Neuropharmacological Studies Research Articles

Unraveling the Role of Wnt Signaling Pathway in the Pathogenesis of Autism Spectrum Disorder (ASD): A Systematic Review.

Autism spectrum disorder (ASD), or simply autism, is a neurodevelopmental disorder characterized by social communication deficit, restricted interests, and repetitive behavior. Several studies suggested a link between autism and the dysregulation of the Wnt signaling pathway which is mainly involved in cell fate determination, cell migration, cell polarity, neural patterning, and organogenesis. Despite the absence of effective therapy, significant progress has been made in understanding the pathogenesis of ASD. Neuropharmacological studies showed that drugs acting on the Wnt pathway like Canagliflozin can alleviate autistic-like behavior in animal models. Hence, this pathway could potentially be a futuristic therapeutic target to mitigate autism's symptoms. This systematic review aims to collect and analyze evidence that elucidates how alterations in the Wnt pathway may contribute to the pathogenesis of autism in animal models at the molecular, cellular, and physiological levels. Comprehensive searches were conducted across multiple databases, including PubMed, Web of Science, Embase, and Scopus to identify relevant studies up to March 2024. The inclusion criteria encompassed experimental studies that focused on the link between autism and this pathway, and the quality assessment was ensured by SYRCLE's risk of bias tools. Collectively, the included articles highlighted the possible implication of this pathway in the abnormalities found in autism, which impacted processes such as energy metabolism, oxidative stress, and neurogenesis. These alterations could underlie autistic behavior by affecting synaptic transmission and mitochondrial function.

Prospects of Electrocorticography in Neuropharmacological Studies in Small Laboratory Animals.

Electrophysiological methods of research are widely used in neurobiology. To assess the bioelectrical activity of the brain in small laboratory animals, electrocorticography (ECoG) is most often used, which allows the recording of signals directly from the cerebral cortex. To date, a number of methodological approaches to the manufacture and implantation of ECoG electrodes have been proposed, the complexity of which is determined by experimental tasks and logistical capabilities. Existing methods for analyzing bioelectrical signals are used to assess the functional state of the nervous system in test animals, as well as to identify correlates of pathological changes or pharmacological effects. The review presents current areas of applications of ECoG in neuropharmacological studies in small laboratory animals. Traditionally, this method is actively used to study the antiepileptic activity of new molecules. However, the possibility of using ECoG to assess the neuroprotective activity of drugs in models of traumatic, vascular, metabolic, or neurodegenerative CNS damage remains clearly underestimated. Despite the fact that ECoG has a number of disadvantages and methodological difficulties, the recorded data can be a useful addition to traditional molecular and behavioral research methods. An analysis of the works in recent years indicates a growing interest in the method as a tool for assessing the pharmacological activity of psychoactive drugs, especially in combination with classification and prediction algorithms.

The Conventional and Breakthrough Tool for the Study of L-Glutamate Transporters.

In our recent report, we clarified the direct interaction between the excitatory amino acid transporter (EAAT) 1/2 and polyunsaturated fatty acids (PUFAs) by applying electrophysiological and molecular biological techniques to Xenopus oocytes. Xenopus oocytes have a long history of use in the scientific field, but they are still attractive experimental systems for neuropharmacological studies. We will therefore summarize the pharmacological significance, advantages (especially in the study of EAAT2), and experimental techniques that can be applied to Xenopus oocytes; our new findings concerning L-glutamate (L-Glu) transporters and PUFAs; and the significant outcomes of our data. The data obtained from electrophysiological and molecular biological studies of Xenopus oocytes have provided us with further important questions, such as whether or not some PUFAs can modulate EAATs as allosteric modulators and to what extent docosahexaenoic acid (DHA) affects neurotransmission and thereby affects brain functions. Xenopus oocytes have great advantages in the studies about the interactions between molecules and functional proteins, especially in the case when the expression levels of the proteins are small in cell culture systems without transfections. These are also proper to study the mechanisms underlying the interactions. Based on the data collected in Xenopus oocyte experiments, we can proceed to the next step, i.e., the physiological roles of the compounds and their significances. In the case of EAAT2, the effects on the neurotransmission should be examined by electrophysiological approach using acute brain slices. For new drug development, pharmacokinetics pharmacodynamics (PKPD) data and blood brain barrier (BBB) penetration data are also necessary. In order not to miss the promising candidate compounds at the primary stages of drug development, we should reconsider using Xenopus oocytes in the early phase of drug development.

