Major Central Nervous System Disorders Research Articles

The Development of a Regulator of Human Serine Racemase for N-Methyl-D-aspartate Function.

It is crucial to regulate N-methyl-D-aspartate (NMDA) function bivalently depending on the central nervous system (CNS) conditions. CNS disorders with NMDA hyperfunction are involved in the pathogenesis of neurotoxic and/or neurodegenerative disorders with elevated D-serine, one of the NMDA receptor co-agonists. On the contrary, NMDA-enhancing agents have been demonstrated to improve psychotic symptoms and cognition in CNS disorders with NMDA hypofunction. Serine racemase (SR), the enzyme regulating both D- and L-serine levels through both racemization (catalysis from L-serine to D-serine) and β-elimination (degradation of both D- and L-serine), emerges as a promising target for bidirectional regulation of NMDA function. In this study, we explored using dimethyl malonate (DMM), a pro-drug of the SR inhibitor malonate, to modulate NMDA activity in C57BL/6J male mice via intravenous administration. Unexpectedly, 400 mg/kg DMM significantly elevated, rather than decreased (as a racemization inhibitor), D-serine levels in the cerebral cortex and plasma. This outcome prompted us to investigate the regulatory effects of dodecagalloyl-α-D-xylose (α12G), a synthesized tannic acid analog, on SR activity. Our findings showed that α12G enhanced the racemization activity of human SR by about 8-fold. The simulated and fluorescent assay of binding affinity suggested a noncooperative binding close to the catalytic residues, Lys56 and Ser84. Moreover, α12G treatment can improve behaviors associated with major CNS disorders with NMDA hypofunction including hyperactivity, prepulse inhibition deficit, and memory impairment in animal models of positive symptoms and cognitive impairment of psychosis. In sum, our findings suggested α12G is a potential therapeutic for treating CNS disorders with NMDA hypofunction.

Functional and molecular insights of hydrogen sulfide in the major central nervous system disorders

Functional and molecular insights of hydrogen sulfide in the major central nervous system disorders

Screening of anticonvulsant effect of carvedilol on electrically induced convulsions in Wistar albino rats

Background: Epilepsy is one of the major central nervous system disorders. The parent study aimed to screen the anticonvulsant effect of carvedilol on electrically induced convulsions in Wistar albino rats.Methods: This study was done in Wistar albino rats. A total of 30 rats were divided into 6 groups each of six rats. group-I (0.9% normal saline), group-II diphenylhydantoin (10 mg/kg/BW/ip), group-III carvedilol (1mg/kg/BW/PO), group-IV carvedilol (2 mg/kg/BW/PO) and group-V carvedilol (4 mg/kg/BW/PO). All the groups were administered drugs and subjected to electric shock. Scores of seizures and percentage of protection were recorded to compare between the groups. One was ANOVA (post hoc) followed by Dunnet t test applied to find the statistically significant between the groups.Results: Group-I showed significant difference compared to other groups. Group-II showed significant difference with group-III and IV not with V. High dose of test drug and standard drug showed similar results in percentage of seizures prevention. Control and low doses of test drugs showed significant difference compared to standard and high dose of test drug in seizures prevention.Conclusions: High of carvedilol showed significant seizures prevention compared to low doses and control group.

Therapeutic Effect of Agmatine on Neurological Disease: Focus on Ion Channels and Receptors.

The central nervous system (CNS) is the most injury-prone part of the mammalian body. Any acute or chronic, central or peripheral neurological disorder is related to abnormal biochemical and electrical signals in the brain cells. As a result, ion channels and receptors that are abundant in the nervous system and control the electrical and biochemical environment of the CNS play a vital role in neurological disease. The N-methyl-D-aspartate receptor, 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid receptor, kainate receptor, acetylcholine receptor, serotonin receptor, α2-adrenoreceptor, and acid-sensing ion channels are among the major channels and receptors known to be key components of pathophysiological events in the CNS. The primary amine agmatine, a neuromodulator synthesized in the brain by decarboxylation of L-arginine, can regulate ion channel cascades and receptors that are related to the major CNS disorders. In our previous studies, we established that agmatine was related to the regulation of cell differentiation, nitric oxide synthesis, and murine brain endothelial cell migration, relief of chronic pain, cerebral edema, and apoptotic cell death in experimental CNS disorders. In this review, we will focus on the pathophysiological aspects of the neurological disorders regulated by these ion channels and receptors, and their interaction with agmatine in CNS injury.

