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 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.
A circulating digoxin-like factor contributes to the pathogenesis of myocardial ischaemia induced ventricular arrhythmias. As propranolol pretreatment of coronary artery ligated rats inhibited the Na, K(+)-pump in myocardium, the inhibitory effect of endogenous digoxin-like factor on Na+, K(+)-ATPase was probably masked in propranolol naive animals by the stimulatory action of catecholamines on Na+, K(+)-ATPase described previously.
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