RESUMO

Recent evidence suggests that P-glycoprotein (P-gp) overexpression mediates hyperexcitability and is associated with epileptogenesis. Transcranial focal electrical stimulation (TFS) delays epileptogenesis and inhibits P-gp overexpression after a generalized seizure. Here, first we measured P-gp expression during epileptogenesis and second, we assessed if TFS antiepileptogenic effect was related with P-gp overexpression avoidance. Male Wistar rats were implanted in right basolateral amygdala and stimulated daily for electrical amygdala kindling (EAK), P-gp expression was assessed during epileptogenesis in relevant brain areas. Stage I group showed 85% increase in P-gp in ipsilateral hippocampus (p < 0.001). Stage III group presented 58% and 57% increase in P-gp in both hippocampi (p < 0.05). Kindled group had 92% and 90% increase in P-gp in both hippocampi (p < 0.01), and 93% and 143% increase in both neocortices (p < 0.01). For the second experiment, TFS was administrated daily after each EAK stimulation for 20 days and P-gp concentration was assessed. No changes were found in the TFS group (p > 0.05). Kindled group showed 132% and 138% increase in P-gp in both hippocampi (p < 0.001) and 51% and 92% increase in both cortices (p < 0.001). Kindled + TFS group presented no changes (p > 0.05). Our experiments revealed that progression of EAK is associated with increased P-gp expression. These changes are structure-specific and dependent on seizure severity. EAK-induced P-gp overexpression would be associated with neuronal hyperexcitability and thus, epileptogenesis. P-gp could be a novel therapeutical target to avoid epileptogenesis. In accordance with this, TFS inhibited P-gp overexpression and interfered with EAK. An important limitation of the present study is that P-gp neuronal expression was not evaluated under the different experimental conditions. Future studies should be carried out to determine P-gp neuronal overexpression in hyperexcitable networks during epileptogenesis. The TFS-induced lessening of P-gp overexpression could be a novel therapeutical strategy to avoid epileptogenesis in high-risk patients.

RESUMO

Salvia amarissima Ortega is an endemic species of Mexico used in folk medicine to alleviate pain and as a nervous tranquilizer. The S. amarissima extract and one of its abundant metabolites, identified and isolated through chromatographic techniques, were investigated to obtain scientific evidence of its potential effects to relieve nociplastic pain such as fibromyalgia. Then, the extract and amarisolide A (3-300 mg/kg, i.p.) were pharmacologically evaluated in reserpine-induced fibromyalgia-type chronic pain and in depressive-like behavior (as a common comorbidity) by using the forced swimming test in rats. The 5-HT1A serotonin receptor (selective antagonist WAY100635, 1 mg/kg, i.p.) was explored after the prediction of a chemical interaction using in silico analysis to look for a possible mechanism of action of amarisolide A. Both the extract and amarisolide A produced significant and dose-dependent antihyperalgesic and antiallodynic effects in rats, as well as significant antidepressive behavior without sedative effects when the antinociceptive dosages were used. The 5-HT1A serotonin receptor participation was predicted by the in silico descriptors and was corroborated in the presence of WAY100635. In conclusion, S. amarissima possesses antihyperalgesic, antiallodynic, and anti-depressive activities, partially due to the presence of amarisolide A, which involves the 5-HT1A serotonin receptor. This pharmacological evidence suggests that S. amarissima and amarisolide A are both potential alternatives to relieve pain-like fibromyalgia.