High-Affinity Aptamers for In Vitro and In Vivo Cocaine Sensing.

The ability to quantify cocaine in biological fluids is crucial for both the diagnosis of intoxication and overdose in the clinic as well as investigation of the drug's pharmacological and toxicological effects in the laboratory. To this end, we have performed high-stringency in vitro selection to generate DNA aptamers that bind cocaine with nanomolar affinity and clinically relevant specificity, thus representing a dramatic improvement over the current-generation, micromolar-affinity, low-specificity cocaine aptamers. Using these novel aptamers, we then developed two sensors for cocaine detection. The first, an in vitro fluorescent sensor, successfully detects cocaine at clinically relevant levels in 50% human serum without responding significantly to other drugs of abuse, endogenous substances, or a diverse range of therapeutic agents. The second, an electrochemical aptamer-based sensor, supports the real-time, seconds-resolved measurement of cocaine concentrations in vivo in the circulation of live animals. We believe the aptamers and sensors developed here could prove valuable for both point-of-care and on-site clinical cocaine detection as well as fundamental studies of cocaine neuropharmacology.

Neuropharmacological Study on Capsaicin in Scopolamine-injected Mice.

To evaluate the potential beneficial role of Capsaicin in cognitive dysfunction, mitochondrial impairment, and oxidative damage induced by scopolamine in mice. Capsaicin is the chief phenolic component present in red chili and is responsible for its pungent and spicy flavor. It affects TRPV1 channels in nociceptive sensory neurons and is present in the hippocampus, and hypothalamus of the brains of rodents and humans. The main objective is to investigate the effective role of capsaicin in attenuating cognitive dysfunction, mitochondrial impairment, and oxidative damage induced by scopolamine in mice and examine the feasible mechanisms. Various doses of capsaicin (5, 10, and 20 mg/kg) were given orally to mice daily for 7 consecutive days after the administration of scopolamine. Various behavioral tests (motor coordination, locomotor counts, hole board test) and biochemical assay (Pro-inflammatory cytokines, catalase, lipid peroxidation, nitrite, reduced glutathione, and superoxide dismutase), mitochondrial complex (I, II, III, and IV) enzyme activities, and mitochondrial permeability transition were evaluated in the distinct regions of the brain. Scopolamine-treated mice showed a considerable reduction in the entries and duration in the light zone as well as in open arms of the elevated plus maze. Interestingly, capsaicin at different doses reversed the anxiety, depressive-like behaviors, and learning and memory impairment effects of scopolamine. Scopolamine-administered mice demonstrated substantially increased pro-inflammatory cytokines levels, impaired mitochondrial enzyme complex activities, and increased oxidative damage compared to the normal control group. Capsaicin treatment reinstated the reduced lipid peroxidation, nitric oxide, catalase, superoxide dismutase, reduced glutathione activity, decreasing pro-inflammatory cytokines and restoring mitochondrial complex enzyme activities (I, II, III, and IV) as well as mitochondrial permeability. Moreover, the IL-1β level was restored at a dose of capsaicin (10 and 20 mg/kg) only. Capsaicin reduced the scopolamine-induced acetylcholinesterase activity, thereby raising the acetylcholine concentration in the hippocampal tissues of mice. Preservation of neuronal cell morphology was also confirmed by capsaicin in histological studies. From the above experimental results, capsaicin at a dose of 10 mg/kg, p.o. for seven consecutive days was found to be the most effective dose. The experiential neuroprotective effect of capsaicin through the restoration of mitochondrial functions, antioxidant effects, and modulation of pro-inflammatory cytokines makes it a promising candidate for further drug development through clinical setup.

