MPTP-induced degeneration: interference with glutamatergic toxicity

Parkinson's disease (PD) is characterised by the progressive degeneration of nigrostriatal dopamine (DA) neurons resulting in the major symptoms of akinesia and rigidity. Although the primary cause of PD is still not known some features make this disorder a model for neurodegenerative diseases in general. It has been known for some time that symptomatic PD can be attributed to insults with symptoms occurring many years later such as post-encephalitic PD or PD following manganese poisoning. More recently, MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) has been identified as a neurotoxin selective for melanin-containing dopaminergic neurons in humans and non-human primates. The specificity of this neurotoxin and the striking clinical similarities to idiopathic PD, seen in primates, make MPTP-induced parkinsonism the most useful animal model of a neurological disease. There are numerous theoretical possibilities to interfere with both MPTP-induced neurotoxicity and the symptomatology of PD. In recent years excitatory amino acids have gained considerable interest since they can cause excitotoxic lesion of neurons under a number of pathological conditions (Olney et al., 1989; Choi, 1988). Here we summarise the present data and provide new experimental evidence indicating that MPTP-induced degeneration of dopaminergic neurons does involve glutamate-mediated toxicity. It is concluded that glutamate-mediated excitotoxicity results in the destruction of DAergic somata in the substantia nigra. Non-competitive or competitive NMDA antagonists protect nigral neurons from MPTP-induced degeneration whereas their striatal terminals still seem to degenerate

The effects of electrical hippocampal kindling of seizures on amino acids and kynurenic acid concentrations in brain structures

Our study demonstrated that the development of seizures during the electrically induced kindling of seizures is associated with significant changes in the concentration of kynurenic acid (KYNA) and its precursor, tryptophan (TRP). The primary finding of our study was an increase in KYNA levels and the KYNA/TRP ratio (a theoretical index of activity of the kynurenine pathway) in the amygdala and hippocampus of kindled animals. We also found decreases in the concentration of tryptophan in the hippocampus and prefrontal cortex. Changes in the concentration of KYNA and TRP in the amygdala were accompanied by a significant decrease in γ-Aminobutryic Acid (GABA) levels and an increase in the glutamate/GABA ratio. Moreover, we found a significant negative correlation between the local concentrations of KYNA and glutamate in the amygdala of kindled rats. However, there were no changes in the local concentrations of the following amino acids: glutamate, aspartate, glutamine, glycine, taurine and alanine. In conclusion, these new results suggest a modulatory influence of KYNA on the process of epileptogenesis, characterized by a negative relationship between the KYNA and glutamate systems in the amygdala

Tryptophan pathway abnormalities in a murine model of hereditary glaucoma

Background: It has been shown that a possible pathogenetic mechanism of neurodegenera-tion in the mouse model of glaucoma (DBA/2J) may be an alteration of kynurenic acid (KYNA) in the retina. This study aimed to verify the hypothesis that alterations of tryptophan (TRP) metabolism in DBA/2J mice is not limited to the retina. Methods: Samples of the retinal tissue and serum were collected from DBA/2J mice (6 and 10 months old) and control C57Bl/6 mice of the same age. The concentration of TRP, KYNA, kynurenine (KYN), and 3-hydroxykynurenine (3OH-K) was measured by HPLC. The activity of indoleamine 2,3-dioxygenase (IDO) was also determined as a KYN/TRP ratio. Results: TRP, KYNA, L-KYN, and 3OH-K concentration were significantly lower in the retinas of DBA/2J mice than in C57Bl/6 mice. 3OH-K concentration was higher in older mice in both strains. Serum TRP, L-KYN, and KYNA concentrations were lower in DBA/2J than in age-matched controls. However, serum IDO activity did not differ significantly between compared groups and strains. Conclusions: Alterations of the TRP pathway seem not to be limited to the retina in the murine model of hereditary glaucoma

Tryptophan and Kynurenine Pathway Metabolites in Animal Models of Retinal and Optic Nerve Damage: Different Dynamics of Changes

Kynurenines, products of tryptophan (TRP) metabolism, display neurotoxic (e.g., 3-hydroxykynurenine; 3-HK), or neuroprotective (e.g., kynurenic acid; KYNA) properties. Imbalance between the enzymes constituting the kynurenine pathway (KP) plays a role in several disease, including neurodegeneration. In this study, we track changes in concentrations of tryptophan and its selected metabolites after damage to retinal ganglion cells and link this data with expression of KP enzymes. Brown-Norway rats were subjected to intravitreal N-methyl-D-aspartate (NMDA) injection or partial optic nerve crush (PONC). Retinas were collected 2 and 7 days after the completion of PONC or NMDA injection. Concentrations of TRP, kynurenine (KYN), and KYNA were determined by high performance liquid chromatography (HPLC). Data on gene expression in the rat retina were extracted from GEO, public microarray experiments database. Two days after NMDA injection concentration of TRP decreased, while KYN and KYNA increased. At day 7 compared to day 2 decrease of KYN, KYNA and further reduction of TRP concentration were observed, but on day 7 KYN concentration was still elevated when compared to controls. At day 2 and 7 after NMDA injection no statistically significant alterations of 3-HK were observed. TRP and 3-HK concentration was higher in PONC group than in controls. However, both KYN and KYNA were lower. At day seven concentration of TRP, 3-HK, and KYN was higher, whereas concentration of KYNA declined. In vivo experiments showed that retinal damage or optic nerve lesion affect TRP metabolism via KP. However, the pattern of changes in metabolite concentrations was different depending on the model. In particular, in PONC KYNA and KYN levels were decreased and 3-HK elevated. These observations correspond with data on expression of genes encoding KP enzymes assessed after optic nerve crush or transection. After intraorbital optic nerve crush downregulation of KyatI and KyatIII between 24 h and 3 days after procedure was observed. Kmo expression was transiently upregulated (12 h after the procedures). After intraorbital optic nerve transsection (IONT) Kmo expression was upregulated after 48 h and 7 days, KyatI and KyatIII were downregulated after 12, 48 h, 7 days and upregulated after 15 days. Collected data point to the conclusion that development of therapeutic strategies targeting the KP could be beneficial in diseases involving retinal neurodegeneration

