Causes and consequences of pathogenic processes in evolution: implications from experimental epilepsy in animals.

Examples from experimental epilepsy in animals are used to illustrate the view that a crucial role of the transfer of mechanisms from compensatory into pathogenic (e.g. lethal ones in the course of a disease), is played by the power of pathologic stimuli. In the genesis of epilepsy it is suggested that a critical increase of endogenous factors may underlie the conversion of the absence form of epilepsy into a generalized self-supporting form. The ability to precipitate endogenous self-augmenting mechanisms of diseases may have increased in the course of evolution. The lethal result of a serious pathogenic process leads to the suggestion that organisms cope with the disease by dying. This prevents spreading of the putative infectious disease within the population. This mechanism of disease aggravation could play a role in the survival of the species and in further evolutionary progress. This may explain why certain species may have survived in evolution and supports the theory of synthetic evolution.

The role of TNF-alpha in amygdala kindled rats.

In the present study, the interaction between epileptogenesis and the immune system were studied in a kindling model. First, the effects of a single administration of TNF-alpha (5.0 microg/kg, i.p.) on seizure and EEG activity were investigated in amygdala-kindled rats. TNF-alpha treated rats showed more prolonged epileptiformic discharges than control rats. TNF-alpha also induced a decrease in the power of delta band and an increase in theta and alpha activity. In addition, a marked increase in the power of beta and gamma band was observed. The EEG changes were most numerous in the frontal cortex and amygdala. All effects were registered 24 h after TNF-alpha administration. Finally, electrical stimulation enhanced the level of TNF-alpha in blood serum from 1.9 +/- 1.5 to 12.7 +/- 3.8 pg/ml and in brain tissue 56.8 +/- 6.0 to 109.2 +/- 6.0 pg/mg, as was determined via the ELISA method. It can be concluded that there is a mutual facilitative interaction of both epileptogenic and cytokine-derived mechanisms on this type of seizure. The changes in the power spectrum of the EEG after TNF-alpha might contribute to intensify thalamic-derived facilitation of epileptic discharge in cortical structures.

Effects of delta-sleep-inducing peptide on NMDA-induced convulsive activity in rats.

Acute experiments on rats showed that the ED100 of NMDA for induction of clonic convulsions was 0.53 microgram, while the ED100 of NMDA for inducing tonic extension of the forelimbs was 5.02 micrograms/animal. Determination of these parameters after administration of delta-sleep-inducing peptide (100 micrograms/kg, i.p.) revealed 2.3- and 4.46-fold increases. These results provide evidence for a neuroprotective role of delta-sleep-inducing peptide in relation to excitatory amino acid receptor agonists.

Delta-sleep-inducing peptide and its analogs and the serotoninergic system in the development of anticonvulsive influences.

Experiments on rats were carried out to study the effects of administration of delta-sleep-inducing peptide (DSIP) and its analogs (9-14) into the reticular part of the substantia nigra and ventral hippocampus on picrotoxin- and kainate-induced epileptic activity. Additionally, the uptake of [3H]tryptophan by brain structures was studied. Intranigral and intrahippocampal microinjections of peptide and its analogs were found to have anticonvulsant effects against both picrotoxin- and kainate-induced epileptic activity. Studies of the effects of DSIP and its structural analogs on the uptake of tryptophan by brain structures showed that peptides predominantly increased uptake of this amino acid. It is suggested that brain structures which modulate tryptophan uptake are largely responsible for the anticonvulsant actions of DSIP and its analogs. The results obtained here provide evidence that the serotoninergic system is not of key importance in mediating the anticonvulsant effects of DSIP and its analogs.

Effects of delta-sleep-inducing peptide in cerebral ischemia in rats.

Experimental studies were carried out to investigate the neuroprotective effects of delta sleep-inducing peptide in animals with cerebral ischemia induced by bilateral compression of both carotid arteries, and to compare the efficacy of this peptide with that of MK-801. These studies led to the conclusion that the peptide had pronounced anti-ischemic effects, which were evident within 24 h and consisted of reductions in the severity of postural abnormalities in rats with bilateral cerebral ischemia, along with a reduction in lethality. Comparison of the efficacies of peptide and MK-801 showed the peptide to have the greater neuroprotective effect. These results are regarded as providing an experimental basis for using the peptide as a therapeutic agent in patients with stroke.

[Changes in the blastogenic lymphocyte transformation during kindling induced by picrotoxin in rats]. / Izmeneniia blastnoi transformatsii limfotsitov pri kindlinge, vyzvannom primeneniem pikrotoksina u krys.

Picrotoxin-induced kindling was shown to suppress the blastogenic response to bacterial lipopolysaccharide and phytogemagglutinin in male Wistar rats. The delta-sleep-inducing peptide as well as carbamazepine prevented the epileptogenic effects of picrotoxin. Carbamazepine was also effective against decreasing of phytogemagglutinin-induced blastogenic response.

