István Szatmári

Neuroprotective effects of a novel kynurenic acid analogue in a transgenic mouse model of Huntington's disease.

Huntington’s disease (HD) is a progressive neurodegenerative disorder, the pathomechanism of which is not yet fully understood. Excitotoxicity is known to be involved in the development of HD and antiglutamatergic agents may, therefore, have beneficial neuroprotective effects. One of these agents is the tryptophan metabolite kynurenic acid (KYNA), which is an endogenous NMDA receptor antagonist. However, its pharmacological properties rule out its systemic administration in CNS disorders. We have tested a novel KYNA analogue, N-(2-N,N-dimethylaminoethyl)-4-oxo-1H-quinoline-2-carboxamide hydrochloride, in the N171-82Q transgenic mouse model of HD. The analogue exhibited several significant effects: it prolonged the survival of the transgenic mice, ameliorated their hypolocomotion, prevented the loss of weight and completely prevented the atrophy of the striatal neurons. The beneficial effects of this KYNA analogue are probably explained by its complex anti-excitotoxic activity. As it did not induce any appreciable side-effect at the protective dose applied in a chronic dosing regime in this mouse model, it appears worthy of further thorough investigations with a view to eventual clinical trials.

Cellular multiadaptive analogic architecture: a computational framework for UAV applications

An efficient adaptive algorithm in real-time applications should make optimal use of the available computing power for reaching some specific design goals. Relying on appropriate strategies, the spatial resolution/temporal rate can be traded against computational complexity; and sensitivity traded against robustness, in an adaptive process. In this paper, we present an algorithmic framework where a spatial multigrid computing is placed within a temporal multirate structure, and at each spatial grid point, the computation is based on an adaptive multiscale approach. The algorithms utilize an analogic (analog and logic) architecture consisting of a high-resolution optical sensor, a low-resolution cellular sensor-processor and a digital signal processor. The proposed framework makes the acquisition of a spatio-temporally consistent image flow possible even in case of extreme variations (relative motion) in the environment. It ideally supports the handling of various difficult problems on a moving platform including terrain identification, navigation parameter estimation, and multitarget tracking. The proposed spatio-temporal adaptation relies on a feature-based optical-flow estimation that can be efficiently calculated on available cellular nonlinear network (CNN) chips. The quality of the adaptation is evaluated compared to nonadaptive spatio-temporal behavior where the input flow is oversampled, thus resulting in redundant data processing with an unnecessary waste of computing power. We also use a visual navigation example recovering the yaw-pitch-roll parameters from motion-field estimates in order to analyze the adaptive hierarchical algorithmic framework proposed and highlight the application potentials in the area of unmanned air vehicles.

Neuroprotection with a new kynurenic acid analog in the four-vessel occlusion model of ischemia

Global forebrain ischemia results in damage to the pyramids in the CA1 hippocampal subfield, which is particularly vulnerable to excitotoxic processes. Morphological and functional disintegration of this area leads to a cognitive dysfunction and neuropsychiatric disorders. Treatment with N-methyl-d-aspartate receptor antagonists is a widely accepted method with which to stop the advance of excitotoxic processes and concomitant neuronal death. From a clinical aspect, competitive glycine- and polyamine-site antagonists with relatively low affinity and moderate side-effects are taken into account. Endogenous kynurenic acid acts as an antagonist on the obligatory co-agonist glycine site, and has long been at the focus of neuroprotective trials. In the present study, we estimated the neuroprotective capability of a novel kynurenic acid analog in transient global forebrain ischemia, measuring the rate of hippocampal CA1 pyramidal cell loss and the preservation of long-term potentiation at Schaffer collateral-CA1 synapses. The neuroprotective potential was reflected by a significantly diminished hippocampal CA1 cell loss and preserved long-term potentiation expression. The neuroprotective effect was robust in the event of pretreatment, and also when the drug was administered at the time of reperfusion. This result is beneficial since a putative neuroprotectant proven to be effective as post-treatment is of much greater benefit.

Syntheses, Transformations and Pharmaceutical Applications of Kynurenic Acid Derivatives

The syntheses and transformations of 4-hydroxyquinoline-2-carboxylic acid, kynurenic acid, are reviewed, and special attention is paid to the pharmacological activities and pharmaceutical applications of its derivatives.

Inter- or intramolecular N⋯H-O or N-H⋯O hydrogen bonding in 1,3-amino-α/β-naphthols: An experimental NMR and computational study

The existence of intermolecular or intramolecular N...H-O or N-H...O hydrogen bonding in three series (series 1, substituted 1-aminoalkyl-2-naphthols: R = H, Me, Et, Pr, i-Pr; series 2, substituted 1-alpha-aminobenzyl-2-naphthols: H, p-OMe, p-F, p-Cl, p-Br, p-NO2, p-Me; series 3, substituted 2-alpha-aminobenzyl-1-naphthols: R = H, p-Me, p-F, p-Br, p-OMe, m-NO(2), m-Br) are studied by NMR spectroscopy and computed at the DFT level of theory [B3LYP/6-311+G(d,p)]. The correct nature of the H-bond was assigned unequivocally both experimentally and computationally by potential energy scans rotating the involved dihedral angles. We investigated the effects of substituents on the strength of the H-bond by evaluating the corresponding hyperconjugative stabilization energy n(lonepair) --> sigma*(X-H) and Hammett substituent constant plots. By this means, steric and electronic substituent effects could be easily quantified and separated.

