Anxiolytic potential of resveratrol and rufinamide combination by modulating GABA-ergic transmission: insights from experiments, molecular docking and dynamics simulations.

Resveratrol is a polyphenolic phytocompound known to possess anxiolytic-like effects but its impact on central gammaaminobutyric acid (GABA) modulation has never been explored. The purpose of this study was to analyze the anxiolytic-like effects of resveratrol alone and in combination with rufinamide, an antiepileptic drug which has never been studied for its anxiolytic potential. The BALB/c mice were tested in a battery of behavior testing after administration of resveratrol (50 mg/kg) and rufinamide (50 mg/kg) alone and in combination. Moreover, molecular docking studies were also carried out to understand the interaction of resveratrol and rufinamide with GABA aminotransferase, GABA receptor and GABA-A transporter type 1. Resveratrol alone exerted notable anxiolytic-like effects and improved outcomes in few experiments but rufinamide alone did not yield any beneficial outcomes. However, the animal co-administered with resveratrol and rufinamide behaved exceptionally well (p<0.05) and preferred open, illuminated and exposed areas of open field, light/dark and elevated plus maze. Further, these animals showed reduced anxiety towards anxiogenic stimuli i.e. holes and marbles in hole board and marble bury tests, respectively. Resveratrol and rufinamide showed moderate to strong binding affinities with GABA proteins, indicating the potential to treat anxiety-like neurological disorders. Moreover, resveratrol and rufinamide were analyzed using molecular docking to determine their interaction with GABA receptors, transporters, and transaminase. The results suggest that their anxiolytic-like effects may be due to inhibiting GABA reuptake transporter 1 protein, leading to increased synaptic levels of GABA neurotransmitter, as seen in stable molecular dynamics results with the 7SK2 GABA transporter protein.

Happy Birthday "One Flew Over the Cuckoo's Nest": A Momentous Tale in the Quest for an Effective and Ethical Approach to Psychosurgery.

The anniversary of the publication of 'One Flew Over the Cuckoo's Nest' by Ken Kesey offers an opportunity for reflection on the use of neurosurgery in psychiatry. We used a narrative, historical and dialectical method to deliver an account of the controversial subject. A balanced representation of the negative and positive aspects, acknowledging some of the questionable ethical practices while describing well-reasoned applications is provided. It includes neurosurgeons, psychiatrists who have embraced these procedures with unwarranted enthusiasm and those who have opposed. Neurosurgical techniques for the treatment of severe mental disorders have evolved from rudimentary procedures which were used to 'correct' unwanted behaviours associated with a wide range of severe mental disorders to more refined and selective approaches used as a last resort to treat specific mental health conditions. In the absence of specific aetiological models to guide ablative surgical targets, non-ablative, stimulatory techniques have more recently been developed to allow reversibility when surgical treatment fails to obtain a sizeable improvement in quality of life. The subject is concretely illustrated by two eloquent clinical images: one on a series of brain computed tomography scans carried out on a Canadian population of subjects, who underwent leukotomy decades ago, and the other more contemporary on an implantation surgery to epidural stimulation. Alongside technical advances in psychosurgery, a regulatory framework has gradually developed to ensure vigilance in the appropriateness of patients' selection. Nevertheless, harmonisation of protocols around the world is necessary to ensure consistency in obtaining and maintaining the highest possible ethical standards for the benefit of patients. If the neurosciences promise today, in their new, better framed, and reversible applications, to provide answers to unmet therapeutic needs, we still must remain attentive to drifts linked the introduction of intrusive technologies for purposes of domination or behaviour modification that would impede our individual freedom.

Acetylcholinesterase inhibitory potential of scorpion venom in Aedes aegypti (Diptera: Culicidae).

Scorpion venom contains a variety of neurotoxins which interact with ion channels and affect their activities. The present study was designed to evaluate the potential of scorpion venom as acetylcholinesterase (AChE) inhibitor by using Aedes aegypti as model organism. Venoms of two species, Hottentota tamulus (Fabricus, 1798) and Androctonus finitimus (Pocock, 1897) were selected for this study. Two peptides (36 kDa from H. tamulus and 54 kDa from A. finitimus) were separated from scorpion venom by using HPLC. Selected peptides caused significantly higher mortality in larvae and adults of Aedes aegypti than control (no mortalities were observed in control groups). Significant acetylcholinesterase (AChE) inhibitory potential of both peptides was recorded by spectrophotometer. The peptide of A. finitimus caused significantly higher mortality (95±1.53% in larvae and 100% in adults) than the peptide of H. tamulus (84.33±2.33% in larvae and 95.37±1.45% in adults). While H. tamulus peptide was more efficient in reducing AChE activity (0.029±0.012 in larvae and 0.03±0.003 in adults) than the peptide of A. finitimus (0.049±0.005 in larvae and 0.047±0.001 in adults). It was concluded that H. tamulus venom peptide was more efficiently reducing AChE activity, thus it could be a potential bio-insecticide which can be synthesized at industrial scale for the control of harmful insects.