[The delta sleep-inducing peptide, its analogs and the serotoninergic system in the development of anticonvulsant action]. / Del'ta-son indutsiruiushchii peptid, ego analogi i serotoninergicheskaia sistema v razvitii protivosudorozhnogo deistviia.

A seizure-protecting effect of the delta-sleep-inducing peptide (DSIP) and its analogues was revealed. An intensive sorption of H3 tryptophan occurred under the effect of the DSIP and its analogues. The data obtained suggests that the serotoninergic system plays no important part in the seizure-protecting effect.

[Effects of delta-sleep-inducing peptide during ischemic injury of the rat brain]. / Effekty del'ta-son-indutsiruiushchego peptida v usloviiakh ishemicheskogo povrezhdeniia golovnogo mozga u krys.

An anti-ischemic effect of the delta-sleep-inducing peptide (DSIP) was found in rats. The DSIP effect was more obvious than that of the MK-801. The data obtained is discussed considering a possible use of the DSIP for brain stroke prophylaxis.

[The effect of the delta sleep-inducing peptide on NMDA-induced seizure activity in rats]. / Vliianie del'ta-son indutsiruiushchego peptida na sudorozhnuiu aktivnost', vyzvannuiu NMDA u krys.

The ED100 of the NMDA inducing clonic seizures (0.53 mcg) or tonic extension of forelimbs (5.02 mcg) increased their efficiency 2.3-fold and 4.46-fold, resp., due to the delta-sleep-inducing peptide administration in rats. The data obtained suggests a neuroprotective effect of the peptide on agonists of excitatory amino acid receptors action.

Effect of intranigral dosage with delta-sleep-inducing peptide and its analogs on movement and convulsive activity in rats.

Studies were carried out in rats on the effects of the administration of delta-sleep-inducing peptide (DSIP) and its analogs (1-4) into the reticular part of the substantia nigra on movement and convulsive activity. Intranigral microinjection of DSIP, and of DSIP-1 and DSIP-4, reduced horizontal and vertical movement activity as well as excursions to the center of the open field. DSIP, DSIP-2, and DSIP-3 had anticonvulsant effects, consisting of increases in the latent periods of the first convulsion and clonicotonic convulsions induced by picrotoxin, and reductions in the mean intensity of convulsions. It is suggested that changes in the structure of DSIP are accompanied by alterations in the strength of the effects of this peptide on horizontal and convulsive activity after dosage into the reticular part of the substantia nigra. The results indicating that these peptides have protective activity in experimental convulsive syndrome suggest that a relationship exists between DSIP-induced reductions in movement activity and the anticonvulsive efficacy of DSIP analogs when administered intranigrally, this being one of the components of the nigrodependent mechanisms of inhibition of convulsions.

[A rotational syndrome induced by administration of the delta sleep-inducing peptide into the reticular portion of the rat substantia nigra]. / Rotatsionnyi sindrom, vyzyvaemyi vvedeniem del'ta-son-indutsiruiushchego peptida v retikuliarnuiu chast' chernogo veshchestva krys.

Unilateral intranigral administration of a delta-sleep-induced peptide (DSIP) evoked a contralateral rotation. Naloxon prevented development of the effect whereas haloperidol administration enhanced the DSIP cataleptogenic effect.

Chemical kindling: implications for antiepileptic drugs - sensitive and resistant epilepsy models.

The efficacy of phenobarbital (PB) and phenytoin (PHT) was evaluated against the convulsions in chemically (picrotoxin, PTX) kindled rats. Two protocols were used: assessment of seizures immediately after the completion of the kindling procedure and after the 2-week postkindling PTX-free period, as compared with acute PTX seizures. Kindled convulsions were more sensitive than acute PTX seizures to the antiepileptic action of PB and PHT. On the other hand, the "postkindling state" was characterized by the enhancement of the severity of the convulsions in comparison with both kindled and acute PTX seizures and dramatic increase in the resistance to the action of antiepileptic drugs (AEDs). It is concluded that the two paradigms--kindling proper and "postkindling"--could be applied as models for AED-sensitive and AED-resistant animal epilepsy models correspondingly.

[The role of the delta sleep-inducing peptide in the formation of neuropathological syndromes]. / Rol' del'ta-son-indutsiruiushchego peptida v formirovanii neiropatologicheskikh sindromov.

The authors considered the pathogenetic role of delta-sleep inducing peptide (DSIP) in different neuropathological syndromes development and manifestation. According to own as well as published in the literature data authors showed the parkinsonian and the rotational syndromes development following DSIP central administration. Briefly, DSIP is a neuropeptide which play significant role in the mechanisms of development of different neuropathological syndromes, namely, epileptic, parkinsonian, withdrawal, rotational and others syndromes.

[The role of the substantia nigra in the mechanisms of the cessation of epileptic activity]. / Rol' chernogo veshchestva v mekhanizmakh prekrashcheniia épilepticheskoi aktivnosti.

