RESUMEN
Septo-hippocampal pathway, crucial for physiological functions and involved in epilepsy. Clinical monitoring during epileptogenesis is complicated. We aim to evaluate tissue changes after lesioning the medial septum (MS) of normal rats and assess how the depletion of specific neuronal populations alters the animals' behavior and susceptibility to establishing a pilocarpine-induced status epilepticus. Male Sprague-Dawley rats were injected into the MS with vehicle or saporins (to deplete GABAergic or cholinergic neurons; n = 16 per group). Thirty-two animals were used for diffusion tensor imaging (DTI); scanned before surgery and 14 and 49 days post-injection. Fractional anisotropy and apparent diffusion coefficient were evaluated in the fimbria, dorsal hippocampus, ventral hippocampus, dorso-medial thalamus, and amygdala. Between scans 2 and 3, animals were submitted to diverse behavioral tasks. Stainings were used to analyze tissue alterations. Twenty-four different animals received pilocarpine to evaluate the latency and severity of the status epilepticus 2 weeks after surgery. Additionally, eight different animals were only used to evaluate the neuronal damage inflicted on the MS 1 week after the molecular surgery. Progressive changes in DTI parameters in both white and gray matter structures of the four evaluated groups were observed. Behaviorally, the GAT1-saporin injection impacted spatial memory formation, while 192-IgG-saporin triggered anxiety-like behaviors. Histologically, the GABAergic toxin also induced aberrant mossy fiber sprouting, tissue damage, and neuronal death. Regarding the pilocarpine-induced status epilepticus, this agent provoked an increased mortality rate. Selective septo-hippocampal modulation impacts the integrity of limbic regions crucial for certain behavioral skills and could represent a precursor for epilepsy development.
RESUMEN
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.