Pavel Mareš

Pentylenetetrazol-induced seizures in rats : an ontogenetic study

SummaryA quantitative description of motor seizures induced by pentylenetetrazol (PTZ, metrazol) was performed. Seizures were induced by PTZ in doses from 40 to 120 mg/kg s.c. in 477 male albino rats of the Wistar strain 7 to 90 days old. Two patterns of seizures were elicited: minimal, i.e. predominantly clonic seizures of facial and forelimb muscles with preserved righting ability, and major, i.e. generalized tonic-clonic seizures with a loss of righting reflex. Minimal seizures could be reliably elicited since the age of 18 days; the CD50 for these seizures did not significantly differ with age. Major seizures were elicited regularly at all developmental stages studied. Their CD50 did not significantly differ among 7-, 12- and 25-day-old rat pups but the value for 18-day-old rats was smaller and for adult animals larger than for these three age groups.

Effects of flunarizine on Metrazol-induced seizures in developing rats

Antimetrazol action of flunarizine (5, 10, 20 and 40 mg/kg i.p.) was tested during ontogenesis on male Wistar rats aged 7, 12, 18, 25 and 90 days. The latencies and incidences of jerks, minimal Metrazol seizures and major Metrazol seizures remained unchanged by flunarizine in all age groups. A specific action (an abolition of the tonic phase of major seizures) was seen throughout the development and was reflected in lower scores of seizures.

Excitatory amino acid antagonists and pentylenetetrazol-induced seizures during ontogenesis. I.:The effects of 2-amino-7-phosphonoheptanoate

The anticonvulsant action of 2-amino-7-phosphonoheptanoate (AP7) was assessed during ontogenesis of the rat. Animals of five age groups (7, 12, 18, 25, and 90 days) were pretreated with AP7 i.p. in the doses from 15 to 60 mg/kg 30 min prior to pentamethylenetetrazol (PTZ; metrazol; 100 mg/kg s.c.). The incidence and latency of minimal seizures (pure clonic without the loss of righting ability) and of generalized tonic-clonic seizures (major) were evaluated and compared with the control groups. Minimal metrazol seizures were not regularly observed in controls between ages 7 and 12 days. An increased incidence was noticed in AP7-treated groups. In animals of 18 days of age and older the AP7-pretreatment did not influence incidence of minimal seizures; the latencies were significantly lengthened only in 18-day-old animals. Major seizures were significantly suppressed with the highest dose of AP7 (60 mg/kg) in all groups except 7-day-old rats. In 90-day-old rats all doses of AP7 were effective in the suppression of major seizures. The latencies of major seizures were increased in 7 and 18 days old rats. It appears that the blockade of NMDA receptor substantially influences the major seizures induced by PTZ, whereas minimal (clonic) seizures are affected weakly. This suggests an important role of NMDA receptor-mediated transmission in the genesis of generalized tonic-clonic seizure pattern.

Excitatory amino acid antagonists and pentylenetetrazol-induced seizures during ontogenesis. II : The effects of MK-801

MK-801 is a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist with anticonvulsant and neuroprotective properties. The action of MK-801 (0.05–10 mg/kg IP) was assessed against pentylenetetrazol-induced seizures (PTZ; 100 mg/kg SC; 30 min after MK-801) in rats aged 7, 12, 18, 25, and 90 days (N=263). We observed pronounced ataxia and hypermobility after MK-801 pretreatment during the whole ontogenesis, and the animals exhibited head-weaving and body-rolls. After the combination of MK-801 and PTZ “wet dog shakes” were detected in 18-, 25-, and 90-day-old rats (never seen in controls receiving PTZ only). MK-801 only insignificantly modified the latencies of minimal (clonic) seizures in 18-day-old and older rats where this seizure type is regularly elicited. In 12-day-old rats an increased incidence of minimal seizures was detected. MK-801 nearly completely blocked or strongly delayed major (generalized tonic-clonic) seizures and attenuated the seizure severity during ontogenesis in a dose-dependent manner. Present results suggest the important role of NMDA receptors in the genesis of generalized tonic-clonic seizures whilst the role of NMDA receptors in minimal seizures appears to be negligible during the whole ontogenetic development.

Anticonvulsant effects of phenobarbital and primidone during ontogenesis in rats.

