Seizures triggered by pentylenetetrazol in marmosets made chronically epileptic with pilocarpine show greater refractoriness to treatment.

The efficiency of most of the new antiepileptic drugs (AEDs) on clinical trials still falls short the success reported in pre-clinical studies, possibly because the validity of the animal models is insufficient to fully represent the human pathology. To improve the translational value for testing AEDs, we propose the use of non-human primates. Here, we suggest that triggering limbic seizures with low doses of PTZ in pilocarpine-treated marmosets might provide a more effective basis for the development of AED. Marmosets with epileptic background were more susceptible to seizures induced by PTZ, which were at least 3 times longer and more severe (about 6 times greater frequency of generalized seizures) in comparison to naïve peers. Accordingly, PTZ-induced seizures were remarkably less attenuated by AEDs in epileptic than naïve marmosets. While phenobarbital (40mg/kg) virtually abolished seizures regardless of the animal's background, carbamazepine (120mg/kg) and valproic acid (400mg/kg) could not prevent PTZ-induced seizures in epileptic animals with the same efficiency as observed in naïve peers. VPA was less effective regarding the duration of individual seizures in epileptic animals, as assessed in ECoG (p=0.05). Similarly following CBZ treatment, the behavioral manifestation of generalized seizures lasted longer in epileptic (p<0.05), which were also more frequent than in the naïve group (p<0.05). As expected, epileptic marmosets experiencing stronger seizures showed more NPY- and ΔFosB-immunostained neurons in a number of brain areas associated with the generation and spread of limbic seizures. Our results suggest that PTZ induced seizures over an already existing epileptic background constitutes a reliable and controllable mean for the screening of new AEDs.

Maximal electroshock-induced seizures are able to induce Homer1a mRNA expression but not pentylenetetrazole-induced seizures.

OBJECTIVE: Homer1a is a protein that regulates metabotropic glutamate receptors involved in neural plasticity processes. Recently, we demonstrated that Homer1a mRNA is enhanced after pilocarpine-induced status epilepticus. Here, we investigated whether a single acute seizure triggered by means of pentylenetetrazole (PTZ) injection or maximal electroshock (MES) stimulation (2 different seizure models) would alter Homer1a expression in the hippocampus. METHODS: Male Wistar rats subjected to the PTZ or MES model were analyzed 2h, 8h, 24h, and 7days after seizure induction. Homer1a, mGluR1, and mGluR5 mRNA expression levels in hippocampal extracts were analyzed by quantitative PCR. RESULTS: Quantitative PCR revealed Homer1a overexpression at 2h after MES-induced tonic-clonic seizures compared to control, but the overexpression did not remain elevated after 8h. Pentylenetetrazole-induced seizures, in contrast, were not able to change Homer1a mRNA expression. No differences were observed at these time points after seizures for mGluR1 and mGluR5 mRNA expression in any of the models. SIGNIFICANCE: Our data indicate that the levels of Homer1a mRNA were transiently increased only after MES-induced tonic-clonic seizures (and not after PTZ-induced seizures). We suggest that Homer1a expression may be dependent on seizure intensity or on specific brain circuit activation. We suggest that Homer1a may contribute to counteract hyperexcitability processes.

Effect of neuronal precursor cells derived from medial ganglionic eminence in an acute epileptic seizure model.

Most of the gamma-aminobutyric acid (GABA)ergic interneurons in the cerebral cortex originate from restricted regions of the ventral telencephalon known as the caudal and medial ganglionic eminence (MGE) and from the preoptic area. It is well established that dysfunction of GABAergic interneurons can lead to epilepsy. During the last decade new approaches to prevent, reduce, or reverse the epileptic condition have been studied, including cell-based therapy from different sources. Recent studies have shown that transplanted neuronal precursor cells derived from MGE have the ability to migrate, differentiate into inhibitory GABAergic interneurons, and integrate into cortical and hippocampal networks, modifying the inhibitory tone in the host brain. Therefore, transplantation of neuronal precursors derived from MGE into the postnatal central nervous system (CNS) could modify the neuronal circuitry in neurologic diseases in which inhibitory synaptic function is altered, such as in epilepsy. Here, we evaluated the seizure susceptibility of mice transplanted with MGE-derived cells in the maximum electroconvulsive shock (MES) model and we review some data from different studies using GABAergic precursor or GABA-releasing cell grafts in animal models of seizure and epilepsy.

Behavioral characterization of pentylenetetrazol-induced seizures in the marmoset.

This study was designed to characterize seizures induced with pentylenetetrazol (PTZ) in marmosets. Thirteen adult marmosets (Callithrix sp.) received 20, 30, or 40 mg/kg of PTZ intraperitoneally. PTZ caused all animals to switch their natural behavioral repertoire to early convulsive behavior. Seizure scores were low at lower PTZ doses, whereas the highest dose of PTZ led to seizure scores IV and V (according to Racine's scale) in 69% of animals. To further characterize the model we performed a preliminary evaluation of the efficacy of three antiepileptic drugs: phenobarbital, phenytoin, and carbamazepine. Phenobarbital prevented PTZ-induced seizures in 100% of trials. As expected, phenytoin and carbamazepine were not effective against PTZ-induced seizures. The present study describes the PTZ model of seizures in marmosets with a drug-response profile similar to that of the rodent model, thus bringing to a well-known model (PTZ in rodents) the complexity of a nonhuman primate brain.

Effect of moxibustion at acupoints Ren-12 (Zhongwan), St-25 (Tianshu), and St-36 (Zuzanli) in the prevention of gastric lesions induced by indomethacin in Wistar rats.

This study was aimed at assessing the physical characteristics underlying the action of moxibustion at acupoints Ren-12 (Zhongwan), St-25 (Tianshu), and St-36 (Zuzanli) in preventing acute injuries of the gastric mucous membrane induced by indomethacin in Wistar rats. Induction of gastric lesions, by means of intragastric administration of indomethacin (100 mg/kg), in adult male Wistar rats was followed by treatment with moxibustion using Artemisia vulgaris dried leaves at 60 or 45 degrees C, heating with Artemisia vulgaris charcoal at 50 degrees C, heating with a regular tobacco cigar at 50 degrees C, and heating with a regular water pad at 50 degrees C, The effects of the different heating protocols over the gastric lesions were then compared. In addition, another group of animals was pretreated with capsaicin (100 mg/kg, s.c.), in order to lesion C fibers and, 15 days later, subjected to indomethacin administration and moxibustion treatment. Moxibustion was significantly more efficient at 60 degrees C than at 45 degrees C in preventing gastric lesions triggered by indomethacin. Moxibustion applied in acupoints provided a significant reduction of the lesion area, which was two times less than that of animals stimulated in a nonacupoint (sham group). Comparing the therapeutic effects provided by different forms of heating over the gastric lesions, the burning of dry leaves of Artemisia vulgaris was significantly more efficient in preventing gastric lesions than moxibustion made with Artemisia charcoal or tobacco (cigar) or by heating the animal with a water pad. Desensitization of the afferent sensory C fibers by capsaicin significantly diminished the ability of moxibustion to block the lesions in the gastric mucous membrane. Moxibustion can efficiently prevent indomethacin-induced gastric lesions in rats and this effect is dependent on the temperature, the material used for moxibustion, the use of acupuncture points, and the integrity of C fibers.