Reactive oxygen species and reactive nitrogen species: relevance to cyto(neuro)toxic events and neurologic disorders. An overview.

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are formed under physiological conditions in the human body and are removed by cellular antioxidant defense system. During oxidative stress their increased formation leads to tissue damage and cell death. This process may be especially important in the central nervous system (CNS) which is vulnerable to ROS and RNS damage as the result of the brain high O(2) consumption, high lipid content and the relatively low antioxidant defenses in brain, compared with other tissues. Recently there has been an increased number of reports suggesting the involvement of free radicals and their non-radical derivatives in a variety of pathological events and multistage disorders including neurotoxicity, apoptotic death of neurons and neural disorders: Alzheimer's (AD), Parkinson's disease (PD) and schizophrenia. Taking into consideration the basic molecular chemistry of ROS and RNS, their overall generation and location, in order to control or suppress their action it is essential to understand the fundamental aspects of this problem. In this presentation we review and summarize the basics of all the recently known and important properties, mechanisms, molecular targets, possible involvement in cellular (neural) degeneration and apoptotic death and in pathogenesis of AD, PD and schizophrenia. The aim of this article is to provide an overview of our current knowledge of this problem and to inspire experimental strategies for the evaluation of optimum innovative therapeutic trials. Another purpose of this work is to shed some light on one of the most exciting recent advances in our understanding of the CNS: the realisation that RNS pathway is highly relevant to normal brain metabolism and to neurologic disorders as well. The interactions of RNS and ROS, their interconversions and the ratio of RNS/ROS could be an important neural tissue injury mechanism(s) involved into etiology and pathogenesis of AD, PD and schizophrenia. It might be possible to direct therapeutic efforts at oxidative events in the pathway of neuron degeneration and apoptotic death. From reviewed data, no single substance can be recommended for use in human studies. Some of the recent therapeutic strategies and neuroprotective trials need further development particularly those of antioxidants enhancement. Such an approach should also consider using combinations of radical(s) scavengers rather than a single substance.

Metexyl (4-methoxy-2,2,6,6-tetramethylpiperidine-1-oxyl) as an oxygen radicals scavenger and apoptosis inducer in vivo.

A stable nitroxide radical named Metexyl (4-methoxy-2,2,6,6-tetramethylpiperidine-1-oxyl) was synthesized and its antioxidant and antitumor properties were investigated and compared with these of another nitroxide derivatives previously designed in our laboratories. Three experimental models were used: xanthine/xanthine oxidase system, pulse radiolysis and experimental rat cancer (Yoshida Sarcoma) in vivo. In this work we measured the rate constant of the reactions of Metexyl with enzymatically generated O2.- or radiolytically produced .OH. For comparison, the reactions of non radical derivative (4-acetamide-2,2,6,6-tetramethylpiperidinium acetate) or nitroxide Tempace (4-acetamide-2,2,6,6-tetramethylpiperidine-1-oxyl) with the above mentioned reactive oxygen radicals were also studied. The comparative ability of Metexyl to act as an inducer of apoptosis in vivo was also investigated in pharmacological test. The ring substituent (-OCH3) at position 4 of the Metexyl molecule had significant influence on its properties as antioxidant and apoptosis inducer. The results in this study suggest that Metexyl is a promising nitroxide antioxidant, which can induce apoptosis of tumor cells in vivo, thus providing a base for its further investigations in vitro and pharmacological applications.

Negative cortical DC shifts preceding and accompanying simple and complex sequential movements.

Negative cortical DC shifts preceding and accompanying the execution of four different motor tasks were analysed in 18 subjects (Ss): Repetitive flexions and extensions of the forefinger had to be performed either by the right (1) or the left (2) hand. This simple motor task was compared to a complex one in which flexions and extensions of forefinger and hand had to be alternated in a fixed sequence. The complex task had either to be performed by the right (3) or the left (4) hand. Thus, the four conditions differed in the side of the performing hand (right/left) and in task-complexity (simple/complex). After its voluntary initiation, each task had to be performed for at least a period of six seconds. A Bereitschaftspotential (BP) preceded the voluntary initiation of the movement. Task-performance was accompanied by a negative DC shift called a performance-related negativity (N-P). Amplitudes of BP and N-P were compared by analysis of variance (ANOVA) using the factors "performing hand" (right/left) and "task-complexity" (simple/complex). "Performing hand" had significant effects on N-BP and N-P in C3* and C4* (positioned over the primary motor cortex) but did not influence mid-central (Cz*), frontal (F3, Fz, and F4) or parietal (P3, Pz, P4) recordings. "Task-complexity" had significant effects on N-P in mid-central (Cz*, C1*, C2*) and parietal (P3, Pz) recordings with higher negativity for complex movements. Recordings in C3* and C4* did not vary with "task complexity".(ABSTRACT TRUNCATED AT 250 WORDS)

Negative cortical DC shifts preceding and accompanying simultaneous and sequential finger movements.

Cortical DC shifts preceding and accompanying the execution of five different bimanual motor tasks were analysed in 20 subjects. All tasks required repetitive flexions and extensions of the two forefingers for a period of at least six seconds. The temporal and spatial structures organization varied in the different tasks: (1) Simultaneous agonistic performance (forefinger flexion on both sides), (2) simultaneous antagonistic performance (e.g. flexion of the right, extension of the left forefinger), (3) sequential agonistic performance, (4) sequential antagonistic performance, (5) uncoordinated flexions and extensions of the two forefingers. Compared to (1) and (2), conditions (3) and (4) included a temporal delay between the performance of the two forefingers; compared to (1) and (3), conditions (2) and (4) required the subjects to perform movements of opposite directions with their two forefingers. Effects of the temporal factor (T; simultaneous vs. sequential) and the spatial factor (S; agonistic vs. antagonistic) on cortical DC shifts were investigated. The voluntary initiation of each motor task was preceded by a Bereitschaftspotential (BP). The performance of the complex tasks (1-4) was accompanied by a slow negative DC potential shift (N-P). In general, the BP did not differ depending on the temporal or spatial structures of the tasks (1-4). However, amplitudes of N-P (i.e. during tasks) were influenced by the temporal factor with significantly larger amplitudes in sequential than in simultaneous tasks. This difference was not a global phenomenon in all recordings but was selectively found in the recordings over the fronto-central midline.(ABSTRACT TRUNCATED AT 250 WORDS)