The GABAergic System and Endocannabinoids in Epilepsy and Seizures: What Can We Expect from Plant Oils?

Seizures and epilepsy are some of the most common serious neurological disorders, with approximately 80% of patients living in developing/underdeveloped countries. However, about one in three patients do not respond to currently available pharmacological treatments, indicating the need for research into new anticonvulsant drugs (ACDs). The GABAergic system is the main inhibitory system of the brain and has a central role in seizures and the screening of new ACD candidates. It has been demonstrated that the action of agents on endocannabinoid receptors modulates the balance between excitatory and inhibitory neurotransmitters; however, studies on the anticonvulsant properties of endocannabinoids from plant oils are relatively scarce. The Amazon region is an important source of plant oils that can be used for the synthesis of new fatty acid amides, which are compounds analogous to endocannabinoids. The synthesis of such compounds represents an important approach for the development of new anticonvulsant therapies.

Behavioural, electrocorticographic, and electromyographic alterations induced by Nerium oleander ethanolic extract: Anticonvulsant therapeutics assessment.

Nerium oleander Linn. is an Apocynaceae shrub which is among the most toxic ornamental plants. Although seizures are one of the symptoms associated with N. Oleander poisoning in humans, only a few studies are available on the behavioural and electrophysiological alterations caused by this plant poisoning. This study aimed at providing a thorough description of the electroencephalographic (EEG) and electromyographic (EMG) profiles throughout the experimental poisoning of Wistar rats (200-250 g) using ethanolic extract of N. oleander (EENO). Further, seizure control was assessed using different anticonvulsants. Male Wistar rat's behaviour was assessed upon EENO (150 mg/kg) administration and the animals were evaluated for muscle and neural activities through EMG and EEG recordings, respectively. The behavioural test showed two distinct phases of CNS activity: Phase I - myorelaxation and depression, and Phase II - excitability (agitated behaviour and seizures). Such phases were consistent with the EEG and EMG tracing patterns attained. Within the first 400 s of the recordings, during Phase I, the EMG showed no tracing amplitude variation. Later, the tracing pattern was changed and an intensification of the muscle contraction power in higher frequencies was observed during Phase II. The EEG showed initially a slight flattening in the tracings with a reduction in the intensity of the signal as per spectrogram of frequency attained. Thereafter, during Phase II, much higher amplitude tracings could be noted with an intensification of the signal, compatible with seizures. Seizure control was evaluated using four agents: phenytoin, phenobarbital, diazepam and scopolamine (at 10 mg/kg in all cases). While scopolamine was not effective in the seizure control, diazepam was the most efficient drug for the attenuation of the poisoning. Our results indicate the possibility of including phenytoin, phenobarbital and diazepam, mainly the latter, in the poisoning therapeutic protocol, including for those individuals who could be more susceptible to the poisoning by Nerium oleander as in the case of epileptic patients.

Towards Therapeutic Alternatives for Mercury Neurotoxicity in the Amazon: Unraveling the Pre-Clinical Effects of the Superfruit Açaí (Euterpe oleracea, Mart.) as Juice for Human Consumption.

Methylmercury (MeHg) exposure is a serious problem of public health, especially in the Amazon. Exposure in riverine populations is responsible for neurobehavioral abnormalities. It was hypothesized that consumption of Amazonian fruits could protect by reducing mercury accumulation. This work analyzed the effects of commercial samples of Euterpe oleracea (EO) for human consumption (10 µL/g) against MeHg i.p. exposure (2.5 mg/Kg), using neurobehavioral (open field, rotarod and pole tests), biochemical (lipid peroxidation and nitrite levels), aging-related (telomerase reverse transcriptase (TERT) mRNA expression) and toxicokinetic (MeHg content) parameters in mice. Both the pole and rotarod tests were the most sensitive tests accompanied by increased lipid peroxidation and nitrite levels in brains. MeHg reduced TERT mRNA about 50% demonstrating a strong pro-aging effect. The EO intake, similar to that of human populations, prevented all alterations, without changing the mercury content, but avoiding neurotoxicity and premature aging of the Central Nervous System (CNS). Contrary to the hypothesis found in the literature on the possible chelating properties of Amazonian fruits consumption, the effect of EO would be essentially pharmacodynamics, and possible mechanisms are discussed. Our data already support the regular consumption of EO as an excellent option for exposed Amazonian populations to have additional protection against MeHg intoxication.

Aqueous Coriandrum sativum L. extract promotes neuroprotection against motor changes and oxidative damage in rat progeny after maternal exposure to methylmercury.

This study aimed to investigate the effects of Coriandrum sativum aqueous extract (CSAE) on the rat progeny of mothers exposed to methylmercury (MeHg). The presence of bioactive compounds and CSAE's antioxidant capacity been evaluated, and the offspring were assessed for their total mercury levels, motor behavioral parameters and oxidative stress in the cerebellum. The analysis of the bioactive compounds revealed significant amounts of polyphenols, flavonoids, and anthocyanins, as well as a variety of minerals. A DPPH test showed the CSAE had important antioxidant activity. The MeHg + CSAE group performed significantly better spontaneous locomotor activity, palmar grip strength, balance, and motor coordination in behavioral tests compared the MeHg group, as well as in the parameters of oxidative stress, with similar results to those of the control group. The MeHg + CSAE group also had significantly reduced mercury levels in comparison to the MeHg group. Based on the behavioral tests, which detected large locomotor, balance, and coordination improvements, as well as a reduction in oxidative stress, we conclude that CSAE had positive functional results in the offspring of rats exposed to MeHg.

