Multi-target Phenylpropanoids Against Epilepsy.

Epilepsy is a neurological disease with no defined cause, characterized by recurrent epileptic seizures. These occur due to the dysregulation of excitatory and inhibitory neurotransmitters in the central nervous system (CNS). Psychopharmaceuticals have undesirable side effects; many patients require more than one pharmacotherapy to control crises. With this in mind, this work emphasizes the discovery of new substances from natural products that can combat epileptic seizures. Using in silico techniques, this review aims to evaluate the antiepileptic and multi-target activity of phenylpropanoid derivatives. Initially, ligand-based virtual screening models (LBVS) were performed with 468 phenylpropanoid compounds to predict biological activities. The LBVS were developed for the targets alpha- amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), voltage-gated calcium channel Ttype (CaV), gamma-aminobutyric acid A (GABAA), gamma-aminobutyric acid transporter type 1 (GAT-1), voltage-gated potassium channel of the Q family (KCNQ), voltage-gated sodium channel (NaV), and N-methyl D-aspartate (NMDA). The compounds that had good results in the LBVS were analyzed for the absorption, distribution, metabolism, excretion, and toxicity (ADMET) parameters, and later, the best molecules were evaluated in the molecular docking consensus. The TR430 compound showed the best results in pharmacokinetic parameters; its oral absorption was 99.03%, it did not violate any Lipinski rule, it showed good bioavailability, and no cytotoxicity was observed either from the molecule or from the metabolites in the evaluated parameters. TR430 was able to bind with GABAA (activation) and AMPA (inhibition) targets and demonstrated good binding energy and significant interactions with both targets. The studied compound showed to be a promising molecule with a possible multi-target activity in both fundamental pharmacological targets for the treatment of epilepsy.

Anticonvulsant activity of Tetrahydrolinalool: behavioral, electrophysiological, and molecular docking approaches.

Tetrahydrolinalool (THL) is an acyclic monoterpene alcohol, produced during linalol metabolism and also a constituent of essential oils. As described in the literature, many monoterpenes present anticonvulsant properties, and thus we became interested in evaluating the anticonvulsant activity of Tetrahydrolinalool using in mice model as well as in silico approaches. Our results demonstrated that THL increased latency to seizure onset and also reduced the mortality, in picrotoxin induced seizure tests. The results may be related to GABAergic regulation, which was also suggested in seizure testing induced by 3-mercapto-propionic acid. In the strychnine-induced seizure testing, none of the groups pretreated with THL modulated the parameters indicative of anticonvulsant effect. The electrophysiological results revealed that THL treatment reduces seizures induced by pentylenetetrazole. The in silico molecular docking studies showed that the interaction between THL and a GABAA receptor model formed a stable complex, in comparison to the crystaligraphic structure of diazepam, a structurally related ligand. In conclusion, all the evidences showed that THL presents effective anticonvulsant activity related to the GABAergic pathway, being a candidate for treatment of epileptic syndromes.

An In Silico Approach to Exploring the Antinociceptive Biological Activities of Linalool and its Metabolites.

Pain is characterized by the unpleasant sensory and emotional sensation associated with actual or potential tissue damage, whereas nociception refers to the mechanism by which noxious stimuli are transmitted from the periphery to the CNS. The main drugs used to treat pain are nonsteroidal anti-inflammatory drugs (NSAIDs) and opioid analgesics, which have side effects that limit their use. Therefore, in the search for new drugs with potential antinociceptive effects, essential oils have been studied, whose constituents (monoterpenes) are emerging as a new therapeutic possibility. Among them, linalool and its metabolites stand out. The present study aims to investigate the antinociceptive potential of linalool and its metabolites through a screening using an in silico approach. Molecular docking was used to evaluate possible interactions with important targets involved in antinociceptive activity, such as α2-adrenergic, GABAergic, muscarinic, opioid, adenosinergic, transient potential, and glutamatergic receptors. The compounds in the investigated series obtained negative energies for all enzymes, representing satisfactory interactions with the targets and highlighting the multi-target potential of the L4 metabolite. Linalool and its metabolites have a high likelihood of modulatory activity against the targets involved in nociception and are potential candidates for future drugs.

