity, neuronal development, survival and excitotoxicity. Signalling through the MAP kinase (Erk1/2) cascade may be central to these processes. We previously demonstrated that Ca2+-permeable AMPA receptors activate Erkl/2 through a phosphatidylinositol 3-kinase (PI 3-kinase)-dependent mechanism.