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In order to investigate a potential anticonvulsive action of sertraline (i.p.), its effects on seizures, EEG epileptiform activity and EEG amplitude increases induced by two convulsive agents were evaluated and compared with the effects of carbamazepine. Around 20 min following 4-aminopyridine (4-AP, 2.5 mg/kg, i.p.), tonic-clonic seizures and epileptiform activity were observed in control animals. A single sertraline pre-injection of 2.5 mg/kg, but not of 0.75 mg/kg, prevented these changes to 4-AP. Repeated daily administration of 0.75 mg/kg for one week, however, effectively inhibited the changes induced by 4-AP. The first generalized tonic-clonic seizure and EEG changes in response to pentylenetetrazole (PTZ, 50 mg/kg, i.p.) were observed near the first minute in control animals. Single sertraline doses above 5 mg/kg prevented the PTZ-induced changes. Moreover, a single carbamazepine dose of 25 mg/kg (i.p.), but not of 15 mg/kg, prevented the changes induced by the above convulsive agents. An anti-seizure action of the antidepressant sertraline is strongly suggested by these findings., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The effects of two classic antiepileptic drugs (carbamazepine and phenytoin), a potential antiepileptic (vinpocetine) and a monoamine-oxidase inhibitor (clorgyline) on the simultaneous changes (detected by HPLC) on Glu, Asp, dopamine and DOPAC inside and outside striatal isolated nerve endings were investigated. Under resting conditions phenytoin, carbamazepine and clorgyline increased dopamine release. Phenytoin and clorgyline increased internal dopamine and decreased DOPAC formation. Carbamazepine decreased internal dopamine and practically did not change DOPAC formation. Glu and Asp release was unchanged. Neurotransmitter release induced by the Na+ channel opener veratridine was reduced by all the antiepileptic drugs tested, except phenytoin which, like clorgyline, facilitated veratridine-induced dopamine release. We conclude that besides the antagonism exerted by carbamazepine, phenytoin and vinpocetine on excitatory neurotransmitters release triggered by Na+ channel activation, that might importantly contribute to their anticonvulsant action, they exert different actions on striatal dopamine distribution, that might explain their different side effect profiles.

Objective: To compare the acute, chronic and post-treatment effects of the classic antiepileptic drug carbamazepine (CBZ) and the potential antiepileptic vinpocetine (VPC), successfully used in the treatment of brain vascular origin disorders, on 4-aminopyridine (4-AP)-induced increase in auditory threshold, brain-auditory-evoked-potentials (BAEPs) later waves alterations and epileptiform activity., Methods: BAEP and EEG recordings before and following 4-AP (3mg/kg, i.p.) were obtained in guinea pigs. One week after, the animals received a daily injection (i.p.) of vehicle, 3mg/kg VPC or 17 mg/kg CBZ for 13 days. The acute and chronic effects before and following 4-AP were tested at the 1st and last days, respectively, and the post-treatment effect 1 month after the end of treatment., Results: CBZ and 4-AP increased BAEPs threshold and BAEPs P4 wave latency. Chronic CBZ inhibited 4-AP-induced increase in P3 amplitude. In the VPC-treated group, all the 4-AP-induced BAEPs changes were prevented. Seizures were prevented in 50% and 75% of the animals by chronic CBZ and VPC, respectively. After acute VPC and after the end of VPC-treatment 4-AP failed to induce seizures in 50% of the animals., Conclusion: VPC inhibits 4-AP-induced seizures and hearing loss, even after post-treatment, at a concentration about 10 times lower than CBZ., Significance: The complications in hearing that can accompany epilepsy can be prevented by VPC, indicating its advantage as an alternative antiepileptic.