In vitro antileishmanial effects of Physalis angulata root extract on Leishmania infantum.

OBJECTIVE: In the present study, we evaluated the effects of the aqueous extract of Physalis angulata root (AEPa) on Leishmania infantum proliferation, morphology, and the driving mechanism in leishmanicidal activity and modulatory action on macrophages. METHODS: L. infantum promastigotes were treated with 50 and 100 µg/mL AEPa for 72 h and then antipromastigote assay was performed by counts in a Newbauer chamber, morphological changes were analyzed by transmission electron microscopy and the mechanism of the leishmanicidal activity was detected. In addition, macrophages were infected with L. infantum and were used to evaluate anti-amastigote activity of AEPa and effects of AEPa on cytokine secretion after 72-hour treatment. RESULTS: Treatment with AEPa reduced the numbers of L. infantum promastigotes (50% inhibitory concentration (IC50) = 65.9 µg/mL; selectivity index (SI) = 22.1) and amastigotes (IC50 = 37.9 µg/mL; SI = 38.5) compared with the untreated control. Amphotericin B reduced 100% of the promastigote numbers after 72 h of treatment (IC50 = 0.2 µg/mL). AEPa induced several morphological changes and increased the production of reactive oxygen species and apoptotic death in promastigotes after treating for 72 h. AEPa (100 µg/mL) promoted tumor necrosis factor-α secretion in macrophages infected with L. infantum after 72 h of treatment, but did not induce an increase in this cytokine in noninfected macrophages. In addition, AEPa showed no cytotoxic effect on J774-A1 cells (50% cytotoxic concentration >1000 µg/mL). CONCLUSION: AEPa presented antileishmanial activity against the promastigotes and amastigotes of L. infantum without macrophage cytotoxicity; these results show that natural products such as P. angulata have leishmanicidal potential and in the future may be an alternative treatment for leishmaniasis.

Libidibia ferrea mature seeds promote antinociceptive effect by peripheral and central pathway: possible involvement of opioid and cholinergic receptors.

Libidibia ferrea (LF) is a medicinal plant that holds many pharmacological properties. We evaluated the antinociceptive effect in the LF aqueous seed extract and Lipidic Portion of Libidibia ferrea (LPLF), partially elucidating their mechanisms. Histochemical tests and Gas chromatography of the LPLF were performed to characterize its fatty acids. Acetic acid-induced abdominal constriction, formalin-induced pain, and hot-plate test in mice were employed in the study. In all experiments, aqueous extract or LPLF was administered systemically at the doses of 1, 5, and 10 mg/kg. LF aqueous seed extract and LPLF demonstrated a dose-dependent antinociceptive effect in all tests indicating both peripheral anti-inflammatory and central analgesia properties. Also, the use of atropine (5 mg/kg), naloxone (5 mg/kg) in the abdominal writhing test was able to reverse the antinociceptive effect of the LPLF, indicating that at least one of LF lipids components is responsible for the dose related antinociceptive action in chemical and thermal models of nociception in mice. Together, the present results suggested that Libidibia ferrea induced antinociceptive activity is possibly related to its ability to inhibit opioid, cholinergic receptors, and cyclooxygenase-2 pathway, since its main component, linoleic acid, has been demonstrated to produce such effect in previous studies.

Estradiol reduces cumulative mercury and associated disturbances in the hypothalamus-pituitary axis of ovariectomized rats.

The aim of this research was to verify the incidence of endocrine dysfunction associated with mercury intoxication in the hypothalamus-pituitary reproductive system of normally cycling or castrated female rats and the possible protective action of estrogen replacement therapy. We found no differences in the frequency of estrus cycle stages (diestrus I, diestrus II, proestrus, and estrus) in normally cycling female rats during 54 days of daily oral administration of 0.004, 0.02, and 1 mg/kg MeHgCl. Conversely, the higher dose (1 mg/kg) induced a significant decrease in content of luteinizing hormone releasing hormone (LHRH) into the medial hypothalamus when administered daily during 3 days in ovariectomized rats. This effect was associated with increased levels of mercury found in the anterior pituitary gland and medial hypothalamus, rather than the anterior and posterior hypothalamus, striatum or cerebellum. A decrease in plasma levels of luteinizing hormone (LH) was also detected after administration of 7.5 mg/kg MeHgCl. These disturbances in LHRH and LH secretion induced by mercury were abolished or superimposed (respectively) by estrogenic replacement therapy (0.025 mg/kg 17beta estradiol cypionate, intramuscular). These effects were associated with a significant reduction in mercury content of the anterior pituitary gland and medial hypothalamus, suggesting a protective estrogenic effect.