RESUMO

BACKGROUND: Variation in the temporal patterns of electrical pulses in stimulation trains has opened a new field of opportunity for the treatment of neurological disorders, such as pharmacoresistant temporal lobe epilepsy. Whether this novel type of stimulation affects epileptogenesis remains to be investigated. OBJECTIVE: The purpose of this study was to analyze the effects of temporally irregular deep brain stimulation on kindling-induced epileptogenesis in rats. METHODS: Temporally irregular deep brain stimulation was delivered at different times with respect to the kindling stimulation. Behavioral and electrographic changes on kindling acquisition were compared with a control group and a temporally regular deep brain stimulation-treated group. The propagation of epileptiform activity was analyzed with wavelet cross-correlation analysis, and interictal epileptiform discharge ratios were obtained. RESULTS: Temporally irregular deep brain stimulation delivered in the epileptogenic focus during the interictal period shortened the daily afterdischarge duration, slowed the progression of seizure stages, diminished the generalized seizure duration and interfered with the propagation of epileptiform activity from the seizure onset zone to the ipsi- and contralateral motor cortex. We also found a negative correlation between seizure severity and interictal epileptiform discharges in rats stimulated with temporally irregular deep brain stimulation. CONCLUSION: These results provide evidence that temporally irregular deep brain stimulation interferes with the establishment of epilepsy by delaying epileptogenesis by almost twice as long in kindling animals. Thus, temporally irregular deep brain stimulation could be a preventive approach against epilepsy.

Assuntos

RESUMO

RATIONALE: The use of electrical stimulation therapy to treat epilepsy is currently being studied in experimental animals and patients. Our study was designed to evaluate the effects of electrical stimulation applied in the thalamic reticular nucleus (TRN) on the development of pentylentetrazole-induced seizures. MATERIALS AND METHODS: Experiments were performed using male Wistar rats with electrodes stereotaxically implanted in the left TRN. Epidural EEG recording screws were implanted in the motor cortex for EEG recording. The rats were classified in seven groups: one sham group, four groups receiving either high- or low-frequency preemptive stimulation for either 10 or 60 minutes, and two groups receiving either high- or low-frequency responsive stimulation for ten minutes. All animals received a single dose of pentylentetrazole throughout five days. EEG recordings were obtained from the cortex and were evaluated to assess ictal behavior more than 45 to 90 minutes. RESULTS: Ten minutes of preemptive high-frequency stimulation in the TRN induced a significant decrease in seizure severity compared to 60 minutes of preemptive stimulation and ten minutes of responsive stimulation. Additionally, ten minutes of preemptive high-frequency stimulation protected against death as aftereffect of status epilepticus. The spike-wave complex frequency was not modified. CONCLUSIONS: These data could contribute to the characterization of the TRN in mediating the initiation and spreading of seizure activity and provide preclinical support for optimal parameters to use to obtain beneficial effects against convulsive activity.

Assuntos

RESUMO

The vagus nerve participates in the control and regulation of important autonomous functions, emotional tasks, and neural activity. Electrical vagus nerve stimulation (VNS) is an approved procedure for the treatment of refractory epilepsy in humans. VNS has also been shown to improve mood complaints and cognitive function in both human patients and animals. Thus, the purpose of this study was to analyse and describe the effects of VNS on the development and establishment of sensory habituation and electrographic activity of the visual pathway in freely moving cats. Six cats had implants placed in the optic chiasm (OC), lateral geniculate body (LGB), mesencephalic reticular formation (MRF), primary visual cortex (VC) of the left hemisphere, and left vagus nerve. Immediately after surgery, all cats presented anisocoria and relaxation of the left nictitant membrane. Also showed vegetative-type responses such as myosis, licking, and swallowing during VNS. Animals were then subjected to repeated luminous stimuli at intervals of 1 and 3s to cause habituation. The effect of VNS on the frequency and latency of the habituation episodes and the electrographic changes in the registered brain structures were analysed. Latency analysis showed that VNS delayed the first habituation episode. VNS had transitory effects on the neural activity of the primary visual pathway structures, which caused a small but measurable delay in the establishment of habituation. In conclusion, VNS interferes with the development and establishment of visual habituation, an elementary form of non-associative learning, in freely moving cats.