The effect of carbamazepine, phenytoin, valproate, oxcarbazepine, lamotrigine and topiramate, that are among the most widely used antiepileptic drugs (AEDs), and of the new putative AED vinpocetine on the Ca(2+) channel-mediated release of [(3)H]Glu evoked by high K(+) in hippocampal isolated nerve endings was investigated. Results show that carbamazepine, oxcarbazepine and phenytoin reduced [(3)H]Glu release to high K(+) to about 30% and 55% at concentrations of 500 microM and 1500 microM, respectively; lamotrigine and topiramate to about 27% at 1500 microM; while valproate failed to modify it. Vinpocetine was the most potent and effective; 50 microM vinpocetine practically abolished the high K(+) evoked release of [(3)H]Glu. Comparison of the inhibition exerted by the AEDs on [(3)H]Glu release evoked by high K(+) with the inhibition exerted by the AEDs on [(3)H]Glu release evoked by the Na(+) channel opener, veratridine, shows that all the AEDs are in general more effective blockers of the presynaptic Na(+) than of the presynaptic Ca(2+) channel-mediated response. The high doses of AEDs required to control seizures are frequently accompanied by adverse secondary effects. Therefore, the higher potency and efficacy of vinpocetine to reduce the permeability of presynaptic ionic channels controlling the release of the most important excitatory neurotransmitter in the brain must be advantageous in the treatment of epilepsy.

Objective: To characterize the acute and chronic effects of the antiepileptic drugs (AEDs): carbamazepine (CBZ), phenytoin (PHT), valproic acid (VPA) and vinpocetine (VPC), at doses 20, 6, 30 and 2mg/kg, respectively, on the latencies and amplitudes of the waves of brainstem auditory evoked potentials (BAEPs) elicited by a supra-threshold stimulus alongside BAEP threshold., Methods: BAEPs elicited by a stimulus of high (100dB nHL) intensity and BAEP thresholds were obtained at 4 and 8kHz: before, after the start of treatment, and following 28 days of a daily injection of the AEDs., Results: After the start of treatment BAEPs were unchanged. After the long term treatment, CBZ and PHT increased P3 and P4 wave peak latencies and reduced P4 amplitude. Chronic VPA did not modify BAEP waves, and chronic VPC reduced P3 and P4 latencies. P1 and P2 were unchanged. BAEP thresholds at 4 and 8kHz were increased by CBZ, PHT and VPA, and decreased by VPC., Conclusions: The chronic administration of several AEDs modifies BAEP waves of retro-cochlear origin., Significance: Alterations in the generators of the later waves of BAEPs underlie, in most cases, the changes in hearing sensitivity produced by the long term treatment with AEDs at therapeutic relevant doses.

Several of the most effective antiepileptic drugs are believed to stop the paroxysmal neuronal activity acting as Na(+) channel blockers. However, no single study comparing in parallel the potency and efficacy of the most commonly used antiepileptic drugs on brain Na(+) channel-mediated responses is available. In the present study the effects of increasing concentrations of carbamazepine, phenytoin, lamotrigine, oxcarbazepine and topiramate, which are among the most frequently used antiepileptic drugs, and of the new putative antiepileptic drug, vinpocetine, on the release of glutamate (Glu) elicited by the Na(+) channel opener, veratridine were investigated in hippocampal isolated nerve endings preloaded with the labeled excitatory amino acid neurotransmitter. The present results show that carbamazepine, phenytoin, lamotrigine and oxcarbazepine, in the range from 150 to 1500 microM, progressively inhibit [(3)H]Glu release induced by veratridine. Also vinpocetine progressively inhibits the veratridine-induced response, but in a much lower range of concentrations (from 1.5 to 15 microM), whereas topiramate only exerts a modest inhibition (20%) of Glu release to veratridine at the highest dose tested (1500 microM). These results indicate that the mechanism of action of several of the most widely used antiepileptic drugs involves reduction in cerebral presynaptic voltage sensitive Na(+) channels permeability. Considering that the high doses of antiepileptic drugs required to control seizures are frequently accompanied by adverse secondary effects, the higher potency of vinpocetine to reduce Na(+) channels permeability might be advantageous.