The role of the anterior cingulate cortex in aggression and impulsivity.

Aggression is a complex social behavior that evolved in the context of defending a territory, fighting for limited resources, and competing for mates and protection. Although aggression considered as a negative or undesirable emotion is an essential part of many species' repertoire of social behaviors. For humans, the motivations, actions, and limits of aggressive acts are not always clear. However, uncontrolled aggression may have destructive consequences, and it develops inappropriately into violence. At the neural level, several studies demonstrated that aggression is related to cortical abnormalities, including the anterior cingulate cortex (ACC). This review summarizes the state of the literature regarding the involvement of ACC in the neurobiology of aggression and impulsivity. We will first review structural and neuroanatomical studies, including volumetric and functional investigations of aggression. Next, we will discuss the neurochemical and neuropharmacological studies of aggression related to the ACC. We will focus mainly on the gamma-aminobutyric acid/glutamate balance, as well as the serotoninergic system. Finally, we will try to integrate these results and reconcile discrepancies in the field and suggest recommendations for future studies. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

In-Vitro Antioxidant, Anti-Arthritis, Anti-inflammatory, Thrombolysis, Anti-bacterial, and in-Vivo Neuropharmacological Activities of Bioactive Metabolites of Solanum americanum Mill.

Aims: The purpose of this research was to examine the effects of methanol-prepared leaf extracts from the Solanum americanum Mill. plant on a variety of in vitro activities, including antioxidant, anti-Arthritis, anti-inflammatory, thrombolysis, anti-bacterial, and in-vivo neuropharmacological activities.
 Study Design: Methanolic extract of Solanum americanum leaf (MESAL) was primarily evaluated via phytochemical screening. The potential for in vitro activities, including antioxidant, anti-arthritis, anti-inflammatory, thrombolysis, and anti-bacterial activity were determined to study due to the pharmacological interest in the plant's chemical constituent. Whether there is statistical significance to the changes seen in its in vivo neuropharmacological characteristics when tested in experimental animals.
 Place and Duration of Study: This research was carried out between November 2022 to January 2023 at the Laboratory of Phytochemistry and Pharmacology in the Department of Pharmacy and Laboratory of Microbiology, Stamford University Bangladesh and Bangladesh Council of Scientific and Industrial Research, Dhaka.
 Methodology: The plant was subjected to phytochemical screening utilizing a variety of test reagents and potential antioxidant, anti-arthritis, anti-inflammatory, thrombolytic, anti-bacterial, and neuropharmacological activities of MESAL were investigated. Antioxidant, anti-arthritic, anti-inflammatory, thrombolytic, and antibacterial activities were tested at different doses utilizing the DPPH Free Radical Scavenging Assay, Protein Denaturation Assays, Clot Lysis, and the Disk Diffusion Method. Swiss albino mice were tested using open-field and hole-cross methods to measure their locomotion as part of the neuropharmacological study.
 Results: The MESAL phytochemical screening findings demonstrated that the plants' chemical compositions varied. Most antioxidant activities were found in MESA, with an IC50 of 11.73 µg/mL compared to Ascorbic acid's IC50 of 28.86 µg/mL. When compared to the standard, the percent inhibition value of MESAL's anti-arthritis activity was significantly higher. With a maximum protein denaturation value of 94.03% at a concentration of 1000µg/mL, MESAL possesses potent anti-inflammatory activity. The value of MESAL in terms of clot lysis is very significant which is 90.257%. While MESAL's antibacterial value is moderate, it is still worth considering. However, the extract was proven to be less effective than Diazepam in improving motor coordination in the Open Field and Hole Cross Tests.
 Conclusion: Several pathological conditions, including neurodegenerative diseases, may benefit in the future from the use of plant-derived pharmacological agents due to their neuropharmacological, antioxidant, anti-inflammatory, and anti-arthritic activity, which can replace the use of NSAIDs.

