Effects of ionotropic glutamate receptor channel blockers on the development of pentylenetetrazol kindling in mice

Abstract

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.

N‐methyl‐D‐aspartate receptor channel blockers prevent pentylenetetrazole‐induced convulsions and morphological changes in rat brain neurons

“…Previously reported data on the protective efficacy of IEM‐1921 in PTZ tests are scarce. One group reported that IEM‐1921 protected only four of 10 mice at a dose of 30 mg/kg in a PTZ seizure test (s.c. injection at the CD97 convulsant dose [85 mg/kg] of PTZ; Rogawski et al, ) and that it was highly effective at low concentrations against the development of PTZ kindling (Lukomskaya et al, ).…”

“…There is evidence that ketamine, another NMDA receptor channel blocker, is useful in the treatment of refractory status epilepticus (Dorandeu et al, ). A structurally similar compound, 1‐phenylcyclohexylamine (IEM‐1921), is a more potent anticonvulsant and causes less motor impairment than ketamine at anticonvulsant doses (Rogawski et al, ; Blake et al, ; Parsons et al, ; Lukomskaya et al, ; Kim et al, ). However, its anticonvulsant and neuroprotective properties have not been fully elucidated.…”

Pharmacodynamics of Memantine: An Update

“…kindling starting at a dose of 3 mg/kg i.p. [ 156 ]. Similar effects were seen against NMDA convulsions whereas ataxic side effects were first seen at doses some 6-fold higher [ 157 , 235 ].…”

The role of calcium-permeable AMPA receptors in disynaptic feedforward inhibition in the rat prefrontal cortex

“…In particular, it has been revealed that dicationic compounds possess a selective blocking capability against CP AMPARs [21]; the maximum activity was demonstrated by com pounds with the distance between nitrogen atoms equal to five methylene groups [22]. The capability of quite a number of newly developed channel blockers of CP AMPA and/or NMDA receptors to prevent experimentally induced convulsive and cataleptic states in rats and mice has been studied as well [23][24][25][26][27]. At the same time, it was found that the efficiency of therapy for such states with selective CP AMPAR blockers was altogether less than with NMDAR blockers.…”

“…At the same time, it was found that the efficiency of therapy for such states with selective CP AMPAR blockers was altogether less than with NMDAR blockers. More over, under certain conditions CP AMPAR blockers even contributed to the expression of pathological symptoms [23].…”