Time course evaluation of lacosamide alone and in polypharmacy on behavioral manifestations and oxidative stress in lithium-pilocarpine-induced model.

The lithium-pilocarpine model in rats is commonly used to study the characteristic events of acute status epilepticus (SE), epileptogenesis and temporal lobe epilepsy (TLE). Here we investigated the impact of lacosamide alone and in combination with other drugs (pregabalin, piracetam and scopolamine) on spontaneous recurrent seizures (SRSs) and behavioral parameters during the time frame of 6 weeks after SE. In addition, the level of oxidative stress in the hippocampus was accessed by real-time microdialysis study (8-isoprostanes) and antioxidants enzymes in the homogenate. Results revealed severe behavioral deficits with the control epileptic group and animals displayed hyperexcitability, aggression apprehension and memory insufficiency. Pharmacological manipulation for 6 weeks with lacosamide (L) - 80 mg/kg; in polypharmacy with pregabalin (L/P) - 50/50 mg/kg and piracetam (L/Pi) - 50/140 mg/kg significantly (P < 0.05) ameliorated the anxiety-related behavior (open filed, elevated plus maze, light/dark tests), depression (forced swim test) and improved spatial/reference memory (Morris water maze). There were low incidences of seizures in L, L/P and L/Pi groups revealing disease-modifying effects of employed drugs. Furthermore, the chronic use of scopolamine (L/P/S; 50/50/2 mg/kg) as polypharmacy with the concept of antagonizing the cholinergic inputs in the epileptogenic phase aberrated the behavioral situation further worse. Treatments with L/P and L/Pi significantly attenuated (P < 0.05) the oxidative stress by reducing 8-isoprostanes and malondialdehyde (MDA) levels. Furthermore, superoxide dismutase (SOD) and glutathione peroxidase (GPx) levels in the L/P group were significantly (P < 0.05) improved. Overall, our findings support the use of a combination of drugs (L/P and L/Pi) in lithium-pilocarpine model which remarkably ameliorated SRSs, reduced anxiety-related behaviors, retention of spatial/reference memory and lowered oxidative stress in a time-course evaluation 6 weeks post- SE insult.

Synthesis and morphological control of europium doped cadmium sulphide nanocrystals.

Europium doped cadmium sulphide (Cd(0.98)Eu(0.2)S) nanostructures were synthesised by chemical co-precipitation method using ethylene glycol (EG) and deionized water (Eu:CdS-1), and isopropyl alcohol (IPA) and deionized water (Eu:CdS-2) as mixed solvents. It has been found that the nanostructure of the europium doped CdS can be controlled by simply varying the mixed solvent system. Powder XRD pattern reveals the formation of hexagonal (wurtzite) and cubic (zinc blende) structure for Eu:CdS-1, and Eu:CdS-2, respectively. The crystallite size of the sample prepared using IPA and deionized water was measured to be 2.64 nm which is much smaller than that of the sample prepared using EG and deionized water as mixed solvent (3.65 nm). Morphology of the materials can also be changed from flower shaped crystals to paddy like structures by varying the mixed solvents. Band gap values of Eu3+ doped CdS nanocrystals synthesized from two different solvents were estimated using UV-reflectance spectra. The size and crystallinity of the samples were confirmed by HRTEM and SAED analysis. A significant change in the PL emission of the CdS nanocrystals was observed for the europium doped CdS which is mainly due to the presence of EU3+ ions which also play a significant role in the energy transfer process. It was also observed that the shift in the emission and efficiency depends on size and shape of the synthesised nanoparticles.

Ketamine for bone marrow aspiration and trephine biopsy in children.

To make bone marrow aspiration and trephine biopsy less painful and more acceptable in children a short acting anaesthetic ketamine was used in a dose of 1-2 mg/kg body weight intravenously or 4-5 mg/kg intramuscularly. One hundred cases aged 2 to 13 years were studied. The actual procedure time ranged between 20 seconds and 3 minutes, adequate samples were obtained in 80% of children on first attempt. Vomiting was the only side effect noted in two children. Ketamine is safe and recommended in all children undergoing bone marrow aspiration and trephine biopsies.

Endoscopic laser pancreatic cystogastrostomy. An alternative for internal drainage of pancreatic pseudocysts.

Traditionally the drainage of pancreatic pseudocysts has been carried out operatively, forming a cystenterostomy. A simple endoscopic method of forming a pancreatic cystogastrostomy with laser is presented. This procedure does not require a general anesthetic, is safe, and allows resolution of symptoms.