Anticonvulsant activity of Valeriana edulis roots and valepotriates on the pentylenetetrazole-induced seizures in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: For many centuries, Mexican Valerian (Valeriana edulis ssp. procera) has been an important plant in folk medicine. It has been considered useful to control epilepsy; however, electroencephalographic evidence of its anticonvulsant activity is missing in literature. AIM OF THE STUDY: In the present study, in situ electroencephalographic (EEG) analysis was performed along with administration of a crude ethanol extract of V. edulis and its valepotriate fraction on the pentylenetetrazole (PTZ)-induced convulsive behavior in rats. MATERIALS AND METHODS: Experiments were performed using male Wistar rats with nail-shaped electrodes implanted in the frontal and parietal cortices for EEG recording. All animals received a single dose of PTZ (35 mg/kg, i.p.) to test the anticonvulsant activity of V. edulis crude extract and valepotriate fraction (100 mg/kg, i.p.) 15 and/or 30 min after administration. EEG recordings were obtained from the cortices and were evaluated to assess ictal behavior over 60-75 min. Chromatographic analysis of the valepotriate fraction and in silico predictions of pharmacodynamic properties were also explored. The latency, frequency and duration of seizures evaluated using EEG recordings from the frontal and parietal cortices of rats showed significant changes demonstrating the inhibition of paroxystic activity. RESULTS: The spectral analysis confirmed the reduction of excitatory activity induced by V. edulis extract, which was improved in the presence of the valepotriate fraction as compared to that induced by ethosuximide (a reference anticonvulsant drug). The presence of valepotriates such as: isodihydrovaltrate (18.99%), homovaltrate (13.51%), 10-acetoxy-valtrathydrin (4%) and valtrate (1.34%) was identified by chromatographic analysis. Whereas, not only GABAA receptor participation but also the cannabinoid CB2 receptor was found to be likely involved in the anticonvulsant mechanism of action after in silico prediction. CONCLUSIONS: Our data support the anticonvulsant properties attributed to this plant in folk medicine, due to the presence of valepotriates.

Reelin reverts biochemical, physiological and cognitive alterations in mouse models of Tauopathy.

Reelin is an extracellular protein crucial for adult brain plasticity. Moreover, Reelin is protective against amyloid-ß (Aß) pathology in Alzheimer's Disease (AD), reducing plaque deposition, synaptic loss and cognitive decline. Given that Tau protein plays a key role in AD pathogenesis, and that the Reelin pathway modulates Tau phosphorylation, here we explored the involvement of Reelin in AD-related Tau pathology. We found that Reelin overexpression modulates the levels of Tau phosphorylation in AD-related epitopes in VLW mice expressing human mutant Tau. in vitro, Reelin reduced the Aß-induced missorting of axonal Tau and neurofilament proteins to dendrites. Reelin also reverted in vivo the toxic somatodendritic localization of phosphorylated Tau. Finally, overexpression of Reelin in VLW mice improved long-term potentiation and long-term memory cognitive performance thus masking the cognitive and physiological deficits in VLW mice. These data suggest that the Reelin pathway, which is also protective against Aß pathology, modulates fundamental traits of Tau pathology, strengthening the potential of Reelin as a therapeutic target in AD.

Effects of High- and Low-Frequency Stimulation of the Thalamic Reticular Nucleus on Pentylentetrazole-Induced Seizures in Rats.

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.

Behavioral and electroencephalographic evaluation of the anticonvulsive activity of Moringa oleifera leaf non-polar extracts and one metabolite in PTZ-induced seizures.

BACKGORUND: Moringa oleifera Lamarck is a species that has long been used in high demand in folk medicine, including for the treatment of epilepsy. Nevertheless, scientific studies demonstrating its anticonvulsant properties and the nature of the bioactive constituents are lacking. HYPOTHESIS/AIM: The aim of this study was to evaluate the anticonvulsant activities of the Moringa oleifera leaves in non-polar vs. polar extracts using behavioral and electroencephalographic (EEG) analyses in rodents. METHODS: First, PTZ (80 mg/kg, i.p.)-induced tonic-clonic seizures were assayed via a dose-response (100, 200 and 300 mg/kg, i.p.) evaluation in mice. Then, a dosage of the extracts (100 or 300 mg/kg) and one metabolite (30 mg/kg, i.p.) was selected to evaluate its effect on PTZ (35 mg/kg, i.p.)-induced EEG paroxystic activities in rats compared to the effects of ethosuximide (reference anticonvulsant drug, 100 mg/kg, i.p.). Latent onset of the first paroxystic spike, first seizure and frequency as well as seizure severity, were determined using Racine's scale. RESULTS: Moringa oleifera ethanol and hexane extracts produced a delay in the seizure latency in mice and rats; this effect was improved in the presence of the hexane extract containing the active metabolite hexadecanoic acid. The anticonvulsant effects were corroborated in the spectral analysis by the potency of the EEG due to a reduction in the spike frequency and amplitude, as well as in the duration and severity of the seizures. The effects of the hexane extract resembled those observed in the reference antiepileptic drug ethosuximide. CONCLUSION: Moringa oleifera leaves possess anticonvulsant activities due to the complementary of the non-polar and polar constituents. However, the non-polar constituents appear to exert an important influence via the partial participation of fatty acids, providing evidence of the effects of this plant in epilepsy therapy.

Short-term deep brain stimulation of the thalamic reticular nucleus modifies aberrant oscillatory activity in a neurodevelopment model of schizophrenia.

Dysfunction of thalamo-cortical networks involving particularly the thalamic reticular nucleus (TRN) is implicated in schizophrenia. In the neonatal ventral hippocampal lesion (NVHL), a heuristic animal model of schizophrenia, brain oscillation changes similar to those of schizophrenic patients have been reported. The aim of this study was to analyze the effects of short-term deep brain stimulation (DBS) in the thalamic reticular nucleus on electroencephalographic (EEG) activity in the NVHL. Male and female Sprague-Dawley rats were used and the model was prepared by excitotoxicity damage of the ventral hippocampus on postnatal day 7 (PD-7). Chronic bilateral stainless steel electrodes were implanted in the TRN, thalamic dorsomedial nucleus and prelimbic area at PD-90. Rats were classified as follows: sham and NVHL groups, both groups received bilateral DBS in the TRN for one hour (100Hz, 100µs pulses, 200µA). All animals showed a sudden behavioral arrest accompanied by widespread symmetric bilateral spike-wave discharges, this activity was affected by DBS-TRN. Additionally, the power spectra of 0.5-100Hz and the coherence of 0.5-4.5 and 35-55Hz frequencies were modified by DBS-TRN. Our results suggest that DBS in the TRN may modify functional connectivity between different parts of the thalamo-cortical network. Additionally, our findings may suggest a beneficial effect of DBS-TRN on some preclinical aberrant oscillatory activities in a neurodevelopmental model of schizophrenia.