Potassium channels as prominent targets and tools for the treatment of epilepsy.

INTRODUCTION: K+ channels are of great interest to epilepsy research as mutations in their genes are found in humans with inherited epilepsy. At the level of cellular physiology, K+ channels control neuronal intrinsic excitability and are the main contributors to membrane repolarization of active neurons. Recently, a genetically modified voltage-dependent K+ channel has been patented as a remedy for epileptic seizures. AREAS COVERED: We review the role of potassium channels in excitability, clinical and experimental evidence for the association of potassium channelopathies with epilepsy, the targeting of K+ channels by drugs, and perspectives of gene therapy in epilepsy with the expression of extra K+ channels in the brain. EXPERT OPINION: Control over K+ conductance is of great potential benefit for the treatment of epilepsy. Nowadays, gene therapy affecting K+ channels is one of the most promising approaches to treat pharmacoresistant focal epilepsy.

Intracortical microinjections may cause spreading depression and suppress absence seizures.

Intracerebral microinjection is a commonly used technique for local delivery of biologically active agents. However, it is known that mechanical injury of the cortex can induce spreading depression (SD), a wave of transient cellular depolarization. We examined the effects of intracortical microinjections of a new selective I(h) channel antagonist ORG 34167 and of different control treatments (saline and sham microinjections) on spontaneously occurring spike-wave discharges (SWDs) in WAG/Rij rats, a valid genetic model of absence epilepsy. Electroencephalographic (EEG) recording in awake rats has shown that both the drug and control microinjections are followed by long-term (for more than an hour) suppression of SWDs. dc-EEG recording in WAG/Rij rats has revealed that sham microinjections induce SD in 65% (31/48) cases. Number of SWDs decreased substantially for at least 90 min after the sham injections which induced cortical SD but remained unchanged if SD was not triggered by microinjection. These findings suggest that SD induced by intracortical microinjection may contribute to long-term suppression of non-convulsive epileptic activity after this experimental procedure.

Lateral asymmetry of early seizure manifestations in experimental generalized epilepsy.

Reorganization of seizure networks during epileptogenesis involves cortico-subcortical and interhemispheric interactions. In the audiogenic kindling (AK) model of generalized tonic-clonic seizures, upstream seizure propagation along ascending brainstem-to-forebrain pathways determines progressive intensification of repeated sound-induced convulsions. Full-blown audiogenic seizures are bilaterally symmetric and their repetition results in bisynchronous recruiting the cortex in secondary epileptogenesis. The present study describes lateral asymmetry of initial behavioral and EEG manifestations of audiogenic seizures and AK in Wistar and WAG/Rij rats with acoustic hypersensitivity. These rats exhibit consistent individual lateralization of running seizures (run directionality) induced by repeated binaural stimulation. Since this initial preconvulsive running reflects seizure onset in the auditory brainstem, the running asymmetry suggests non-symmetric early epileptic activation of brainstem substrates by sound in these rats. Repetition of the asymmetric brainstem seizures led to asynchronous recruiting the cortex into seizure network and lateralization of running seizures was predictive for asymmetry of early cortical seizure manifestations in Wistar and WAG/Rij rats. Both electrographic markers of AK, spreading depression (SD) and post-running afterdischarge, first appeared in the cortex ipsilateral to run direction, suggesting lateralized brainstem-to-forebrain seizure generalization during AK. At the population level, no bias in lateralization of running and SD was found in Wistar and WAG/Rij rats but incidence of secondary cortical seizures varied, depending on strain and run laterality. Among Wistar rats, cortical seizures developed more rarely in right-runners than in left-runners, suggesting enhanced resistance of the right hemisphere to epileptogenesis in rats of this strain. WAG/Rij rats with mixed (absence and audiogenic) epilepsy showed weak lateralization of early cortical seizures and no left-right difference in their incidence during AK. Present findings suggest (1) lateralized brainstem-to-forebrain seizure propagation and hemispheric difference in its facility in Wistar rats, (2) alterations of intra- and interhemispheric seizure propagation in WAG/Rij rats with genetic absence epilepsy.

