Common Brain Disorder Research Articles

Designing of Hybrid form of Benzothiazole-quinazoline as GABA-A Inhibitor with Anticonvulsant Profile: An <i>i</i><i>n-silico</i> Approach

Epilepsy is a common but serious brain disorder. It is universal, with no age, sex, geographical, social class or racial boundaries. One of the most important mechanisms for handling it is the inhibition of the GABA-A receptor. In same context while studying the treatment of epilepsy we found the significant effects of the derivatives of the benzothiazole and quinazolines, this promotes us to develop a hybrid form of these two moieties by the means of <i>in-silico</i> resources with antiepileptic/anticonvulsant effects. Molecular docking approaches are routinely used in modern drug design to help understand drug–receptor interaction. This study has been performed with the help of Chemdraw Ultra 7.0, AutoDock Vina (Python Prescription 0.8), and PaDEL software. Results revealed that ligand-protein interaction affinity of all designed 10 hybrid molecules ranges from -6.8 Kcal/mol to -6.2 Kcal/mol which is approximately double as compared to pre-existing GABA-A inhibitor i.e. γ-aminobutyric acid (CID: 119, ligand-protein interaction affinity is -3.2 Kcal/mol).

Therapeutic prospects for migraine: can paradise be regained?

Migraine is a common, complex brain disorder whose biology is becoming better understood. Despite being the most disabling of the neurological disorders on a worldwide basis, headache disorders broadly, and migraine in particular, have poor research funding and a limited academic base. Given a modicum of investment, new targets, such as calcitonin gene-related peptide-based mechanisms, and entirely novel neuromodulation approaches illustrate that much can be done to improve patient care. Genetics and neuroimaging combined with excellent clinical phenotyping and translational neuroscience approaches are set to transform life for a cohort of patients with these common brain disorders.

Genome-wide meta-analysis identifies new susceptibility loci for migraine.

Migraine is the most common brain disorder, affecting approximately 14% of the adult population, but its molecular mechanisms are poorly understood. We report the results of a meta-analysis across 29 genome-wide association studies, including a total of 23,285 individuals with migraine (cases) and 95,425 population-matched controls. We identified 12 loci associated with migraine susceptibility (P<5×10(-8)). Five loci are new: near AJAP1 at 1p36, near TSPAN2 at 1p13, within FHL5 at 6q16, within C7orf10 at 7p14 and near MMP16 at 8q21. Three of these loci were identified in disease subgroup analyses. Brain tissue expression quantitative trait locus analysis suggests potential functional candidate genes at four loci: APOA1BP, TBC1D7, FUT9, STAT6 and ATP5B.

Epigenetic mechanisms in migraine: a promising avenue?

Migraine is a disabling common brain disorder typically characterized by attacks of severe headache and associated with autonomic and neurological symptoms. Its etiology is far from resolved. This review will focus on evidence that epigenetic mechanisms play an important role in disease etiology. Epigenetics comprise both DNA methylation and post-translational modifications of the tails of histone proteins, affecting chromatin structure and gene expression. Besides playing a role in establishing cellular and developmental stage-specific regulation of gene expression, epigenetic processes are also important for programming lasting cellular responses to environmental signals. Epigenetic mechanisms may explain how non-genetic endogenous and exogenous factors such as female sex hormones, stress hormones and inflammation trigger may modulate attack frequency. Developing drugs that specifically target epigenetic mechanisms may open up exciting new avenues for the prophylactic treatment of migraine.