Assuntos

RESUMO

resumen está disponible en el texto completo

Abstract: Introduction. Epileptic activity modifies the endogenous opioid system by increasing its levels at the end of the ictal phase, and in post-ictal and interictal phases. This increase originates a cortical excitatory effect which suppresses both slow wave sleep and REM. The epileptic activity is initiated with the presence of interictal epileptiform activity, which may be induced through penicillin administration into amygdaline nuclei. Interictal epileptiform activity is a widely employed tool used to determine the localization of epileptic foci characterized by the sudden presence of spikes or acute waves in an electroencephalogram (EEG). In the present work, this tool was used to study the participation of the opioid system in the installation and propagation of epileptic activity induced in temporal lobe amygdala. In the epiloptogenetic study, amygdaline interictal epileptiform activity was used to assess changes induced by opioids and an antagonist in the occurrence of interictal activity using an event histogram. Propagation was studied with the cortical topographic mapping technique, which shows EEG frequency components in a power spectrum, as well as the rhythmic EEG patterns. The aim of the present study was to analyze the effect of enkephalins on epileptiform activity induced with penicillin in tem poral lobe amygdala and its propagation to the cerebral cortex. Method. Fifteen male Wistar rats were submitted to an acute preparation; they were anesthetized with urethane (1.2 g/kg, i.p.). A stainless steel bipolar electrode provided with a cannula was directed toward the left amygdaline basolateral nucleus and a second concentric bipolar electrode to the right amygdaline basolateral nucleus. Two types of cortical recordings were carried out: global mapping and restricted areas. The first consisted of the placement of a 16 stainless steel electrode matrix (in which the electrodes from the vertex were removed) on the scalp, taking care that the tips of the electrodes were in contact with the cortex; this arrangement covered the whole cerebral cortex. The second involved a 4x4mm square matrix consisting of 16 equidistant electrodes placed on the cerebral cortex. The cortical recording was a result of placing this matrix in four different positions so that the whole cerebral cortex was monitored. To monitor cortical recordings, experimental groups were injected penicillin into the amygdaline nuclei. To perform global mapping, enkephalins, [D-ala]-methionine and [D-ala]-leucine, were topically applied into the amygdaline nuclei and naloxone was administered systemically. Analogical signals were recorded in a video-tape and were digitized in parallel with an HP workstation. Off-line analysis was carried as follows: a) information recorded in video-tapes was acquired in a computer designed for this purpose, using amygdaline interictal epileptiform activity to plot event histograms; b) EEG digitized signal, obtained from global mapping, was used to obtain a spectral analysis, consisting of color images maps in time and frequency domains, using RBEAM software. The recording of electrical activity obtained with the square matrix was visually analyzed only. At the end of each experiment, animals were perfused and each brain was fixed intracardially with 10% formaldehyde. To verify the recording and sub-cortical injection sites, the rapid procedure was used. Results. During control stages, cortical records showed slow activity in the form of spindles in all the recording channels; this was due to urethane. Penicillin administration in amygdaline nuclei induced epileptiform activity with a specific pattern: immediate appearance after penicillin application with a gradual increase in amplitude until stabilization was reached within 5-10 minutes of administration. Analyses of global mapping in the frequency domain showed a specific mode of amygdaline interictal epileptiform activity propagation, starting in ipsilateral temporal, prefrontal and fron tal cortices, appearing subsequently in contralateral prefrontal and frontal cortices, and finally in temporal cortex. In the time domain spectrum, an electric dipole generating an interictal spike was found in cerebral cortex. Restricted areas mapping approach showed interictal epileptiform activity and its propagation along the ipsilateral fronto-temporal region. Data revealed an antero-posterior medial cortical activation spreading with decreasing intensity toward occipital regions. Application of enkephalins-[D-ala]-methionine and [D-ala]-leucine produced no epileptic activity, but an increase in basal EEG of cortical epileptiform activity was detected, as well as a decrease in amplitude and frequency of amygdaline epileptiform activity. Naloxone originated a facilitatory effect, since its administration induced focal and generalized electrocorticographic seizures. Conclusions. Focal penicillin is a reliable model of interictal spikes, paroxysms and generalized seizures. The study in rats showed a propagation of epileptic activity to prefrontal cortices prior to contralateral amygdala. Our results showed that enkephalins produced a double effect. First, they originated an increase in basal EEG in temporal cortical areas, as well as a putative participation in propagation mechanisms. Second, they exerted an inhibitory effect on epilepsy installation mechanisms. The inhibitory effect originated by enkephalins was reverted by naloxone.