DEVELOPMENT OF MURINE STEM CELLS WITH CONDITIONAL KNOCKOUT OF HUMANIZED SNCA GENE

α-synuclein is one of the key molecular links in the pathogenesis of Parkinson’s disease. The accumulated data indicate that pathogenic mutations in the Snca gene are associated with the development of neurodegenerative brain damage, indicating the relevance of studying the synuclein neurobiological role.The aim of the study was to create a genetically modified clone of mouse stem cells with a conditional knockout of humanized α-synuclein, which can be used for the reinjection into mouse blastocysts, as well as for basic and applied in vitro research in the field of pathophysiology and neuropharmacology.Materials and methods. To create mouse stem cells with a conditional knockout of the humanized Snca gene, a previously obtained clone with the first Snca exon flanked by LoxP sites, was used. The CRISPR/Cas9-mediated homologous recombination system with donor DNA oligonucleotides of the human sites of the corresponding gene sites was used to humanize the fourth and fifth exons. Cas9 nuclease, single guide RNA, and donor DNA were transfected into mouse cells.Results. An approach to obtaining clones of mouse genetically modified stem cells expressing pathological humanized α-synuclein, has been proposed and implemented. The resulting clones were plated on Petri dishes for propagation and a further genetic analysis. Clone 126-2F4 was found out carrying the necessary genetic modifications. The results obtained are fundamentally important not only for understanding the development of the pathological process in α-synucleinopathies, but which is more important, for the development of new therapeutic approaches that will stop the extension of the human α-synuclein aggregation pathology throughout the nervous system, and the validation of these approaches in preclinical trials.Conclusion. As a result of the study, a strategy for CRISPR/Cas9-assisted homologous recombination in the genome of mouse embryonic stem cells has been developed to create a fully humanized Snca gene encoding α-synuclein, and the clone genome of mouse embryonic stem cells has been edited using a CRISPR technology. The RNA and DNA oligonucleotides necessary for the creation of RNP complexes that carry out a directed homologous recombination in the Snca locus of the mouse genome have been synthesized. The developed cell clone can serve to create a line of genetically modified mice that serve as a test system for pathophysiological and neuropharmacological studies associated with synucleinopathies. Herewith, before the induction of the Cre-dependent recombination, this line is a representative model for studying a biological role of mutant Snca. At the same time, after a Cre-dependent knockout activation, it is possible to imitate the pharmacological inhibition of α-synuclein, which is of particular interest for applied research in neuropharmacology.

ON THE PSYCHOPATHOLOGICAL MAP OF NEUROFINANCE

Describing the violations detected in standard finance through factors related to the psychology of the individual brought about the emergence of fields such as behavioral and neurofinance and made it necessary for research to work on a common ground with disciplines such as psychiatry, neurology and pharmacology. The first studies in neurofinance started with the study of brain injuries and have already expanded into a neuro-psycho-pharmacological field. However, human and animal lesion studies and neuro-pharmacological studies both require highly qualified preparations and are subject to ethical limitations. The psychiatric aspect of the subject, on the other hand, has turned into an important field of study by providing an environment that is rich in lesions and because of the variety of symptomatologies of psychopathology, which facilitates these difficulties, as well as eliminates manipulation and preparation, and thus provides an environment ready for experimentation. Besides, the findings obtained from studies conducted on neurotic and psychotic cohorts include completely real behaviors rather than an attitude statement. In this study, it is aimed to compile the findings of researches in the field of finance and in the context of psychopathology and to present a description to the literature.

Pharmacological investigations of effort-based decision-making in humans: Naltrexone and nicotine.