[Social hygienic study of motor activity in children of school age].

Findings on motor activity impact on health status of children of primary school age are discussed. It is revealed that among first grade children dynamics of health conditions, physical development and physical readiness and characteristics of cardiac rhythm regulation evenly are impacted by regimen of disciplined motor activity during school year. At that, actual and as a rule increased school load of growing child combined with decreased motor activity negatively impacts health and morphologic functional characteristics of first grade children. Research findings were used to develop regional standards of assessment of physical development and physical readiness of seven-year-old children to be applied in pediatrician practice. Standards are to be used during mass and individual medical check-ups, medical groups assignment for physical training and sporting sections selection. Organizational technologies of intersectoral approach are discussed.

Audiogenic seizures associated with a cortical spreading depression wave suppress spike-wave discharges in rats.

To study the role of the cortex and sub-cortical structures in the generation of epileptic spike-wave discharges in more detail, cortical and striatal activity was eliminated by the induction of spreading depression in a non-invasive way. EEG and DC potentials were recorded from the cortex and striatum of WAG/Rij rats. Several of these rats show two forms of generalised epilepsy: spontaneously occurring non-convulsive absence seizures, together with convulsive audiogenic seizures. The latter can be evoked by a brief sound stimulation, provoking a fit of wild running, which is regarded as the first phase of an audiogenic seizure. In a majority of fits the cortical DC potential does not show main changes, while the spontaneously occurring spike-wave discharges are briefly suppressed for some minutes. In a minority of fits, however, audiogenic seizures are associated with a spreading depression wave, clearly expressed in the cortical DC potential. This wave is bilaterally initiated in the cortex and propagates to the caudate nucleus of the striatum. In these cases spontaneously occurring spike-wave discharges are fully suppressed for about 1 h. It is suggested that cortical spreading depression, triggered by a short audiogenic seizure, induces a long-lasting suppression of spike-wave discharges. These results are in line with the concept that spike-wave discharges are originally initiated in the cortex, as proposed by the 'cortical focus' theory. The precise role of the striatum remains less clear, although this structure seems not to play a pivotal role in spike-wave generation.

[Audiogenic kindling in WAG/Rij rats: change in behavioral and electrophysiological responses to repetitive short acoustic stimulation]. / Audiogennyi kindling u krys Wag/Rij: ismenenie povedencheskikh i élektrofiziologicheskikh reaktsii na povtornoe pred''iavlenie korotkoi zvukovoi stimuliatsii.

Running and tonic convulsions induced by sound stimulation (audiogenic seizures, AS) are known to be brainstem-dependent, but their repeated induction leads to the recruiting forebrain structures into AS expression manifested by the development of clonic convulsions and cortical epileptic activity (audiogenic kindling). Behavioral and electrophysiological manifestations of audiogenic kindling were studied in AS-prone WAG/Rij rats exhibiting two types of genetically determined generalized seizures: convulsive audiogenic and nonconvulsive absence (spontaneous spike-wave discharges generated by thalamocortical circuits). Twenty three repeated (with 2 days intervals) sound stimulations inducing a short running episode led to a progressive increase in AS duration from 6.2 +/- 0.4 s to 24.7 +/- 2.9 s mainly due to the appearance of additional postrunning facial-forelimb clonic convulsions of increasing duration and severity. Fully kindled (Racine's stage 5) seizures were accompanied by a bilateral slow-potential wave of cortical spreading depression (SD) nonsynaptically propagating to both striata and by a long-term postictal suppression of spontaneous absence seizures. Neither corticostriatal SD, nor the spike-wave discharges suppression were observed after running induced by sound in non-kindled rats or by attenuated (subthreshold for clonus) sound in kindled rats. Subthreshold stimulation of kindled rats provoked postictal high-amplitude spiking in the cortex. It is concluded that the recruitment of the cortex into a kindled AS network triggers a corticostriatal SD which may underlie the postictal inhibition of non-convulsive seizures, which follow the kindled AS.

[Ischemic and hypoxic depolarization in the rat neocortex]. / Ishemicheskaia i gipoksicheskaia depoliarizatsiia v neokortekse krys.

