No abstract

Cognitive impairment in six-week -old rats has been studied in the lithium-pilocarpine model of adolescent temporal lobe epilepsy in humans. The pilocarpine-treated rats (n =21) exhibited (a) a decreased exploratory activity in comparison with control rats (n = 20) in the open field (OP) test and (b) a slower extinction of exploratory behavior in repeated OP tests. The Morris Water Maze (MWM) test showed that the effect of training was less pronounced in the pilocarpine-treated rats, which demonstrated disruption of predominantly short-term memory. Therefore, our study has shown that lithium-pilocarpine seizures induce substantial changes in exploratory behavior and spatial memory in adolescent rats. OP and MWM tests can be used in the search of drugs reducing cognitive impairments associated with temporal lobe epilepsy.

The common final stage in convulsive syndrome is an excess of rhythmic activity of motor cortex neurons. The initial points in the development of this stage can be located in different brain structures and can be the targets of different etiological factors. The pathways of the pathogenesis of convulsions from target to appearance of intense electrical spike activity in the motor centers are also various. The main approaches to studying the pathogenesis of epilepsy and identification of the molecular mechanisms underlying it and seeking anticonvulsive agents include experimental models of convulsive states [20].The clear multiplicity in the nosological forms of human epilepsy dictates the need to use and compare different models of convulsive states induced in animals. The role of convulsants, i.e., actions provoking transient (convulsive seizures) or prolonged recurrent convulsive states, can be played by many chemical agents with different mechanisms of action, as well as electrical stimulation. Depending on the intensity and duration of action, these produce increased convulsive readiness and/or active convulsive foci detected by neurological observations of experimental animals, Krushinskii-Molodkina (KM) rats have a genetic predisposition to increased audiogenic convulsive readiness and respond to sound signals with clonic-tonic convulsive seizures reminiscent of epileptic attacks in humans. The aims of the present work were to compare the neurological manifestations of the convulsant pentylenetetrazol (corazol) in Wistar and KM rats, i.e., to identify the contribution of genetically caused audiogenic convulsive readiness, and to assess the abilities of the NMDA receptor blockers memantine and 1-phenylcyclohexylamine (IEM-1921) to prevent the actions of pentylenetetrazol in KM rats. Convulsive reactions to administration of pentylenetetrazol were significantly stronger in KM rats than in Wistar rats, and deaths in KM rats were 2.1 times more frequent. Both blockers demonstrated the ability to reduce convulsive reactions to administration of pentylenetetrazol; the prophylactic action of IEM-1921 was more marked. IEM-1921 decreased the mean intensity of convulsive seizures by 2 points on a 5-point scale, while the total duration of generalized seizures decreased 41-fold. IEM-1921 completely prevented deaths among the animals, while memantine produce no more than a tendency to a decrease in lethality (68% in controls, 50% after administration of memantine). The results obtained here provide evidence that NMDA glutamate receptors play an important role in the molecular mechanisms of convulsive syndromes of different etiologies.

Experiments on frog neuromuscular junction preparations with extracellular recording of nerve terminal action potentials and single-quantum end-plate currents (EPC) were used to assess the time course of evoked quantum secretion of mediator by analyzing histograms of the distribution of true synaptic delays. These studies showed that noradrenaline, isoproterenol, and dobutamine change the kinetics of secretion of quanta, leading to synchronization of the process of mediator release; substances blocking beta-adrenoceptors (atenolol, propranolol) blocked this effect. Clonidine and phenylephrine, which activate alpha-receptors, had no effect on the kinetics of secretion, while the alpha-blocker phentolamine had no effect on the synchronizing action of noradrenaline. Reconstruction of multiquantum EPC from changes in the level of synchronization in the release of individual quanta, showed that EPC amplitude increased in response to noradrenaline by 17%, and that this was due only to alterations in the time course of secretion. These data led to the conclusion that there is a special presynaptic mechanism which facilitates the action of sympathomimetics, acting via beta-adrenoceptors.

Animal models of seizures and epilepsy are very diverse and instrumental for elucidating the mechanisms that underlie convulsive states and epileptogenesis. A single injection of pentylenetetrazole (PTZ) induces seizures, however, does not raise the risk of further development of epilepsy. Pilocarpine, immediately after injection, evokes epileptical state and, following a latent period, results in the development of spontaneous seizures, i.e. the drug triggers epileptogenesis. Assuming that in the PTZ model morphofunctional changes are mainly transient, while changes in the lithium-pilocarpine (PC) model may indicate the brain epileptization, we set ourselves the task of comparing morphological and functional characteristics of the hippocampal field CA1 in control and two experimental animal groups in 24 h after injection of the convulsants. We revealed the changes specific to the PC model and indicating neurodegeneration: a decrease in the cell spacing density, a diminution in the number of the viable NeuN-expressing neurons, an increased activity of the proapoptotic protease caspase-3. A characteristic feature of the PTZ model was the appearance of hyperchromic neurons with normal viability. In both models, the expression of the excitatory amino acid carrier EAAT1 increased by about 40% as compared to control. These morphofucntional correlates of reversible changes in the nervous tissue caused by seizures, as well as the early disorders leading to long-term brain epileptization can be used as indicators allowing assessment of a therapeutic potential of novel anticonvulsive drugs.