PET/SPECT molecular imaging in clinical neuroscience: recent advances in the investigation of CNS diseases.

Molecular imaging is an attractive technology widely used in clinical practice that greatly enhances our understanding of the pathophysiology and treatment in central nervous system (CNS) diseases. It is a novel multidisciplinary technique that can be defined as real-time visualization, in vivo characterization and qualification of biological processes at the molecular and cellular level. It involves the imaging modalities and the corresponding imaging agents. Nowadays, molecular imaging in neuroscience has provided tremendous insights into disturbed human brain function. Among all of the molecular imaging modalities, positron emission tomography (PET) and single photon emission computed tomography (SPECT) have occupied a particular position that visualize and measure the physiological processes using high-affinity and high-specificity molecular radioactive tracers as imaging probes in intact living brain. In this review, we will put emphasis on the PET/SPECT applications in Alzheimer's disease (AD) and Parkinson's disease (PD) as major CNS disorders. We will first give an overview of the main classical molecular neuroimaging modalities. Then, the major clinical applications of PET and SPECT along with molecular probes in the fields of psychiatry and neurology will be discussed.

The CNS under pathophysiologic attack--examining the role of K₂p channels.

Members of the two-pore domain K(+) channel (K2P) family are increasingly recognized as being potential targets for therapeutic drugs and could play a role in the diagnosis and treatment of neurologic disorders. Their broad and diverse expression pattern in pleiotropic cell types, importance in cellular function, unique biophysical properties, and sensitivity toward pathophysiologic parameters represent the basis for their involvement in disorders of the central nervous system (CNS). This review will focus on multiple sclerosis (MS) and stroke, as there is growing evidence for the involvement of K2P channels in these two major CNS disorders. In MS, TASK1-3 channels are expressed on T lymphocytes and are part of a signaling network regulating Ca(2+)-dependent pathways that are mandatory for T cell activation, differentiation, and effector functions. In addition, TASK1 channels are involved in neurodegeneration, resulting in autoimmune attack of CNS cells. On the blood-brain barrier, TREK1 channels regulate immune cell trafficking under autoinflammatory conditions. Cerebral ischemia shares some pathophysiologic similarities with MS, including hypoxia and extracellular acidosis. On a cellular level, K2P channels can have both proapoptotic and antiapoptotic effects, either promoting neurodegeneration or protecting neurons from ischemic cell death. TASK1 and TREK1 channels have a neuroprotective effect on stroke development, whereas TASK2 channels have a detrimental effect on neuronal survival under ischemic conditions. Future research in preclinical models is needed to provide a more detailed understanding of the contribution of K2P channel family members to neurologic disorders, before translation to the clinic is an option.

GABAA receptors and plasticity of inhibitory neurotransmission in the central nervous system

GABAA receptors (GABAA Rs) are ligand-gated Cl(-) channels that mediate most of the fast inhibitory neurotransmission in the central nervous system (CNS). Multiple GABAA R subtypes are assembled from a family of 19 subunit genes, raising the question of the significance of this heterogeneity. In this review, we discuss the evidence that GABAA R subtypes represent distinct receptor populations with a specific spatio-temporal expression pattern in the developing and adult CNS, being endowed with unique functional and pharmacological properties, as well as being differentially regulated at the transcriptional, post-transcriptional and translational levels. GABAA R subtypes are targeted to specific subcellular domains to mediate either synaptic or extrasynaptic transmission, and their action is dynamically regulated by a vast array of molecular mechanisms to adjust the strength of inhibition to the changing needs of neuronal networks. These adaptations involve not only changing the gating or kinetic properties of GABAA Rs, but also modifying the postsynaptic scaffold organised by gephyrin to anchor specific receptor subtypes at postsynaptic sites. The significance of GABAA R heterogeneity is particularly evident during CNS development and adult neurogenesis, with different receptor subtypes fulfilling distinct steps of neuronal differentiation and maturation. Finally, analysis of the specific roles of GABAA R subtypes reveals their involvement in the pathophysiology of major CNS disorders, and opens novel perspectives for therapeutic intervention. In conclusion, GABAA R subtypes represent the substrate of a multifaceted inhibitory neurotransmission system that is dynamically regulated and performs multiple operations, contributing globally to the proper development, function and plasticity of the CNS.