Cortical negative DC potential shifts were studied on two experimental models: focal cortical ischemia provoked by a photothrombotic occlusion of the distal part of the middle cerebral artery (dMCA) and a combination of systemic hypoxia induced by bilateral ligation of the common carotid arteries (temporary ligation of the left artery and permanent ligation of the right one) with breathing with 0.5% carbon monoxide (CO). The perifocal ischemic depolarization (ID) after the dMCA thrombosis was found to reach 28-33 mV and then gradually decline during 80 min to a certain residual level about 5 mV. Spontaneous depolarization didn't occur during hypoxia but it was easily provoked in one or both hemispheres by the waves of the cortical spreading depression (SD). The amplitude of hypoxic depolarization (HD) didn't exceed 20 mV, was remarkably stable during hypoxic condition (more than 60 min) and returned to the baseline level within 20-30 min after the cessation of CO breathing and releasing of the left carotid artery. Despite the similar durations of the ID and HD, their functional consequences differed greatly. The ID led to a damage of the nervous tissue as evidenced by a reduction of the SD amplitude (to 20-25%) and biphasic change in persistent negative potential (PNP) evoked by the SD wave alone. The 1.5-2-fold increase in the PNP amplitude in the perifocal region was the most prominent outcome of the ID. In contrast to the ID, the SD and PNP characteristics were unchanged after the HD. Such a discrepancy between the ID and HD can be related with their different origin. The results suggest that the HD is produced by blood-brain barrier processes associated with the intensive vasospasm and vasogenic edema. Besides these phenomena, the other well-known factors such as a disturbance of permeability of neuronal membranes, glutamatemediated exitotoxicity, and tissue destruction determine the ID noxious influences.

[The persistent negative potential provoked in different structures of the rat brain by a single wave of spreading cortical depression]. / Ustoichivyi negativnyi potentsial, provotsiruemyi v razlichnykh strukturakh golovnogo mozga krysy odinochnoi korkovoi volnoi rasprostraniaiushcheisia depressii.

The persistent negative potential (PNP) developed after a single wave of cortical spreading depression (SD) in the cortex, hippocampus, thalamus, and caudate nucleus. The PNP lasted for about 3-4 hours, its amplitude was 6-7 mV in the ipsilateral and 3-4 mV in the contralateral structures. After development of bilateral primary cortical SD waves the amplitudes of the respective PNP were summed up and reached 9-11 mV. However, after the repeated waves of cortical SD produced with 15-30-min intervals, the PNP level remained unchanged. We think that the PNP is an electrographic manifestation of the well known persistent vasoconstriction after a single wave of cortical SD. It seems to be related with reticular activation due to functional decortication.

[Spreading depression in the corticostriatal system of the rat brain during a seizure process induced by the daily administration of pentylenetetrazole]. / Rasprostraniaiushchaiasia depressiia v kortiko-striatnoi sisteme mozga krysy pri sudorozhnom protsesse, vyzvannom ezhednevnym vvedeniem pentilentetrazola.

Spreading depression (SD) in the cortex and the caudate nucleus induced by 40 mg/kg i.p. pentylenetetrazole (PTZ) injection was studied in awake rats with implanted carbon electrodes. It was shown that spontaneous bilateral occurrence of cortical SD was the most probable and had an effective inhibitory influence on seizures after the first PTZ application. Penetration of cortical SD waves into the caudate nucleus and their return to the cortex substantially prolonged the anticonvulsive effects of SD. In the course of daily repeated PTZ injections the cortico-caudate SD propagation reduced progressively being accompanied by a decrease of efficiency of its inhibitory effect and interictal spike activity intensification. Similar restriction of SD propagation was observed without any seizure manifestations under the conditions of daily cortical electrical stimulation (without systemic drug treatment). So, reducing the cortico-caudate SD incidence during PTZ kindling is rather the cause of seizure facilitation than its consequence.

Reduced incidence of cortical spreading depression in the course of pentylenetetrazol kindling in rats.