Many mental health disorders are characterized by an impaired ability, or willingness, to exert effort to obtain rewards. This impairment is modeled in effort-based decision tasks, and neuropharmacological studies implicate dopamine in this process. However, other transmitter systems such as opioidergic and cholinergic systems have received less attention. Here, in two separate studies we tested the acute effects of naltrexone and nicotine on effort-based decision-making in healthy adults. In Study 1, we compared naltrexone (50mg and 25mg) to placebo, and in Study 2, a pilot study, we compared nicotine (7mg) to placebo. In both studies, participants completed the Effort Expenditure for Rewards Task (EEfRT), which measured effort-based decision-making related to monetary rewards. Although subjects expended greater effort for larger reward magnitude and when there was a higher probability of receiving the reward, neither naltrexone nor nicotine affected willingness to exert effort for monetary rewards. Although the drugs produced significant and typical drug effects on measures of mood and behavior, they did not alter effort-based decision-making. This has implications both for the clinical use of these drugs, as well as for understanding the neuropharmacology of effort-related behavior.

Tension-type headache and low back pain reconsidered

The natural history and clinical course of tension-type headache and non-specific low back pain are reconsidered. By closer examination, these two conditions appear to share several specific clinical features. Both are muscular pain conditions along the spine, they have a preponderance in women, they may occur spontaneously or follow a trivial traumatic incident, and they both have a high risk of chronicity. The affected muscles are tender with tender points. EMG indicates diffuse hyperactivity and abnormal activation pattern, and motor control of the affected muscles and adjacent muscle groups is discoordinated. These shared features suggest analogous pathophysiology involving the neuromotor control of affected and adjacent muscle groups in the cervical and lumbar regions, respectively. As recently suggested for the whiplash disease, we suggest the term spinal dyssynergia for this specific pattern of pathology. This suggestion provides a new perspective for the understanding of these diseases by placing their cause within the central nervous system and not in the spine or spinal musculature. This perspective warrants further clinical, neurophysiological, and neuropharmacological studies of this ‘family’ of common yet poorly understood clinical muscular pain conditions along the spine.

General neuropharmacological studies of piper betel leaves on mice

The Piper betelplant is an evergreen and perennial creeper which is used in several traditional medicines to cure various diseases. The liquid extract of the plant has been used traditionally in curing inflammationand infection of the respiratory tract, cough, dyspnoea, indigestion,diphtheria, hysteria as well as general and sexual debility. The Indian traditional system ofmedicine has identified the Piper betelleaves with digestive and pancreatic lipasestimulant activities. In the present study, 14-day subacute toxicity assays were carried out.The crude extract did not produce toxic symptoms in mice in dose up to 2000mg/kg. This was also contirmed by hematological and histopathology examination.Piper betelshowed hypotensive, cardiac, and respiratory depressant effectssmooth and skeletal muscles relaxant actions, antimicrobial, fungicidal,and nematocidal activity.Piper betel leaves extract contains large number of bioactive molecule like polyphenol, alkaloids, steroids, saponin, and tannin.Alkaloid is the main constituent which is present in the extract has been detected by the Rf. values which were found from the TLC chromatography (HPTLC) has been performed.HPTLC also has been performed.

Neuroprotective potentials of selected natural edible oils using enzyme inhibitory, kinetic and simulation approaches