Monocyte chemoattractant protein-1 affects migration of hippocampal neural progenitors following status epilepticus in rats

BackgroundEpilepsy is a common brain disorder characterized by a chronic predisposition to generate spontaneous seizures. The mechanisms for epilepsy formation remain unknown. A growing body of evidence suggests the involvement of inflammatory processes in epileptogenesis. In the present study, we investigated the involvement of monocyte chemoattractant protein-1 (MCP-1) in aberrant migration of hippocampal progenitors in rats after the insult of status epilepticus (SE).MethodsSE was induced with pilocarpine in Sprague–Dawley rats. Transcriptional expression of MCP-1 in the dentate gyrus (DG) was measured using quantitative real-time PCR. From 1 to 28 days after SE, the temporal profiles of MCP-1 protein expression in DG were evaluated using enzyme-linked immunosorbent assay. Chemokine (C-C motif) receptor 2 (CCR2) expression in doublecortin-positive neuronal progenitors was examined using double-labeling immunohistochemistry. The involvement of MCP-1/CCR2 signaling in aberrant neuronal progenitor migration in the epileptic hippocampus was assessed in the SE rats using a CCR2 antagonist, RS102895, and the ectopic migration of neuronal progenitors was determined using Prox1/doublecortin double immunostaining.ResultsAfter SE, MCP-1 gene was significantly upregulated and its corresponding protein expression in the DG was significantly increased on days 1 and 3. Some hilar ectopic progenitor cells of SE rats expressed the MCP-1 receptor, CCR2. Notably, the ectopic migration of neuronal progenitors into hilus was attenuated by a blockade of the MCP-1/CCR2 interaction with a selective CCR2 inhibitor, RS102895.ConclusionsAn increase in dentate MCP-1 is associated with seizure-induced aberrant migration of neuronal progenitors through the interaction with CCR2. The upregulation of MCP-1 after an insult of SE may play a role in the generation of epilepsy.

Fast monitoring of epileptic seizures using recurrence time statistics of electroencephalography

Epilepsy is a relatively common brain disorder which may be very debilitating. Currently, determination of epileptic seizures often involves tedious, time-consuming visual inspection of electroencephalography (EEG) data by medical experts. To better monitor seizures and make medications more effective, we propose a recurrence time based approach to characterize brain electrical activity. Recurrence times have a number of distinguished properties that make it very effective for forewarning epileptic seizures as well as studying propagation of seizures: (1) recurrence times amount to periods of periodic signals, (2) recurrence times are closely related to information dimension, Lyapunov exponent, and Kolmogorov entropy of chaotic signals, (3) recurrence times embody Shannon and Renyi entropies of random fields, and (4) recurrence times can readily detect bifurcation-like transitions in dynamical systems. In particular, property (4) dictates that unlike many other non-linear methods, recurrence time method does not require the EEG data be chaotic and/or stationary. Moreover, the method only contains a few parameters that are largely signal-independent, and hence, is very easy to use. The method is also very fast—it is fast enough to on-line process multi-channel EEG data with a typical PC. Therefore, it has the potential to be an excellent candidate for real-time monitoring of epileptic seizures in a clinical setting.

Loop Modeling Forward and Feedback Analysis in Cerebral Arteriovenous Malformation

Cerebral Arteriovenous Malformation (CA VM) hemodynamic in disease condition results changes in the flow and pressure level in blood vessels. Cerebral Arteriovenous Malformation (CA VM) is an abnormal shunting of vessels between arteries and veins. It is one of the common Brain disorder. In general, the blood flows of cerebral region are from arteries to veins through capillary bed. This paper is focus on the creation of a new electrical model for spiral loop structures that will simulate the pressure at various locations of the CA VM Complex blood vessels. The proposed model helps Doctors to take diagnostic and treatment planning for treatment by non-invasive measurement.. This can cause rupture or decreased blood supply to the tissue through capillary causing infarct. Measuring flow and pressure without intervention along the vessel is big challenge due to loop structures of feedback and forward flows in Arteriovenous Malformation patients. In this paper, we proposed a lumped model for the spiral loop in CAVM Structures that will help doctors to find the pressure and velocity measurements non-invasively,

Association study of the calcitonin gene-related polypeptide-alpha (CALCA) and the receptor activity modifying 1 (RAMP1) genes with migraine