Mechanisms Involved in the Therapeutic Effect of Cannabinoid Compounds on Gliomas: A Review with Experimental Approach.

INTRODUCTION: Brain tumors have high morbidity and mortality rates, accounting for 1.4% of all cancers. Gliomas are the most common primary brain tumors in adults. Currently, several therapeutic approaches are used; however, they are associated with side effects that affect patients'quality of life. Therefore, further studies are needed to develop novel therapeutic protocols with a more favorable side effect profile. In this context, cannabinoid compounds may serve as potential alternatives. OBJECTIVE: This study aimed to review the key enzymatic targets involved in glioma pathophysiology and evaluate the potential interaction of these targets with four cannabinoid derivatives through molecular docking simulations. METHODS: Molecular docking simulations were performed using four cannabinoid compounds and six molecular targets associated with glioma pathophysiology. RESULTS: Encouraging interactions between the selected enzymes and glioma-related targets were observed, suggesting their potential activity through these pathways. In particular, cannabigerol showed promising interactions with epidermal growth factor receptors and phosphatidylinositol 3- kinase, while Δ-9-tetrahydrocannabinol showed remarkable interactions with telomerase reverse transcriptase. CONCLUSION: The evaluated compounds exhibited favorable interactions with the analyzed enzymatic targets, thus representing potential candidates for further in vitro and in vivo studies.

Computational Studies Applied to Linalool and Citronellal Derivatives Against Alzheimer's and Parkinson's Disorders: A Review with Experimental Approach.

Alzheimer's and Parkinson's are neurodegenerative disorders that affect a great number of people around the world, seriously compromising the quality of life of individuals, due to motor and cognitive damage. In these diseases, pharmacological treatment is used only to alleviate symptoms. This emphasizes the need to discover alternative molecules for use in prevention. Using Molecular Docking, this review aimed to evaluate the anti-Alzheimer's and anti-Parkinson's activity of linalool and citronellal, as well as their derivatives. Before performing Molecular Docking simulations, the compounds' pharmacokinetic characteristics were evaluated. For Molecular Docking, 7 chemical compounds derived from citronellal, and 10 compounds derived from linalool, and molecular targets involved in Alzheimer's and Parkinson's pathophysiology were selected. According to the Lipinski rules, the compounds under study presented good oral absorption and bioavailability. For toxicity, some tissue irritability was observed. For Parkinson-related targets, the citronellal and linalool derived compounds revealed excellent energetic affinity for α-Synuclein, Adenosine Receptors, Monoamine Oxidase (MAO), and Dopamine D1 receptor proteins. For Alzheimer disease targets, only linalool and its derivatives presented promise against BACE enzyme activity. The compounds studied presented high probability of modulatory activity against the disease targets under study, and are potential candidates for future drugs.

Identifying the neuropsychiatric health effects of low-dose lithium interventions: A systematic review.

BACKGROUND: Lithium is widely evidenced for its neuropsychiatric benefits. Advantages of 'sub-therapeutic' doses are increasingly being reported, which is apposite given enduring concerns around adverse effects of 'therapeutic' doses. We aimed to synthesise all available evidence from interventional studies investigating low-dose lithium (LDL) across neuropsychiatric outcomes. METHODS: Electronic databases were systematically searched to include studies where a group of adult humans were treated with LDL (∼serum level ≤0.6 mmol/L), where data describing a neuropsychiatric outcome were reported either before and after treatment, and/or between lithium and a comparator. RESULTS: 18 articles were examined and grouped according to outcome domain (cognition, depression, mania, and related constructs e.g., suicidality). Significant benefits (versus placebo) were identified for attenuating cognitive decline, and potentially as an adjunctive therapy for people with depression/mania. Across studies, LDL was reported to be safe. CONCLUSIONS: Despite the paucity and heterogeneity of studies, LDL's apparent pro-cognitive effects and positive safety profile open promising avenues in the fields of neurodegeneration, and augmentation in affective disorders. We urge future examinations of LDL's potential to prevent cognitive/affective syndromes.