BackgroundEdible oils have proven health benefits in the prevention and treatment of various disorders since the establishment of human era. This study was aimed to appraise neuropharmacological studies on the commonly used edible oils including Cinnamomum verum (CV), Zingiber officinale (ZO) and Cuminum cyminum (CC).MethodsThe oils were analyzed via GC-MS for identifications of bioactive compounds. Anti-radicals capacity of the oils were evaluated via 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radicals scavenging assays. The samples were also tested against two important acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) which are among the important drug targets in Alzheimer’s disease. Lineweaver-Burk plots were constructed for enzyme inhibition studies which correspond to velocity of enzymes (Vmax) against the reciprocal of substrate concentration (Km) in the presence of test samples and control drugs following Michaelis-Menten kinetics. Docking studies on AChE target were also carried out using Molecular Operating Environment (MOE 2016.0802) software.Results(Gas chromatography-mass spectrometry GC-MS) analysis revealed the presence of thirty-four compounds in Cinnamon oil (Cv.Eo), fourteen in ginger oil (Zo.Eo) and fifty-six in cumin oil (Cc.Eo). In the antioxidant assays, Cv.Eo, Zo.Eo and Cc.Eo exhibited IC50 values of 85, 121, 280 μg/ml sequentially against DPPH radicals. Whereas, in ABTS assay, Cv.Eo, Zo.Eo and Cc.Eo showed considerable anti-radicals potentials with IC50 values of 93, 77 and 271 μg/ml respectively. Furthermore, Cv.Eo was highly active against AChE enzyme with IC50 of 21 μg/ml. Zo.Eo and Cc.Eo exhibited considerable inhibitory activities against AChE with IC50 values of 88 and 198 μg/ml respectively. In BChE assay, Cv.Eo, Zo.Eo and Cc.Eo exhibited IC50 values of 106, 101 and 37 μg/ml respectively. Our results revealed that these oils possess considerable antioxidant and cholinesterase inhibitory potentials. As functional foods these oils can be effective remedy for the prevention and management of neurological disorders including AD. Synergistic effect of all the identified compounds was determined via binding energy values computed through docking simulations. Binding orientations showed that all the compounds interact with amino acid residues present in the peripheral anionic site (PAS) and catalytic anionic site (CAS) amino acid residues, oxyanion hole and acyl pocket via π-π stacking interactions and hydrogen bond interactions.

Blood-Brain Barrier Breakdown in Stress and Neurodegeneration: Biochemical Mechanisms and New Models for Translational Research.

Blood-brain barrier (BBB) is a structural and functional element of the neurovascular unit (NVU), which includes cells of neuronal, glial, and endothelial nature. The main functions of NVU include maintenance of the control of metabolism and chemical homeostasis in the brain tissue, ensuring adequate blood flow in active regions, regulation of neuroplasticity processes, which is realized through intercellular interactions under normal conditions, under stress, in neurodegeneration, neuroinfection, and neurodevelopmental diseases. Current versions of the BBB and NVU models, static and dynamic, have significantly expanded research capabilities, but a number of issues remain unresolved, in particular, personification of the models for a patient. In addition, application of both static and dynamic models has an important problem associated with the difficulty in reproducing pathophysiological mechanisms responsible for the damage of the structural and functional integrity of the barrier in the diseases of the central nervous system. More knowledge on the cellular and molecular mechanisms of BBB and NVU damage in pathology is required to solve this problem. This review discusses current state of the cellular and molecular mechanisms that control BBB permeability, pathobiochemical mechanisms and manifestations of BBB breakdown in stress and neurodegenerative diseases, as well as the problems and prospects of creating in vitro BBB and NVU models for translational studies in neurology and neuropharmacology. Deciphering BBB (patho)physiology will open up new opportunities for further development in the related areas of medicine such as regenerative medicine, neuropharmacology, and neurorehabilitation.

Functional brain imaging in larval zebrafish for characterising the effects of seizurogenic compounds acting via a range of pharmacological mechanisms.