Migraine is a common neurovascular brain disorder characterised by recurrent attacks of severe headache that may be accompanied by various neurological symptoms. Migraine is thought to result from activation of the trigeminovascular system followed by vasodilation of pain-producing intracranial blood vessels and activation of second-order sensory neurons in the trigeminal nucleus caudalis. Calcitonin gene-related peptide (CGRP) is a mediator of neurogenic inflammation and the most powerful vasodilating neuropeptide, and has been implicated in migraine pathophysiology. Consequently, genes involved in CGRP synthesis or CGRP receptor genes may play a role in migraine and/or increase susceptibility. This study investigates whether variants in the gene that encodes CGRP, calcitonin-related polypeptide alpha (CALCA) or in the gene that encodes a component of its receptor, receptor activity modifying protein 1 (RAMP1), are associated with migraine pathogenesis and susceptibility. The single nucleotide polymorphisms (SNPs) rs3781719 and rs145837941 in the CALCA gene, and rs3754701 and rs7590387 at the RAMP1 locus, were analysed in an Australian Caucasian population of migraineurs and matched controls. Although we find no significant association of any of the SNPs tested with migraine overall, we detected a nominally significant association (p=0.031) of the RAMP1 rs3754701 variant in male migraine subjects, although this is non-significant after Bonferroni correction for multiple testing.

Genetic Variation in Ataxia Gene ATXN7 Influences Cerebellar Grey Matter Volume in Healthy Adults

An increasing number of candidate genes for common and rare brain disorders are discovered, but the mechanism of action through which these genes cause disease is often still unclear. Some of the genetic factors known to increase the risk for common brain disorders affect brain structure, even in healthy individuals, and therefore possibly have a role in the normal development of specific brain regions. In this study, we explored this principle for a group of rare brain disorders, the spinocerebellar ataxias (SCAs). As a proof of concept, we investigated whether genetic variation in a gene known to cause a polyglutamine-expansion SCA is associated with cerebellar volume in healthy adults. The functional single nucleotide polymorphism (SNP) rs3774729 located in ATXN7 was selected as the variant of interest. Cerebellar grey matter volume was determined using volumetry on magnetic resonance imaging data in a discovery sample scanned at 1.5T (n = 680) and a replication sample scanned at 3T (n = 683), both consisting of healthy adults aged 18 to 35years. The volumes were compared as a function of the presence of the minor allele of SNP rs3774729, which was associated with significantly smaller cerebellar grey matter volume in both the discovery and replication sample (p = 0.033 and p = 0.024, respectively). Our results demonstrate that a common genetic variant in the ataxia-causing gene ATXN7 influences cerebellar grey matter volume in healthy young adults. This finding may also imply that genes associated with cerebellar volume in healthy subjects are valid candidates for causing or modifying ataxia.

Predictive Biomarkers for Alzheimer's Disease Using State-of-the-Art Brain Imaging Techniques

Human life expectancy is increasing steadily as a result of the significant advances made in scientific and medical research, as well as technological and economic development. With the resulting substantial increase in the aging population, there has been a concurrent increase in age-related brain disorders. Of these, Alzheimer’s disease (AD) is one of the most common brain disorders, with an estimated thirty-five million people affected worldwide. AD has become a silent tsunami in the aging population and the resulting economic burden on the healthcare system runs into billions of dollars. The last decade has seen milestone developments in AD research that have been pivotal in furthering our understanding of the disease’s pathobiological-mechanism. However, AD diagnosis continues to primarily rely on various neuropsychological tests, which can detect the disease only after the manifestation of clinical symptoms [1]. There is an urgent need for the development of reliable diagnostic biomarkers that can detect AD pathology at an incipient stage. Such biomarkers will not only aid in the early detection of AD, but will also pave the way to effective clinical trials. The biomarkers presently used for AD are either genetic, such as apolipoprotein E4; cerebrospinal fluid-derived, such as amyloidand tau; or brain pathology-linked

Rainfall drives hydrocephalus in East Africa

Hydrocephalus is one of the most common brain disorders in children throughout the world. The majority of infant hydrocephalus cases in East Africa appear to be postinfectious, related to preceding neonatal infections, and are thus preventable if the microbial origins and routes of infection can be characterized. In prior microbiological work, the authors noted evidence of seasonality in postinfectious hydrocephalus (PIH) cases. The geographical address of 696 consecutive children with PIH who were treated over 6 years was fused with satellite rainfall data for the same time period. A comprehensive time series and spatiotemporal analysis of cases and rainfall was performed. Four infection-onset peaks were found to straddle the twice-yearly rainy season peaks, demonstrating that the infections occurred at intermediate levels of rainfall. The findings in this study reveal a previously unknown link between climate and a neurosurgical condition. Satellite-derived rainfall dynamics are an important factor in driving the infections that lead to PIH. Given prior microbial analysis, these findings point to the importance of environmental factors with respect to preventing the newborn infections that lead to PIH.