In the review of literature and author's own data the participation of pars compacta and pars reticulata of the substantia nigra in mechanisms of epileptic syndrome development and cessation of epileptic activity was shown. The results are given which testified for dependence of substantia nigra-derived effects upon form and intensity of epileptic activity as well as upon neuromediator and peptidergic systems of the brain involvement. The conclusion was made concerning the significance of substantia nigra as a part of antiepileptic system of the brain in the processes of restriction and suppression of epileptiform manifestations.

[The effect of the intranigral use of the delta sleep-inducing peptide and its analogs on the motor and seizure activities of rats]. / Vliianie vnutrinigral'nogo primeneniia del'ta-son indutsiruiushchego peptida i ego analogov na dvigatel'nuiu i sudorozhnuiu aktivnost' krys.

The effects of delta-sleep inducing peptide (DSIP) and its analogues (1-4) administered into substantia nigra pars reticulata on locomotor and seizure activity were estimated in experiments in rats. It was shown that intranigral microinjection of DSIP as well as DSIP-1-DSIP-4 caused decreasing of horizontal, vertical locomotor activity and attendance of central sectors of the "open field". Antiseizure effects, i.e. the first and clonic-tonic picrotoxin-induced convulsive latent period lengthening and their intensity decreasing, revealed DSIP, DSIP-2 and DSIP-3. Authors suppose that changes of DSIP structure lead to changes of effects expression on locomotor and seizure activity in conditions of their administration into substantia nigra reticulata. Obtained data concerning protective effects of studied peptides on experimental seizure syndrome allow to conclude that there is interaction between DSIP-induced hypokinesia and DSIP analogues anticonvulsive effectiveness in case of their intranigral administration which is likelihood is one of the component of nigral-dependent seizure-suppressive mechanism.

Seizure-protecting effects of kyotorphin and related peptides in an animal model of epilepsy.

Administration of peptides kyotorphin (KT), neokyotorphin (NKT), and d-ser-2-NKT into the lateral brain ventricle (10 nmol) increased the latency and attenuated the severity of picrotoxin-induced convulsions in rats. Anticonvulsive effects of the peptides were also observed after their administration into the CA1 hippocampi (2.5, 5, 10 nmol), with the order of potency d-ser-2-NKT-->NKT-->KT. When injected into the substantia nigra reticulata, the 10 nmol dose of NKT and d-ser-2-NKT displayed equal seizure-protecting effect, which was higher than that for KT. It is concluded that kyotorphin and its analogs provide structure-dependent, dose-dependent, and target site-dependent antiepileptic effect.

Influence of the neuropeptide galanin on active avoidance in rats.

It was demonstrated in experiments on rats that the injection of the neuropeptide, galanin (200, 500, and 1000 ng), into the lateral cerebral ventricles induced a dose-dependent decrease in the number of successful attempts at avoidance in rats trained preliminarily to active avoidance by jumping. The preliminary administration of the cholinolytic, atropine (1 mg/kg, intraperitoneally), to the rats also caused an acceleration of the damping of the conditioned reflex and potentiated the indicated effect of galanin during the experiment. The use of the opioid antagonist, naloxone (1 mg/kg, intraperitoneally), did not exert an influence on the animals' behavior, but blocked the galanin-provoked acceleration of the extinction of the active avoidance habit. The intraperitoneal administration of a noncompetitive antagonist of excitatory amino acids, ketamine (10 mg/kg), did not influence the character of the animals' behavior nor the indicated effects of galanin. It was concluded that galanin possesses an amnestic action in the active avoidance test, and that this effect of the peptide is determined by the suppression of cholinergic and activation of opiatergic transmission in the central nervous system.

On the mechanism of antiepileptic peptides appearance in the cerebrospinal fluid.

Intraventricular injection of cerebrospinal fluid obtained from cats with electroshock seizures resulted in suppression of generalized picrotoxin-induced seizures in rats. Antiepileptic action of cerebrospinal fluid was abolished by partial bilateral midbrain destruction that included the region of colliculi superii. Electrical stimulation of cerebellum in cats with such destructions caused the appearance of a pronase-sensitive antiepileptic substances in cerebrospinal fluid.

The influence of activation of the superior colliculi on convulsive activity during picrotoxin kindling.

It has been demonstrated in experiments in rats in which kindling was induced by repeated subconvulsive doses of picrotoxin (1.0 mg/kg) that the bilateral microinjection of picrotoxin, bicuculline, and penicillin into the deep layers of the superior colliculi of the corpora quadrigemina leads to the appearance of a generator of pathologically intensified excitation. An increase in the latent period of the initial convulsive manifestations, the suppression of clonic-tonic convulsive attacks, as well as the prevention of generalized epileptic activity induced by the systemic utilization of picrotoxin were observed under the conditions of the appearance of a generator of pathologically intensified excitation. An inference was drawn regarding the role of the superior colliculi in the mechanisms of the suppression of convulsive activity and regarding their inclusion in the antiepileptic system.