Functional brain imaging using genetically encoded Ca2+ sensors in larval zebrafish is being developed for studying seizures and epilepsy as a more ethical alternative to rodent models. Despite this, few data have been generated on pharmacological mechanisms of action other than GABAA antagonism. Assessing larval responsiveness across multiple mechanisms is vital to test the translational power of this approach, as well as assessing its validity for detecting unwanted drug-induced seizures and testing antiepileptic drug efficacy. Using light-sheet imaging, we systematically analysed the responsiveness of 4days post fertilisation (dpf; which are not considered protected under European animal experiment legislation) transgenic larval zebrafish to treatment with 57 compounds spanning more than 12 drug classes with a link to seizure generation in mammals, alongside eight compounds with no such link. We show 4dpf zebrafish are responsive to a wide range of mechanisms implicated in seizure generation, with cerebellar circuitry activated regardless of the initiating pharmacology. Analysis of functional connectivity revealed compounds targeting cholinergic and monoaminergic reuptake, in particular, showed phenotypic consistency broadly mapping onto what is known about neurotransmitter-specific circuitry in the larval zebrafish brain. Many seizure-associated compounds also exhibited altered whole brain functional connectivity compared with controls. This work represents a significant step forward in understanding the translational power of 4dpf larval zebrafish for use in neuropharmacological studies and for studying the events driving transition from small-scale pharmacological activation of local circuits, to the large network-wide abnormal synchronous activity associated with seizures.

Quantitative analysis of RNAscope staining for c-fos expression in mouse brain tissue as a measure of Neuronal Activation

The expression of c-fos mRNA is an indirect marker of neuronal activity. RNAscope ACD Bio RNAscope (now Biotechne) is a proprietary in-situ mRNA detection technology using branched DNA amplification and z paired probes to deliver a robust and specific assay designed primarily for use on formalin fixed paraffin sections [1]. In the present study we adapted this technology to be used in frozen sections to allow quantitative analysis of c-fos gene expression in different mouse brain regions during neuropharmacology studies. The method was applied by Cosi et al. 2021 [2] and the image analysis is described here in details.•The patented RNAscope (ACD Bio) flourescent in-situ hybridisation technology designed primarily for use on formalin fixed paraffin sections was adapted to be used on frozen section from mouse brain.•We carefully controlled sample preparation and handling to maximise mRNA preservation and used the fluorescent properties of the fast Red substrate combined with fluorescent whole slide scanning and image analysis.•A customized algorithm was set up for image analysis•The method developed permitted the quantitative analysis of c-fos expression in specific brain regions from whole sections.

The Concept of an Epilepsy Brain Bank

Epilepsy comprises more than 40 clinical syndromes affecting millions of patients and families worldwide. To decode the molecular and pathological framework of epilepsy researchers, need reliable human epilepsy and control brain samples. Brain bank organizations collecting and supplying well-documented clinically and pathophysiologically tissue specimens are important for high-quality neurophysiology and neuropharmacology studies for epilepsy and other neurological diseases. New development in molecular mechanism and new treatment methods for neurological disorders have evoked increased demands for human brain tissue. An epilepsy brain bank is a storage source for both the frozen samples as well as the formaldehyde fixed paraffin embedded (FFPE) tissue from epilepsy surgery resections. In 2014, the University of Saskatchewan have started collecting human epilepsy brain tissues for the first time in Canada. This review highlights the necessity and importance of Epilepsy Brain bank that provides unique access for research to valuable source of brain tissue and blood samples from epilepsy patients.

Design, synthesis and neuropharmacological evaluation of new 2,4-disubstituted-1,5-benzodiazepines as CNS active agents

Benzodiazepines (BZDs) represent a class of privilege scaffold in the modern era of medicinal chemistry as CNS active agents and BZD based drugs are used to treat different psychotic disorders. Inspired from the therapeutic potential of BZDs as promising CNS active agents, in the present work three different series of 1,5-benzodiazepines bearing various substitutions at position 2 and 4 of the benzodiazepine core were synthesized by condensing different substituted chalcones with o-phenylenediamine in the presence of piperidine as a base catalyst. Structural characterization of title compounds was done by using various analytical techniques such as IR, NMR, elemental analysis and mass spectral data. All the synthesized compounds (9a-d, 10a-e and 11a-c) were subjected to in vivo neuropharmacological studies to evaluate their CNS depressant and antiepileptic activity. Results of in vivo evaluation data showed that analogue 11b exhibited potent CNS depressant activity which was comparable to the standard drug diazepam. Compounds 10b and 10c displayed significant antiepileptic activity however they were less potent than the standard drug phenobarbitone. Molecular docking studies were performed using MOE software to find the interaction pattern and binding mode at the GABAA receptor (PDB Id: 6HUP). The results of the docking studies were in good agreement with the observed in vivo activity and revealed the satisfactory binding mode of the compounds within the binding site of the protein. The docking scores for the most promising candidates 10c, 11b and Diazepam were found to be −9.18, −9.46 and −9.88, respectively. Further, the compounds showed compliance with the Lipinski’s ‘rule of five’ and exhibited favourable drug-likeness scores. The identified leads can be explored further for the design and development of new BZD based psychotropic agents.