The long-term effect of three of the most widely used antiepileptic drugs at relevant doses on the hearing decline that accompanies pentylenetetrazole (PTZ)-induced experimental epilepsy was investigated here, and compared with the effect of vinpocetine (VPC), which is a drug with antiepileptic potential. For this purpose, cortical activity (monitored by the EEG) and auditory sensitivity, as indicated by brainstem auditory evoked potential (BAEP) threshold at 4 and 8 kHz tone frequencies, were determined in guinea pigs daily injected for 28 days with vehicle (control), 20 mg/kg carbamazepine (CBZ), 6 mg/kg phenytoin (PHT), 30 mg/kg valproate (VPA) or 2 mg/kg vinpocetine (VPC) before and after the administration of PTZ at a convulsing dose (100 mg/kg). Results show that all the antiepileptic drugs tested were more or less effective in preventing PTZ-induced seizures. The long-term treatment with VPC decreased the auditory threshold, whereas the long-term treatment with CBZ, PHT or VPA increased the auditory threshold to a similar extent as the convulsing agent, PTZ. The combined effects of the antiepileptic drugs and PTZ on auditory threshold were additive. Therefore, only VPC prevented the increase in the auditory threshold induced by PTZ. It is concluded that the hearing loss produced by the long-term treatment with the most commonly used antiepileptic drugs could be aggravated by the illness. The prevention exerted by VPC on the hearing decline that accompanies experimental epilepsy, along with its capacity to control seizures at low doses in this and other animal models of epilepsy, would make VPC a valid candidate for the treatment of epilepsy.

The single and combined effects of carbamazepine and vinpocetine on the release of the excitatory amino acid neurotransmitter glutamate, on the rise in internal Na+ (Na(i), as determined with SBFI), and on the rise in internal Ca2+ (Ca(i), as determined with fura-2) induced by an increased permeability of presynaptic Na+ channels, with veratridine, or by an increased permeability of presynaptic Ca2+ channels with high K+, were investigated in isolated hippocampal nerve endings. The present study shows that carbamazepine and vinpocetine, both inhibit dose dependently the release of preloaded [3H]Glu induced by veratridine. However, carbamazepine is two orders of magnitude less potent than vinpocetine. The calculated IC(50)'s for carbamazepine and vinpocetine to inhibit veratridine-induced [3H]Glu release are 200 and 2 microM, respectively. Consistently 150 microM carbamazepine and 1.5 microM vinpocetine reduce the veratridine-induced rise in Na(i) in a similar extent. The single effects of carbamazepine and of vinpocetine on the presynaptic Na+ channel mediated responses, namely the rise in Na(i) and the release of Glu induced by veratridine, are additive. Responses that depend on the entrance of external Ca2+ via presynaptic Ca2+ channels, such as the release of [3H]Glu and the rise in Ca(i) induced by high K+, are insensitive to 300 microM carbamazepine and slightly reduced by 5 microM vinpocetine. It is concluded that the additive effects of carbamazepine, which is one of the most common antiepileptic drugs, and vinpocetine that besides its known neuroprotective action and antiepileptic potential is a memory enhancer, may perhaps be advantageous in the treatment of epileptic patients.

Here we investigate the effect of the neuroprotective drug, vinpocetine on the epileptic cortical activity, on the alterations of the later waves of brainstem auditory evoked potentials (BAEPs) and on the hearing decline induced by the convulsing agent, pentylenetetrazole (PTZ). Vinpocetine at doses from 2 to 10 mg/kg inhibits the tonic-clonic convulsions induced by PTZ (100 mg/kg). Vinpocetine injected at a dose of 2 mg/kg 4 h before PTZ completely prevents the characteristic electroencephalogram (EEG) changes induced by PTZ for the ictal and post-ictal periods. Vinpocetine also abolished the PTZ-induced changes in the amplitude and latency of the later waves of the BAEPs in response to pure tone burst monoaural stimuli (frequency 8 or 4 kHz intensity 100 dB), and the PTZ-induced increase in the BAEP threshold. These results show the antiepileptic potential of vinpocetine and indicate the capability of vinpocetine to prevent the changes in the BAEP waves associated with the hearing loss observed during generalized epilepsy.