Anxiolytic and Antidepressant-like Effects of Monoterpene Tetrahydrolinalool and In silico Approach of new Potential Targets.

INTRODUCTION: Although drugs currently available for the treatment of anxiety and depression act through modulation of the neurotransmission systems involved in the neurobiology of the disorder, yet they often present side effects, which can impair patient adherence to treatment. METHODS: This has driven the search for new molecules with anxiolytic and antidepressant potential. Aromatic plants are rich in essential oils, and their chemical constituents, such as monoterpenes, are being studied for these disorders. This study aims to evaluate the anxiolytic and antidepressant-like potential of the monoterpene tetrahydrolinalool in in vivo animal models and review pharmacological targets with validation through molecular docking. Male Swiss mice (Mus musculus) were treated with THL (37.5-600 mg kg-1 p.o.) and submitted to the elevated plus maze, open field, rotarod, and forced swim tests. In the elevated plus-maze, THL at doses of 37.5 and 75 mg kg-1 induced a significant increase in the percentage of entries (72.7 and 64.3% respectively), and lengths of stay (80.3 and 76.8% respectively) in the open arms tests. RESULTS: These doses did not compromise locomotor activity or motor coordination in the animals. In the open field, rotarod tests, and the forced swimming model, treatment with THL significantly reduced immobility times at doses of 150, 300, and 600 mg kg-1, and by respective percentages of 69.3, 60.9 and 68.7%. CONCLUSION: In molecular docking assay, which investigated potential targets, THL presented satisfactory energy values for: nNOs, SGC, IL-6, 5-HT1A, NMDAr, and D1. These demonstrate the potential of THL (a derivative of natural origin) in in vivo and in silico models, making it a drug candidate.

Melatonin attenuates glucocorticoid effect induced by medroxyprogesterone acetate in rats.

Medroxyprogesterone acetate (MPA) acts on glucocorticoid receptors and, when it is in excess, can cause clinical disorders comparable to hyperadrenocorticism. Melatonin (MEL) is a hormone with potent antioxidant and anti-glucocorticoid activity and it can be beneficial in the excessive activation of glucocorticoid receptors. To evaluate the protective effects of MEL on the glucocorticoid effect of MPA, 34 male Wistar rats were randomized into four groups: CON (control), MEL, MPA, and MPA + MEL. The animals were treated for 28 days, by subcutaneous injection. At the high dose that we used, the MPA caused effects compatible with an excessive activation of glucocorticoid receptors, resulting on a reduction in adrenal size, less weight gain, lower final body weight and feeding efficiency, and fewer lymphocytes compared with the control group. In addition, there was an increase in abdominal fat, cholesterol, very-low-density lipoprotein (VLDL), triglycerides, erythrocytes, hemoglobin, hematocrit, and hepatic vacuolization. We concluded that MEL was effective reducing the mean values of total cholesterol, high-density lipoprotein (HDL), urea, VLDL, triglycerides, hepatic microvacuolization and abdominal fat/weight in rats treated with MPA. These findings indicate that MEL attenuates the harmful effects of MPA.

In vitro activity of N-phenyl-1,10-phenanthroline-2-amines against tachyzoites and bradyzoites of Toxoplasma gondii.