Molecular Imaging in Clinical Investigation of Central Nervous System Diseases

Molecular imaging is an emerging technology used both in basic neurosciences and clinical practice that greatly enhances our understanding of the pathophysiology and treatmentin central nervous system (CNS) diseases. It is a novel multidisciplinary technique that can be defined as real-time visualization, in vivo characterization and qualification of biological processes at the molecular and cellular level. It involves both the imaging modalities and the corresponding imaging agents. Among all of the molecular imaging modalities, positron emission tomography (PET) and single photon emission computed tomography (SPECT) have occupieda particular position that visualize and measure the physiological processes using high-affinity and highspecificity molecular radioactive tracers as imaging probes in intact living brain. Nowadays, amount of excellent and comprehensive literatures indicated that molecular imaging in neuroscience have provided tremendous insights into disturbed human brain function, particularly on its clinical application in Alzheimer's disease (AD) andParkinson’s disease (PD) as major CNS disorders.

Nanoparticles and blood-brain barrier: the key to central nervous system diseases.

Major central nervous system disorders represent a significant and worldwide public health problem. In fact, the therapeutic success of many pharmaceuticals developed to treat central nervous system diseases is still moderate, since the blood-brain barrier (BBB) limits the access of systemically administered compounds to the brain. Therefore, they require the application of a large total dose of a drug, and cause numerous toxic effects. The development of nanotechnological systems are useful tools to deliver therapeutics and/or diagnostic probes to the brain due to nanocarriers having the potential to improve the therapeutic effect of drugs and to reduce their side effects. This review provides a brief overview of the variety of carriers employed for central nervous system drug and diagnostic probes delivery. Further, this paper focuses on the novel nanocarriers developed to enhance brain delivery across the blood-brain barrier. Special attention is paid to liposomes, micelles, polymeric and lipid-based nanoparticles, dendrimers and carbon nanotubes. The recent developments in nanocarrier implementation through size/charge optimization and surface modifications (PEGylation, targeting delivery, and coating with surfactants) have been discussed. And a detailed description of the nanoscaled pharmaceutical delivery devices employed for the treatment of central nervous system disorders have also been defined. The aim of the review is to evaluate the nanotechnology-based drug delivery strategies to treat different central nervous system disorders.

Molecular imaging as a guide for the treatment of central nervous system disorders

Molecular imaging techniques have a number of advantages for research into the pathophysiology and treatment of central nervous system (CNS) disorders. Firstly, they provide a noninvasive means of characterizing physiological processes in the living brain, enabling molecular alterations to be linked to clinical changes. Secondly, the pathophysiological target in a given CNS disorder can be measured in animal models and in experimental human models in the same way, which enables translational research. Moreover, as molecular imaging facilitates the detection of functional change which precedes gross pathology, it is particularly useful for the early diagnosis and treatment of CNS disorders. This review considers the application of molecular imaging to CNS disorders focusing on its potential to inform the development and evaluation of treatments. We focus on schizophrenia, Parkinson's disease, depression, and dementia as major CNS disorders. We also review the potential of molecular imaging to guide new drug development for CNS disorders.

The development of radiotracers for imaging sigma (σ) receptors in the central nervous system (CNS) using positron emission tomography (PET)

Sigma (σ) receptors are unique mammalian proteins, distributed in the central nervous system and elsewhere, which are increasingly implicated in the pathophysiology of virtually all major central nervous system disorders. The heterogeneous but wide distribution of σ1 in the brain has prompted the development of selective radiotracers for imaging these sites using positron emission tomography (PET). To date, some 50 carbon-11-labelled and fluorine-18-labelled candidate PET radioligands targeting σ receptors have been reported. The historical development of selective σ1 receptor ligands as potential PET imaging agents, as well as the radiochemistry and application of the most recently developed examples, is described herein.

Update in neuroimaging.