For exploring a possible connection between the reduced hearing sensitivity and certain abnormalities in the auditory brainstem responses (ABRs) in generalized epilepsy, the effects of two convulsing agents, namely pentylenetetrazole (PTZ) and of 4-aminopyridine (4-AP), on: (1). the cortical activity (EEG), (2). the hearing threshold and (3). the amplitudes and latencies of the ABR waves evoked by a stimulus of high intensity (100 dB) were investigated in guinea pigs. All animals injected (i.p.) with 100mg/kg PTZ or with 2mg/kg 4-AP developed generalized seizures, followed by characteristic EEG patterns for the post-ictal period, that were accompanied by a marked reduction of the hearing sensitivity (as indicated by the elevated threshold of the ABR), as well as by retro-cochlear changes (as judged by the changes in the later ABR waves in response to 100 dB). For instance, both convulsing agents decreased the amplitude and increased the latency of P4, that is the wave component of the ABRs generated in the lateral superior olivary nucleus and while PTZ increased the latency of P3, the wave component of the ABRs generated in the medial superior olivary nucleus, 4-AP dramatically increased its amplitude. Comparison of recordings taken at specific times for the duration of the post-ictal period (i.e. within about 1h for PTZ and 2h for 4-AP) reveals that the extent of the changes on the EEG matches with the increase in the auditory threshold and with the extent of the changes on the later waves of the ABR elicited by 100 dB. These data indicate that changes in the activity of the lateral and the medial nuclei of the superior olivary complex (SOC) accompany the hearing loss and the post-ictal epileptic cortical activity.

The effects of vinpocetine on internal Na+ (Na(i)), cAMP accumulation, internal Ca2+ (Ca(i)) and excitatory amino acid neurotransmitters release, under resting and under depolarized conditions, was investigated in rat striatum synaptosomes. Veratridine (20 microM) or high K+ (30 mM) were used as depolarizing agents. Results show that vinpocetine in the low microM range inhibits the elevation of Na(i), the elevation of Ca(i) and the release of glutamate and aspartate induced by veratridine depolarization. In contrast, vinpocetine fails to inhibit the rise of Ca(i) and the neurotransmitter release induced by high K+, which are both TTX insensitive responses. Results also show that the inhibition exerted by vinpocetine on all the above veratridine-induced responses is not reflected in PDE activity. Our interpretation of these results is that vinpocetine inhibits neurotransmitter release triggered by veratridine activation of voltage sensitive Na+ channels, but not that triggered by a direct activation of VSCC. Thus, the main mechanism involved in the neuroprotective action of vinpocetine in the CNS is unlikely to be due to a direct inhibition of Ca2+ channels or PDE enzymes, but rather the inhibition of presynaptic Na+ channel-activation unchained responses.

Chagas disease, a cause of important morbo-lethality in Latinamerica, is produced by a protozoan which has a circulating and tissular phase the Trypanosoma cruzi. Adhesion between T. cruzi and phagocytes is the first step in cellular parasitism, which has a central role in pathogenesis. Although there are studies on parasite phagocyte interaction with some strains of T. cruzi, and it is known that biological variation does exist. We now report the first studies with a mexican isolate using a mix of different phases of T. cruzi obtained from acellular culture resembling the natural conditions. Murine macrophages adheres to epimastigotes, transitional trypomastigotes and metacyclic trypomastigotes since the first minutes of observation, progression on cell-cell interaction was demonstrated, there were no differences among parasite faces however, in some cases there was a failed adhesion, this suggest a possible parasite evasion mechanism. These studies limited only to morphologic aspects the adhesion phenomena, should be pursued.

Among contemporary problems of cardiovascular therapy, pain management in the cardiac patient is an important issue. Correct selection of a suitable analgesic drug is important in the acute phase of myocardial infarction because pain relief prevents adrenergic response which aggravates unbalance between myocardial oxygen supply and demands. Until today morphine has been the best choice, nevertheless its side effects and limited availability demands pharmacological alternatives. Meperidine has been used for this purpose although its anticholinergic and narcotic profiles do not fulfill the therapeutic requirements. Conorphone is a codeine derivative which retains analgesic potency without other narcotic side effects and which presents an antagonistic profile for the remainder of opiate effects. Preliminary studies demonstrate that conorphone lacks cardiovascular side effects. Conorphone also shows antiarrhythmic effects in experimental models such as in rat in which arrhythmias were induced by coronary ligation. In this paper a morphologic analysis with electron microscopy was done on adjacent myocardial tissue next to an area of infarct. Experimental myocardial infarction was induced by ligation of descendant branch of left coronary artery, four hours prior to rat sacrifice and suitable samples for ultrastructure study were obtained. The experiments demonstrate that a group of rats that received 3.1 mg/kg of conorphone had less expressions of cellular damage when compared with similar myocardial areas of a control group of rats.