Redox and non-redox mechanism of in vitro cyclooxygenase inhibition by natural quinones

In this study, ten anthra-, nine naphtho-, and five benzoquinone compounds of natural origin and five synthetic naphthoquinones were assessed, using an enzymatic in vitro assay, for their potential to inhibit cyclooxygenase-1 and -2 (COX-1 and COX-2), the key enzymes of the arachidonic acid cascade. IC?? values comparable with COX reference inhibitor indomethacin were recorded for several quinones (primin, alkannin, diospyrin, juglone, 7-methyljuglone, and shikonin). For some of the compounds, we suggest the redox potential of quinones as the mechanism responsible for in vitro COX inhibition because of the quantitative correlation with their pro-oxidant effect. Structure-relationship activity studies revealed that the substitutions at positions 2 and 5 play the key roles in the COX inhibitory and pro-oxidant actions of naphthoquinones. In contrast, the redox mechanism alone could not explain the activity of primin, embelin, alkannin, and diospyrin. For these four quinones, molecular modeling suggested similar binding modes as for conventional nonsteroidal anti-inflammatory drugs (NSAIDs).     

High‐frequency gamma oscillations coexist with low‐frequency gamma oscillations in the rat visual cortex in vitro

Synchronization of neuronal activity in the visual cortex at low (30–70 Hz) and high gamma band frequencies (> 70 Hz) has been associated with distinct visual processes, but mechanisms underlying high‐frequency gamma oscillations remain unknown. In rat visual cortex slices, kainate and carbachol induce high‐frequency gamma oscillations (fast‐γ; peak frequency ～ 80 Hz at 37°C) that can coexist with low‐frequency gamma oscillations (slow‐γ; peak frequency ～ 50 Hz at 37°C) in the same column. Current‐source density analysis showed that fast‐γ was associated with rhythmic current sink‐source sequences in layer III and slow‐γ with rhythmic current sink‐source sequences in layer V. Fast‐γ and slow‐γ were not phase‐locked. Slow‐γ power fluctuations were unrelated to fast‐γ power fluctuations, but were modulated by the phase of theta (3–8 Hz) oscillations generated in the deep layers. Fast‐γ was spatially less coherent than slow‐γ. Fast‐γ and slow‐γ were dependent on γ‐aminobutyric acid (GABA)_A receptors, α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptors and gap‐junctions, their frequencies were reduced by thiopental and were weakly dependent on cycle amplitude. Fast‐γ and slow‐γ power were differentially modulated by thiopental and adenosine A₁ receptor blockade, and their frequencies were differentially modulated by N‐methyl‐d ‐aspartate (NMDA) receptors, GluK1 subunit‐containing receptors and persistent sodium currents. Our data indicate that fast‐γ and slow‐γ both depend on and are paced by recurrent inhibition, but have distinct pharmacological modulation profiles. The independent co‐existence of fast‐γ and slow‐γ allows parallel processing of distinct aspects of vision and visual perception. The visual cortex slice provides a novel in vitro model to study cortical high‐frequency gamma oscillations.     

Direct administration of rutin does not protect against catecholamine cardiotoxicity

High levels of catecholamines are cardiotoxic and may trigger acute myocardial infarction (AMI). Similarly, the synthetic catecholamine isoprenaline (ISO) evokes a pathological state similar to AMI. During AMI there is a marked increase of free iron and copper which are crucial catalysts of reactive oxygen species formation. Rutin, a natural flavonoid glycoside possessing free radical scavenging and iron/copper chelating activity, may therefore be potentially useful in reduction of catecholamine cardiotoxicity as was previously demonstrated after its long-term peroral administration. Male Wistar:Han rats received rutin (46 or 11.5 mg kg(-1) i.v.) alone or with necrogenic dose of ISO (100 mg kg(-1) s.c.). Haemodynamic parameters were measured 24h after drug application together with analysis of blood, myocardial content of elements and histological examination. Results were confirmed by cytotoxicity studies using cardiomyoblast cell line H9c2. Rutin in a dose of 46 mg kg(-1) aggravated ISO-cardiotoxicity while the dose of 11 mg kg(-1) had no effect. These unexpected results were in agreement with in vitro experiments, where co-incubation with larger concentrations of rutin significantly augmented ISO cytotoxicity. Our results, in contrast to previous studies in the literature, suggest that the reported positive effects of peroral administration of rutin were unlikely to have been mediated by rutin per se but probably by its metabolite(s) or by some other, at this moment, unknown adaptive mechanism(s), which merit further investigation.     

Personalized dynamic network models of the human brain as a future tool for planning and optimizing epilepsy therapy

Epilepsy is a common neurological disorder, with one third of patients not responding to currently available antiepileptic drugs. The proportion of pharmacoresistant epilepsies has remained unchanged for many decades. To cure epilepsy and control seizures requires a paradigm shift in the development of new approaches to epilepsy diagnosis and treatment. Contemporary medicine has benefited from the exponential growth of computational modeling, and the application of network dynamics theory to understanding and treating human brain disorders. In epilepsy, the introduction of these approaches has led to personalized epileptic network modeling that can explore the patient's seizure genesis and predict the functional impact of resection on its individual network's propensity to seize. The application of the dynamic systems approach to neurostimulation therapy of epilepsy allows designing stimulation strategies that consider the patient's seizure dynamics and long-term fluctuations in the stability of their epileptic networks. In this article, we review, in a nontechnical fashion suitable for a broad neuroscientific audience, recent progress in personalized dynamic brain network modeling that is shaping the future approach to the diagnosis and treatment of epilepsy.