The new framework of applications: The Aladdin system

The first CNN technology-based, high performance industrial visual computer called Aladdin is reported. The revolutionary device is the world premier of the ACE4k Cellular Visual Microprocessor (CVM) chip powering an industrial visual computer. One of the most important features of the Aladdin system is the image processing library. The library reduces algorithm development time, provides efficient codes, error free operation in binary, and accurate operation in grayscale nodes. Moreover the library provides an easy way to use the Aladdin system for those who are not familiar with the CNN technology.

A Nonlinear Wave Metric and its CNN Implementation for Object Classification

In this paper a nonlinear wave metric is introduced for object classification. It is shown that the choice of a metric is a nontrivial problem since it is easy to give examples when well-known distance measures, such as Hamming, Hausdorff, and Nonlinear Hausdorff metrics are completely inadequate for this classification. As an alternative a generalized theorem is proposed that includes the previous metrics as special cases. It is based on nonlinear wave propagation and defines a computational framework that is well-suited for parallel array processors. In this study we investigate different Cellular Neural Network (CNN) architectures and solutions for the proposed metric and analyze its VLSI implementation complexity.

High-performance liquid chromatographic enantioseparation of 1-(phenylethylamino)- or 1-(naphthylethylamino)methyl-2-naphthol analogs and a temperature-induced inversion of the elution sequence on polysaccharide-based chiral stationary phases

The stereoisomers of five 1-(phenylethylamino)methyl-2-naphthol analogs or 1-(naphthylethylamino)methyl-2-naphthol analogs containing two chiral centers were directly separated on chiral stationary phases containing the chiral selectors cellulose tris-(3,5-dimethylphenyl) carbamate (Lux Cellulose-1), cellulose tris-(3-chloro-4-methylphenyl) carbamate (Lux Cellulose-2) and amylose tris-(5-chloro-2-methylphenyl) carbamate (Lux Amylose-2). Experiments were performed in normal-phase mode in a wide temperature range -5 to 70°C. Thermodynamic parameters and T(iso) values were calculated from plots of lnk or lnα vs. 1/T. -Δ(ΔH°) ranged from 1.0 to 4.7 kJ mol(-1), -Δ(ΔS°) from 1.6 to 11.0 J mol(-1) K(-1) and -Δ(ΔG°) from 0.1 to 1.5 kJ mol(-1). The sequence of elution of the stereoisomers was determined in all cases and in one case a temperature-induced inversion of the elution sequence was observed.

Behavioural studies with a newly developed neuroprotective KYNA-amide

The neuroactive properties and neuroprotective potential of endogenous l-kynurenine, kynurenic acid (KYNA) and its derivatives are well established. KYNA acts as an antagonist on the obligatory co-agonist glycine site, and has long been at the focus of neuroprotective trials. Unfortunately, KYNA is barely able to cross the blood–brain barrier. Accordingly, the development and synthesis of KYNA analogs which can readily cross the BBB have been at the focus of research interest with the aim of neuroprotection. Earlier we reported a new KYNA-amide crosses the BBB and proved neuroprotective in several experiments. In the present study, we investigated the locomotor activity, working memory performance, and also the long-lasting, consolidated reference memory of animals treated intraperitoneally (i.p.) with the novel analog. The effects of the novel analog on the spatial orientation and learning ability of rats were assessed in the Morris water maze (MWM) paradigm. The effects on locomotor activity of mice was assessed in the open field (OF) paradigm, and those on the spatial orientation and learning ability of mice were investigated in the radial arm maze (RAM) paradigm. It emerged that there is a dose of this KYNA-amide which is neuroprotective, but does not worsen the cognitive function of the brain. This result is significant in that a putative neuroprotectant without adverse cognitive side-effects is of great benefit.

Synthesis and biological effects of some kynurenic acid analogs.

The overactivation of excitatory amino acid receptors plays a key role in the pathomechanism of several neurodegenerative disorders and in ischemic and post-ischemic events. Kynurenic acid (KYNA) is an endogenous product of the tryptophan metabolism and, as a broad-spectrum antagonist of excitatory amino acid receptors, may serve as a protective agent in neurological disorders. The use of KYNA is excluded, however, because it hardly crosses the blood-brain barrier. Accordingly, new KYNA analogs which can readily cross this barrier and exert their complex anti-excitatory activity are generally needed. During the past 6 years, we have developed several KYNA derivatives, among others KYNA amides. These new analogs included one, N-(2-N,N-dimethylaminoethyl)-4-oxo-1H-quinoline-2-carboxamide hydrochloride (KYNA-1), that has proved to be neuroprotective in several models. This paper reports on the synthesis of 10 new KYNA amides (KYNA-1-KYNA-10) and on the effectiveness of these molecules as inhibitors of excitatory synaptic transmission in the CA1 region of the hippocampus. The molecular structure and functional effects of KYNA-1 are compared with those of other KYNA amides. Behavioral studies with these KYNA amides demonstrated that they do not exert significant nonspecific general side-effects. KYNA-1 may therefore be considered a promising candidate for clinical studies.