Baclofen-induced Changes in the Resting Brain Modulate Smoking Cue Reactivity: A Double-blind Placebo-controlled Functional Magnetic Resonance Imaging Study in Cigarette Smokers.

ObjectiveSmoking cue-(SC) elicited craving can lead to relapse in SC-vulnerable individuals. Thus, identifying treatments that target SC-elicited craving is a top research priority. Reduced drug cue neural activity is associated with recovery and is marked by a profile of greater tonic (resting) activation in executive control regions, and increased connectivity between executive and salience regions. Evidence suggests the GABA-B agonist baclofen can reduce drug cue-elicited neural activity, potentially through its actions on the resting brain. Based on the literature, we hypothesize that baclofen’s effects in the resting brain can predict its effects during SC exposure.MethodsIn this longitudinal, double blind, placebo-controlled neuropharmacological study 43 non-abstinent, sated treatment-seeking cigarette smokers (63% male) participated in an fMRI resting-state scan and a SC-reactivity task prior to (T1) and 3 weeks following randomization (T2; baclofen: 80 mg/day; n = 21). Subjective craving reports were acquired before and after SC exposure to explicitly examine SC-induced craving.ResultsWhole-brain full-factorial analysis revealed a group-by-time interaction with greater resting brain activation of the right dorsolateral prefrontal cortex (dlPFC) at T2 in the baclofen group (BAC) (p FWEcorr = 0.02), which was associated with reduced neural responses to SCs in key cue-reactive brain regions; the anterior ventral insula and ventromedial prefrontal cortex (p FWEcorr < 0.01). BAC, but not the placebo group reported decreased SC-elicited craving (p = 0.02).ConclusionResults suggest that baclofen mitigates the reward response to SCs through an increase in tonic activation of the dlPFC, an executive control region. Through these mechanisms, baclofen may offer SC-vulnerable smokers protection from SC-induced relapse.

The SLC6A3 gene polymorphism is related to the development of attentional functions but not to ADHD

Neuropharmacological and human clinical studies have suggested that the brain dopaminergic system is substantively involved in normal and pathological phenotypes of attention. Dopamine transporter gene (SLC6A3) was proposed as a candidate gene for Attention-Deficit/Hyperactivity Disorder (ADHD). We investigated the effect of the SLC6A3 variants on cognitive performance in ADHD and healthy children and teenagers. Participants completed cognitive tasks measuring attentional switching, selective and sustained attention, and effectiveness of alerting, orienting and executive attention. We estimated the effects of 40 bp variable number of tandem repeat (VNTR) polymorphism located in the 3′ untranslated region (3′ UTR) (9-repeat vs 10-repeat allele) of the SLC6A3 gene, ADHD diagnosis, age, and their interactions as predictors of cognitive performance. ADHD children demonstrated deficits in most of the examined attention processes, persistent within the examined age range (9–16 years). No significant effects were observed for the interaction of ADHD and the SLC6A3 polymorphism, but the results revealed a significant main effect of SLC6A3 genotype in the entire research sample. Subjects carrying 9R allele performed the switching task significantly worse in comparison to children with 10R/10R or 10R/11R genotype. SLC6A3 polymorphism moderated age-related improvements in orienting and attentional switching. Results suggest that SLC6A3 genotype influence these attentional/cognitive functions which deficits are not the key symptoms in ADHD.