The influence of phenobarbital (PHB, 10, 20, 40 or 80 mg/kg i.p.) and primidone (PRI, 40 or 80 mg/kg i.p.) on metrazol-induced motor seizures was studied in rats 7, 12, 15, 18, 25 and 90 days old. PHB blocked both types of seizures induced by metrazol-minimal (mMS) as well as generalized tonic-clonic (MMS)--in all age groups where they appeared under control conditions. The effect against major seizures was always better expressed than against mMS. Pretreatment with PHB led to the appearance of mMS in 7- and 12-day-old rat pups, where control animals did not exhibit this type of seizure. Combined administration of the 2 high doses of PHB and metrazol resulted in the appearance of behavioral automatisms in young rats. PRI abolished MMS in adult rats only, no changes were seen in 25-day-old animals and specific suppression of the tonic phase of MMS was observed in younger rats. mMS were influenced only in 7- and 12-day-old rats, where an increase in their incidence was recorded. Pretreatment with PRI never induced automatisms. The different actions of PHB and PRI speak in favor of an anticonvulsant action of PRI itself.

Ontogenetic development of rhythmic thalamo-cortical phenomena in the rat

Three rhythmic cortical phenomena (rhythmic after-discharges, incremental responses and self-sustained after-discharges formed by spike-and-wave rhythm) were elicited by electrical stimulation of thalamic nuclei during ontogenesis in rats. All three phenomena could be recorded for the first time at the age of 12 days and they matured until the 18th postnatal day. Possible explanation for the delayed development of these rhythmic thalamo-cortical phenomena in comparison with single thalamo-cortical responses are discussed.

Cyclic adenosine 3',5'-monophosphate in epileptogenic foci induced by penicillin.

Abstract Cyclic adenosine 3′,5′-monophosphate (cAMP) increased in the penicillin (PNC) induced epileptic foci (primary and projected) in the cerebral cortex of anesthetized rat. Maximal cAMP level was reached 5 min after appearance of the first epileptic discharge in the primary focus, i.e. 8:25 min after PNC application. After 30 min cAMP in the projected focus returned to the normal level, although discharge rate remained constant (36/min). A possible mechanism of cAMP participation in focal epileptogenesis and its relation to the reported increase in extracellular potassium concentrations are discussed.

Ontogenetic development of convulsant action of Ro 5-3663 in the rat

Motor seizures were induced by Ro 5-3663 in 156 male albino rats aged 7,12,18,25, and 90 days. Both minimal and maximal seizures could be elicited in 18-day-old and older animals, whereas only maximal seizures were induced in the two youngest groups. ECoG changes were studied in other 21 young rats. First changes induced by Ro 5-3663 were formed by isolated sharp waves in 7- and 12-day-old rats and by episodes of rhythmic activity in older animals. An imperfect form of this rhythmic activity could be seen even in 12-day-old rats. Ictal ECoG activity exhibited an increase in frequency of individual graphoelements, in generalization and in synchronization of activity among different cortical regions with maturation. Correlation between motor and ECoG phenomena was poor in 7-day-old rats and ameliorated with age but it never reached perfection. The actions of Ro 5-3663 are identical with those induced by metrazol but they differ from those elicited by bicuculline or 3-mercaptopropionic acid.

Vanadate inhibition of rat cerebral cortex Na+, K+-ATPase during postnatal development

The Na+, K+-ATPase activity and its response to vanadate inhibition was investigated in cerebral cortex homogenates of 7-, 12- and 18-day-old rats. The enzyme was inhibited by vanadate in a dose-dependent manner in all these age groups. Furthermore, there was a different sensitivity towards vanadate during postnatal development; the concentration of V+5 needed for 50% inhibiton of Na+, K+-ATPase was 1.1×10−6M, 2×10−7M and 4.4×10−7M for 7-, 12- and 18-day-old rats, respectively. It is suggested that the different sensitivity of Na+, K+-ATPase towards vanadate inhibition during postnatal development might be due to age-dependent changes in the ratio of various cell types.

EEG changes induced by convulsants interfering with GABAergic inhibition in rats. I: Cortical recordings

Electrocorticographic changes induced by 3 convulsant drugs interfering with the GABA system were studied in 73 adult rats. Aminooxyacetic acid first elicited changes (periods of theta waves) nearly constantly in occipital regions. Bicuculline induced not only occipital theta waves but also groups of spikes with the same frequency in frontal regions; there was no predominance of one of these regions. 3-Mercaptopropionic acid invariably elicited groups of spikes in the frontal region as the first sign of its action. As it progressed, this rhythmic activity became generalized so that differences among the 3 drugs disappeared. Paroxysmal activity induced by the 3 drugs studied was identical. It always started with rhythmic spikes which were gradually transformed into spike-and-wave rhythm. Differences among the 3 convulsants studied were found in the very first electrocorticographic changes. Long latency to the onset of action of 3-mercaptopropionic acid and especially of aminoocyacetic acid qualifies these drugs for studies of preparoxysmal changes.