Nucleation of Quark--Gluon Plasma from Hadronic Matter

The energy densities achieved during central collisions of large nuclei at Brookhaven's AGS may be high enough to allow the formation of quark--gluon plasma. Calculations based on relativistic nucleation theory suggest that rare events, perhaps one in every 10$^2$ or 10$^3$, undergo the phase transition. Experimental ramifications may include an enhancement in the ratio of pions to baryons, a reduction in the ratio of deuterons to protons, and a larger source size as seen by hadron interferometry.Comment: 22 pages, 7 figures available upon request, NUC--MINN--94/5--

Dynamical Viscosity of Nucleating Bubbles

We study the viscosity corrections to the growth rate of nucleating bubbles in a first order phase transition in scalar field theory. We obtain the non-equilibrium equation of motion of the coordinate that describes small departures from the critical bubble and extract the growth rate consistently in weak coupling and in the thin wall limit. Viscosity effects arise from the interaction of this coordinate with the stable quantum and thermal fluctuations around a critical bubble. In the case of 1+1 dimensions we provide an estimate for the growth rate that depends on the details of the free energy functional. In 3+1 dimensions we recognize robust features that are a direct consequence of the thin wall approximation and give the leading viscosity corrections.These are long-wavelength hydrodynamic fluctuations that describe surface waves, quasi-Goldstone modes which are related to ripples on interfaces in phase ordered Ising-like systems. We discuss the applicability of our results to describe the growth rate of hadron bubbles in a quark-hadron first order transition.Comment: 40 pages, 4 figures, revtex, minor changes, to be published in Phys. Rev.

Hippocampal Desynchronization of Functional Connectivity Prior to the Onset of Status Epilepticus in Pilocarpine-Treated Rats

Status epilepticus (SE), a pro-epileptogenic brain insult in rodent models of temporal lobe epilepsy, is successfully induced by pilocarpine in some, but not all, rats. This study aimed to identify characteristic alterations within the hippocampal neural network prior to the onset of SE. Sixteen microwire electrodes were implanted into the left hippocampus of male Sprague-Dawley rats. After a 7-day recovery period, animal behavior, hippocampal neuronal ensemble activities, and local field potentials (LFP) were recorded before and after an intra-peritoneal injection of pilocarpine (350 mg/kg). The single-neuron firing, population neuronal correlation, and coincident firing between neurons were compared between SE (n = 9) and nonSE rats (n = 12). A significant decrease in the strength of functional connectivity prior to the onset of SE, as measured by changes in coincident spike timing between pairs of hippocampal neurons, was exclusively found in SE rats. However, single-neuron firing and LFP profiles did not show a significant difference between SE and nonSE rats. These results suggest that desynchronization in the functional circuitry of the hippocampus, likely associated with a change in synaptic strength, may serve as an electrophysiological marker prior to SE in pilocarpine-treated rats

Modulation of Heat Shock Transcription Factor 1 as a Therapeutic Target for Small Molecule Intervention in Neurodegenerative Disease

A yeast-based small molecule screen identifies a novel activator of human HSF1 and protein chaperone expression and which appears to alleviate the toxicity of protein misfolding diseases

Towards good practice guidelines for the contour method of residual stress measurement

Accurate measurement of residual stress in metallic components using the contour method relies on the achievement of a good quality cut, on the appropriate measurement of the deformed cut surface and on the robust analysis of the measured data. There is currently no published standard or code of practice for the contour method. As a first step towards such a standard, this study draws on research investigations addressing the three main steps in the method: how best to cut the specimens; how to measure the deformation contour of the cut surface; and how to analyse the data. Good practice guidance is provided throughout the text accompanied by more detailed observations and advice tabulated in Appendi

Non-functional ubiquitin C-terminal hydrolase L1 drives podocyte injury through impairing proteasomes in autoimmune glomerulonephritis

In membranous nephropathy autoantibodies target podocytes of the kidney filter resulting in injury. Here the authors show that the ensuing proteostatic disturbances and proteinuria relate to aberrant interactions of non-functional UCH-L1 enzyme with the proteasome, curtailing its capacity.Little is known about the mechanistic significance of the ubiquitin proteasome system (UPS) in a kidney autoimmune environment. In membranous nephropathy (MN), autoantibodies target podocytes of the glomerular filter resulting in proteinuria. Converging biochemical, structural, mouse pathomechanistic, and clinical information we report that the deubiquitinase Ubiquitin C-terminal hydrolase L1 (UCH-L1) is induced by oxidative stress in podocytes and is directly involved in proteasome substrate accumulation. Mechanistically, this toxic gain-of-function is mediated by non-functional UCH-L1, which interacts with and thereby impairs proteasomes. In experimental MN, UCH-L1 becomes non-functional and MN patients with poor outcome exhibit autoantibodies with preferential reactivity to non-functional UCH-L1. Podocyte-specific deletion of UCH-L1 protects from experimental MN, whereas overexpression of non-functional UCH-L1 impairs podocyte proteostasis and drives injury in mice. In conclusion, the UPS is pathomechanistically linked to podocyte disease by aberrant proteasomal interactions of non-functional UCH-L1.Bio-organic Synthesi