Epilepsy as a Disorder of Cortical Network Organization

The brain is naturally considered as a network of interacting elements which, when functioning properly, produces an enormous range of dynamic, adaptable behavior. However, when elements of this network fail, pathological changes ensue, including epilepsy, one of the most common brain disorders. This review examines some aspects of cortical network organization that distinguish epileptic cortex from normal brain as well as the dynamics of network activity before and during seizures, focusing primarily on focal seizures. The review is organized around four phases of the seizure: the interictal period, onset, propagation, and termination. For each phase, the authors discuss the most common rhythmic characteristics of macroscopic brain voltage activity and outline the observed functional network features. Although the characteristics of functional networks that support the epileptic seizure remain an area of active research, the prevailing trends point to a complex set of network dynamics between, before, and during seizures.

Medicinal Plants Used to Treat Neurological Disorders in West Africa: A Case Study with Guinea-Bissau Flora

The sub-Saharan region holds a wide variety of indigenous plant species, still offering the possibility to discover very interesting new natural products with potential therapeutic value. Most of the African population depends on traditional medicine for primary health care, however, neurological disorders are often not considered as common diseases and many people with mental illnesses, like epilepsy, are severely affected by health-related stigma and discrimination. Epilepsy is the most common serious chronic brain disorder, estimated to affect at least 10 million people in Africa. Guinea-Bissau is located in West Africa, and its population is mainly rural with very few health services available. Since the earliest times, Guinea-Bissau flora has constituted the main source of materials used in folk medicine and the local population, who is well versed in the uses of these plants and their properties. The aim of this study was to document the existing knowledge and practices related to the treatment of neurological disorders, namely epilepsy and seizures, in Guinea-Bissau and in other West African countries. The results presented from this study provide information not only on the specific plants used to treat neurological disorders, but also on social knowledge brought in by various ethnic groups, each one having its own culture, beliefs and ways of nature appropriation. Taking into account the existing knowledge on the medicinal properties of plants for treatment of neurologic disorders, it is believed that research in the areas of ethnomedicine and ethnopharmacology in Guinea-Bissau can bring promising results capable of adding value to the very rich natural resources of this country of West Africa.

Unequal gains of function are a headache for migraine mechanisms

Unequal gains of function are a headache for migraine mechanisms

Genetics of GABAergic signaling in nicotine and alcohol dependence.

Both nicotine and alcohol addictions are common chronic brain disorders that are of great concern to individuals and society. Although genetics contributes significantly to these disorders, the susceptibility genes and variants underlying them remain largely unknown. Many years of genome-wide linkage and association studies have implicated a number of genes and pathways in the etiology of nicotine and alcohol addictions. In this communication, we focus on current evidence, primarily from human genetic studies, supporting the involvement of genes and variants in the GABAergic signaling system in the etiology of nicotine dependence and alcoholism based on linkage, association, and gene-by-gene interaction studies. Current efforts aim not only to replicate these findings in independent samples, but also to identify which variant contributes to the detected associations and through what molecular mechanisms.

