Experiments on mice were performed to study the ability of monocationic and dicationic adamantane and phenylcyclohexyl derivatives to prevent the development of kindling induced by i.p. administration of pentylenetetrazol (Corasol, 35 mg/kg). The monocationic phenylcyclohexyl derivative IEM-1921 effectively slowed the development of kindling, this being seen over a wide range of doses (0.0001-0.1 micromol/kg). A monocationic adamantane derivative (memantine), also a selective non-competitive blocker of NMDA receptors, produced a similar effect at doses 100 times higher. The anticonvulsive activity of the dicationic phenylcyclohexyl derivative IEM-1925, which could block both types of glutamate receptors, differed from the activity of the monocationic derivative by having a more complex dose-response relationship. Thus, the development of kindling was suppressed by essentially the same doses as needed for the monocation IEM-1921 (0.001 micromol/kg). However, on reducing the dose by a factor of 10 (0.0001 micromol/kg), IEM-1925 facilitated the development of kindling. This difference in the prophylactic activities of selective NMDA receptor blockers and substances able to block both NMDA and AMPA receptors provides evidence that the mechanism of kindling involves both types of ionotropic glutamate receptor and the effects of compounds depend not only on the ratio of the contributions of these receptors, but also on the kinetic characteristics of the blocking action.

The capability of memantine, a noncompetitive antagonist of the NMDA receptors, to prevent impairments of cognitive functions in rats was investigated in the lithium-pilocarpine model of epilepsy. After status epilepticus, rats exhibited impaired exploratory behavior and spatial memory, and a decline of extinction of orienting behavior. Memantine administration prevented these disturbances. Thus, the blockade of the NMDA receptors immediately after status epilepticus allowed prevention of the development of the possible cognitive impairments.

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 mice addressed the link between convulsive syndrome and morphological changes in hippocampal neurons occurring on development of pentylenetetrazole (PTZ) kindling. Kindling was induced by i.p. PTZ (35 mg/kg) three times a week for one month. By the end of this period, 70% of the mice responded to administration of PTZ with severe clonic or clonic-tonic seizures. Hippocampal sections (stratum pyramidale, field CA1, Nissl staining) from convulsive mice showed large numbers of altered cells (24.7 ± 2.1%). Most of these were pyramidal neurons. These hyperchromic neurons had reduced body sizes, loss of turgor, wrinkling of the cell body, and deformation of dendritic processes. These dark-type changes were present in 2.3 ± 2.1% of neurons in the hippocampus of intact mice and mice resistant to the convulsogenic effect of PTZ (30% of the population). Immunohistochemical studies demonstrated normal expression of NeuN (Fox3) protein in all hippocampal cells, including dark hyperchromic neurons. This is evidence that neurons did not die en masse and were relatively viable. Prophylactic s.c. administration of NMDA receptor blockers (0.5 mg/kg memantine, 0.1 mg/kg IEM-1921, or 1 mg/kg IEM-1958) decreased the proportion of mice developing PTZ kindling from 70% to 40%. The proportion of altered neurons in the 60% of mice given NMDA blockers and not developing PTZ kindling or convulsions in the presence of blockers was 0.1 ± 0.06%, which was the same as in intact mice. Conversely, the hippocampus of mice demonstrating convulsions despite simultaneous administration of NMDA blockers showed 24.0 ± 5.6% hyperchromic neurons. These results provide evidence that pathologically altered neurons appeared after convulsive seizures in animals after PTZ kindling and that blockade of NMDA glutamate receptors could weaken both the development of convulsive syndrome and the concomitant morphological changes to hippocampal neurons.

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