Toxoplasma gondiiis an apicomplexan parasite, the causative agent of toxoplasmosis, a common disease in the world. Toxoplasmosis could be severe, especially in immunocompromised patients. The current therapy is limited, where pyrimethamine and sulfadiazine are the best choices despite being associated with side effects and ineffective against the bradyzoites, the parasitic form present during the chronic phase of the infection. Thus, new therapies against both tachyzoites and bradyzoites from T. gondii are urgent. Herein, we present the anti-T. gondii effect of 1,10-phenanthroline and its N-phenyl-1,10-phenanthroline-2-amine derivatives. The chemical modification of 1,10-phenanthroline tonew derivatives improved the anti-T. gondiiactivity 3.4 fold. The most active derivative presented ED50in the nanomolar range, the smallest value found was for Ph8, 0.1 µM for 96 h of treatment. The host cell viability was maintained after the treatment with the compounds, which were found to be highly selective presenting large selectivity indexes. Treatment with derivatives for 96 h was able to eliminate the T. gondii infection irreversibly. The ultrastructural alterations caused after the treatment with the most effective derivative (Ph8) included signs of cell death, specifically revealed by the Tunel assay for detection of DNA fragmentation. The Phen derivatives were also able to control the growth of the in vitro-derived bradyzoite forms of T. gondii EGS strain, causing its lysis and death. These findings promote the 1,10-phenanthroline derivatives as potential lead compounds for the development of a treatment for acute and chronic phases of toxoplasmosis.

Direct refractive index retrieval from interferometry measurements.

We present an alternative numerical method to the Abel inversion technique, which can be applied to complex non-symmetrical systems. A comparison with the Abel inversion algorithm was conducted. For benchmarking, the method was applied to a synthetic trace representing a plasma waveguide characterized by a constant parabolic density profile. Furthermore, the temperature and refractive index of a plume of hot air surrounding a non-cylindrical soldering iron were retrieved. Temperatures between 50 °C and 200 °C were successfully retrieved within the instrument precision. The proposed method allows robust and fast data retrieval while maintaining the accuracy and resolution of well-known methods, as Abel inversion.

Dilated cardiomyopathy in boxer puppy of 8 months of age: a case report / Cardiomiopatia dilatada em cão da raça boxer de 8 meses de idade: relato de caso

A female Boxer breed dog, at eight months of age, with 8kg, was taken care in the Veterinary Hospital of the Federal University of Goias with emaciation and breathing difficulty. Cyanotic mucosa, ascites, pulmonary rales, arrhythmias and hypophonesis of heart sounds were observed during clinical examination. Chest X-ray, electrocardiogram and echocardiogram were performed, diagnosing dilated cardiomyopathy. The animal, young enough to manifestation of this disease, was treated and showed a survival of 8 months after the beginning of the treatment.

Uma cadela da raça Boxer, oito meses, 8kg, foi atendida no Hospital Veterinário da Universidade Federal de Goiás, com emaciação e dificuldade respiratória. Ao exame clínico observou-se mucosas cianóticas, ascite, estertores pulmonares, arritmias e hipofonese das bulhas cardíacas. Realizou-se radiografia de tórax, eletrocardiograma e ecocardiograma, diagnosticando-se cardiomiopatia dilatada. O animal, bastante jovem para manifestação desta enfermidade, foi tratado e obteve uma sobrevida de oito meses após inicio do tratamento.

Increased bandwidth optical parametric amplification of supercontinuum pulses with angular dispersion.

The use of a controlled, removable angular dispersion applied to the signal beam in a plane orthogonal to that containing the noncollinear angle is experimentally demonstrated as a technique to broaden the gain bandwidth in optical parametric chirped-pulse amplification. With a pump beam centered at 526 nm the supercontinuum signal is amplified in the 900 to 1220 nm range in a beta-barium borate crystal with a gain >1000. This represents a bandwidth improvement greater than 30% relative to conventional designs.

Single adjuster deformable mirror with four contact points for simultaneous correction of astigmatism and defocus.

We show that a deformable mirror with four point actuators is suitable for the simultaneous correction of astigmatism and defocus in a given optical system by adequately choosing the relative position of the actuators. An analytical model is developed that describes adequately the mirror deformation as a function of actuator position, showing that it is possible to continuously tune the weight of each aberration. Experimental measurements with a single adjuster deformable mirror assembly confirm the validity of the model.