Effects of Ionotropic Glutamate Receptor Blockers on Pentylenetetrazole-Induced Seizures in Krushinskii–Molodkina Rats

Abstract

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.

The Role of NMDA Receptors in the Effect of Purinergic P2X7 Receptor on Spontaneous Seizure Activity in WAG/Rij Rats With Genetic Absence Epilepsy

“…Although memantine is mostly used in Alzheimer's disease to improve cognitive function, the anticonvulsant activity of memantine has been demonstrated in various models of experimental epilepsy (Frey and Voits, 1991;Cakil et al, 2011;Kim et al, 2012;Zaitsev et al, 2015). Memantine showed an anticonvulsant effect both in a penicillin-induced epilepsy model and in Krushinsky-Molodkina rats with audiogenic seizures (Cakil et al, 2011;Kim et al, 2012). Memantine was also effective on the tonic component of seizures in a PTZ kindling model, and it prevented neuronal death (Zaitsev et al, 2015).…”

“…On the other hand, NMDA receptors are cation channels, and over-stimulation leads to an increase in intracellular calcium, which could be toxic for cells (Rosini et al, 2019). Memantine, a non-competitive NMDA receptor antagonist, has also shown anticonvulsant effects in many experimental epilepsy models, including a penicillin-induced epilepsy model, an audiogenic seizure model, and a PTZ kindling model (Frey and Voits, 1991;Cakil et al, 2011;Kim et al, 2012;Zaitsev et al, 2015). Only one study has been conducted with WAG/Ola/Hsd rats, which are thought to be a model of genetic absence epilepsy (Frey and Voits, 1991), but there is no much information about this rat substrain.…”

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

“…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.…”

Morphofunctional changes in field CA1 of the rat hippocampus after pentylenetetrazole and lithium-pilocarpine induced seizures

“…Volume of the injected solutions was 0.2 ml/100 g of the rat mass. Video recording of convulsive reactions of each animal was performed, and the intensity of the convulsions was measured in points on a modified Racine's scale [10,11]. The intensity of seizures in all the experimental animals was no lower than 3-5 points, and the first-day lethality was 29% in the PTZ model and 33% in the PC model.…”