Subconvulsive dosages (40 mg/kg) of intraperitoneally applied pentylenetetrazol (PTZ) elicit, after a latency of 1 min, slow potential waves of spreading depression (SD) in the thalamus and 20 s later also in the cerebral cortex of rats. The PTZ-induced SD waves appear only exceptionally in the caudate nucleus and hippocampus. Repeated daily application of 40 mg/kg PTZ elicits kindling of epileptic phenomena manifested by increasing incidence of high-amplitude spikes in the EEG, myoclonic jerks and minimal and later maximal generalized seizures but by decreasing incidence of cortical SD. It is concluded that kindled epileptic activity interferes with the generation of SD waves the reduced incidence of which may contribute to the development of more severe forms of epilepsy.

[The electrophysiological characteristics and behavioral manifestations of hippocampal and thalamic spreading depression]. / Elektrofiziologicheskie osobennosti i povedencheskie proiavleniia gippokampal'noi i talamicheskoi rasprostraniaiushcheisia depressii.

Behavioral manifestations of spreading depression (SD) were compared with SD electrophysiological characteristics in these structures. Carbon electrodes were suitable for recording DC slow potential changes in freely moving animal. It was shown that short (0.1 s) high-frequency (200 Hz) electrical stimulation of thalamus and hippocampus with intensity 50-300 microA easily triggered SD wave in these structures in narcotized and awake rats. The threshold of SD occurrence in dorsal hippocampus was the same or sometimes lower than that of the primary afterdischarge. Penetrating SD into ventral hippocampus provoked long latency seizure discharge and wet-dog shakings in awake rats. Intensity of locomotor activity accompanying bilateral hippocampal SD exceeded orienting response significantly. Contrary to hippocampus, thalamic SD was usually subseizure and unilateral phenomenon and had a clear tranquil effect on the rat locomotor activity. It was found that the rats didn't change the compartment preference after 20-45 SD waves in the thalamus or in the hippocampus.

Re-entry waves of Leao's spreading depression between neocortex and caudate nucleus.

About 40% of spreading depression (SD) waves elicited from the parieto-occipital cortex of anesthetised rats penetrated through the temporal lobe structures (amygdala) into the caudate nucleus. Almost 70% of these SD waves did not terminate in the caudate but returned to the cortex and spread through it toward the site of SD initiation. Longer cortico-caudate (5.9 +/- 0.1 min) than caudate-cortical (4.7 +/- 0.2 min) conduction times suggest that SD enters and leaves caudate through routes of different length. SD waves elicited by KCl microinjection into the caudate reached frontal and parieto-occipital cortical electrodes with latencies indicating that the transit point is 5 mm closer to the rostral than to the caudal electrode. The region best satisfying this condition corresponds to rostral claustrum. The directionally biased SD conduction through the transit zone provides a re-entry path for cortico-caudate-cortical SD propagation and forms thus a natural reverberator the small dimensions of which preclude generation of repetitive SD waves.

[Spreading depression in the thalamus, hippocampus and caudate nucleus of the rat during electrical stimulation of the parietal area of the cortex]. / Rasprostraniaiushchaiasia depressia v talamuse, gippokampe i khvostatom iadre krysy pri élektricheskom razdrazhenii temennoi oblasti kory.

Parameters of electrical stimulation (ES) of the rats cerebral cortex which synaptically induced spreading depression (SD) in deep structures were found. The thalamic SD was regularly triggered by short (0.02-0.05 s) high-frequency (200-500 Hz) ES of the parietal cortical surface. In this case the EEG control showed the absence of any seizure activity in the cortical and subcortical structures. Nembutal (20-40 mg/kg) raised the SD thresholds, but did not prevent the short-latency thalamic SD. The ES of the parietal cortex was not sufficiently effective for SD synaptic excitation in the hippocampus and caudate nucleus. In contrast to the thalamic SD, the hippocampal one was accompanied by the episodes of epileptiform activity at certain SD phases. Thus, the low subseizure threshold of the synaptically triggered cortical and subcortical SD should be taken into account when biological purpose of the SD is discussed.