Ventral midbrain correlation between genetic variation and expression of the dopamine transporter gene in cocaine-abusing versus non-abusing subjects

Altered activity of the human dopamine transporter gene (hDAT) is associated with several common and severe brain disorders, including cocaine abuse. However, there is little a priori information on whether such alterations are due to nature (genetic variation) or nurture (human behaviors such as cocaine abuse). This study investigated the correlation between seven markers throughout hDAT and its mRNA levels in postmortem ventral midbrain tissues from 18 cocaine abusers and 18 strictly matched drug-free controls in the African-American population. Here, we show that one major haplotype with the same frequency in cocaine abusers versus drug-free controls displays a 37.1% reduction of expression levels in cocaine abusers compared with matched controls (P=0.0057). The most studied genetic marker, variable number tandem repeats (VNTR) located in Exon 15 (3'VNTR), is not correlated with hDAT mRNA levels. A 5' upstream VNTR (rs70957367) has repeat numbers that are positively correlated with expression levels in controls (r(2)=0.9536, P=0.0235), but this positive correlation disappears in cocaine abusers. The findings suggest that varying hDAT activity is attributable to both genetics and cocaine abuse.

Diencephalic and brainstem mechanisms in migraine

Migraine is a common and complex brain disorder. Although it is clear that head pain is a key manifestation of the disorder for most patients, what drives the activation of neuronal pain pathways in susceptible patients is less obvious. There is growing evidence that migraine pathophysiology may, in part, include dysfunction of subcortical structures. These include diencephalic and brainstem nuclei that can modulate the perception of activation of the trigeminovascular system, which carries sensory information from the cranial vasculature to the brain. Dysfunction of these nuclei, and their connections to other key brain centres, may contribute to the cascade of events that results in other symptoms of migraine - such as light and sound sensitivity - thus providing a comprehensive explanation of the neurobiology of the disorder.

Using mouse models to investigate sex-linked genetic effects on brain, behaviour and vulnerability to neuropsychiatric disorders

Many brain and behavioural phenotypes in humans exhibit some degree of sexual dimorphism. Moreover, there are large and replicable differences in the vulnerability of the two sexes to a wide range of common brain disorders. Ultimately, sex differences in healthy individuals, or in pathological states, must arise as a consequence of the differential complement of sex-linked genes in males and females. These genes may act indirectly (for example through influencing gonadal hormone secretion), or directly, to influence brain development and function. In this review, I discuss how genetically tractable mouse models may be employed to inform our knowledge of the molecular basis of sexual differentiation of the mammalian brain, and how such models may therefore represent a useful tool through which to identify risk factors predisposing to sex-biased neuropsychiatric disorders.

The utility of omega-3 fatty acids in epilepsy: more than just a farmed tilapia!

The epilepsies are one of the most common serious brain disorders and 20 to 30% of people developing epilepsy continue to have seizures and are refractory to treatment with the currently available therapies. Approximately one in a 1000 patients with chronic epilepsy will die suddenly, unexpectedly, and without explanation, even with post-mortem examination and this phenomenon is called sudden unexplained death in epilepsy (SUDEP). Understanding the mechanisms underlying SUDEP may lead to the identification of previously unrecognized risk factors that are more amenable to correction. We discuss here the possible implications of omega-3 fatty acids consumption on SUDEP prevention.

Application of NMR Spectroscopy in Medicinal Chemistry and Drug Discovery

We describe the details of the magnetic resonance spectroscopy and chemical shift imaging techniques for the human brain which have been developed over the last two decades. With these non-invasive tools, it is now readily possible to repeatedly assay up to 20 common brain metabolites. From the perspective of drug discovery, each of these metabolites could fulfill a number of useful functions: disease biomarker, surrogate marker of drug delivery, surrogate marker of drug efficacy and so on. To facilitate the possible utility of clinical magnetic resonance spectroscopy in future drug discovery, the major portion of the review is devoted to a detailed description of the well-validated neurochemical profiles of many common human brain disorders, for which MRS data now exists. Beyond proton, MRS, the commonest tool provided by the manufacturers of clinical MRI equipment, lays the world of heteronuclear NMR more familiar to chemists. Here too, with relatively little effort it has been possible to define neurochemical profiles of human brain disorders using (13)C MRS in particular. The future for drug discovery scientists is discussed. Finally, recognizing that a known feature of MR is the lack of sensitivity, we describe new efforts to harness hyperpolarization, with its 50,000 signal amplification, to conventional MRS.