Neuroimaging has emerged as an invaluable tool in the study of central nervous system (CNS) structure and function, shedding light on both structural and functional changes. A wide array of neuroimaging techniques, such as computerized tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET), have been part of an unprecedented technological revolution, empowering our ability to diagnose and monitor neurologic conditions. Neuroimaging has a particularly important role in the field of neurotherapeutics for several reasons. The first is its ability to provide early and accurate diagnosis of neurologic disorders so that the appropriate therapy can be started. The second is its ability to monitor the evolution of chronic neurologic disorders so that patients experiencing breakthrough disease, who might require a change in therapy, may be identified. The third is its ability to probe structural and functional changes in both animal and human subjects, resulting in a better understanding of disease mechanisms and the identification of potential new therapeutic targets. We aim to present the current state and future prospects of neuroimaging techniques in evaluating neurological disorders with an emphasis on their impact on the field of neurotherapeutics. We have included 11 review articles in this volume written by the world's leading authorities. To set the stage, the volume begins with a review of imaging of small animal models of CNS diseases, which is at the forefront in the translation of neuroimaging techniques from basic research to human studies. The subsequent reviews focus on human neuroimaging in major CNS disorders, including stroke, hemorrhage, trauma, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson’s disease, dementia, psychiatric disorders, and infections. Each article presents an overview of the role of the most relevant imaging modalities (e.g., CT, MRI, PET, angiography/interventional, and/or neurosonology). The reviews provide a critical analysis of the role of these techniques in clinical diagnosis, longitudinal monitoring, and neurotherapeutic evaluation/development. We conclude with a review of an emerging neuroimaging technique-optical coherence tomography, which has generated significant interest due to its ability to readily quantify damage to the retinal nerve fiber layer and, in turn, provide a surrogate of neurodegeneration, neuroprotection, and repair. We would like to express our gratitude to the authors for the generous contribution of their time and expertise to this volume. Despite our wish to make this edition comprehensive, because of space limitations and publication deadlines, we have not adequately covered a number of neuroimaging-related topics, such as normal aging, epilepsy, neuro-oncology, and spinal cord disorders. Nonetheless, we hope that this volume will prove useful to the trainees, practitioners, and investigators in the clinical and imaging fields of the neurosciences and pique their interest in future studies that may expand and refine the applications of these exciting technologies.

Comparative gene expression analysis in mouse models for multiple sclerosis, Alzheimer's disease and stroke for identifying commonly regulated and disease-specific gene changes

The brain responds to injury and infection by activating innate defense and tissue repair mechanisms. Working upon the hypothesis that the brain defense response involves common genes and pathways across diverse pathologies, we analysed global gene expression in brain from mouse models representing three major central nervous system disorders, cerebral stroke, multiple sclerosis and Alzheimer's disease compared to normal brain using DNA microarray expression profiling. A comparison of dysregulated genes across disease models revealed common genes and pathways including key components of estrogen and TGF-β signaling pathways that have been associated with neuroprotection as well as a neurodegeneration mediator, TRPM7. Further, for each disease model, we discovered collections of differentially expressed genes that provide novel insight into the individual pathology and its associated mechanisms. Our data provide a resource for exploring the complex molecular mechanisms that underlie brain neurodegeneration and a new approach for identifying generic and disease-specific targets for therapy.

Exertional heat illness and hyponatremia in hikers

We compared clinical presentation and course of exercise-associated hyponatremia with heat exhaustion among summertime hikers in Grand Canyon National Park. Cases were selected from among hikers who requested medical help from the National Park Service Emergency Medical Service (EMS) or who presented to the medical clinic on the rim of the canyon with complaints related to exercise in the heat. Of 44 patients who had serum samples analyzed, 7 had hyponatremia with clinically significant symptoms and serum sodium levels <130 mmol/L: 3 had grand mal seizures, 2 had other major central nervous system disorders, and 2 had minor neurological symptoms. Seizures and change of mental status distinguished hyponatremia, ( P = 0.0002). Indirect evidence suggests that hyponatremic patients were hyperhydrated. Other common symptoms included nausea, vomiting, headache, and dizziness, but these symptoms did not predict the level of serum sodium. When exercise in the heat is prolonged, hyponatremia is suggested either by altered mental status or by seizures without hyperpyrexia or hypoglycemia. No mortality or long-term morbidity occurred in any of these cases of hyponatremia.

Further studies on free-radical pathology in the major central nervous system disorders: effect of very high doses of methylprednisolone on the functional outcome, morphology, and chemistry of experimental spinal cord impact injury.

The hypothesis that pathologic free-radical reactions are initiated and catalyzed in the major central nervous system (CNS) disorders has been further supported by the current acute spinal cord injury work that has demonstrated the appearance of specific, cholesterol free-radical oxidation products. The significance of these products is suggested by the fact that: (i) they increase with time after injury; (ii) their production is curtailed with a steroidal antioxidant; (iii) high antioxidant doses of the steroidal antioxidant which curtail the development of free-radical product prevent tissue degeneration and permit functional restoration. The role of pathologic free-radical reactions is also inferred from the loss of ascorbic acid, a principal CNS antioxidant, and of extractable cholesterol. These losses are also prevented by the steroidal antioxidant. This model system is among others in the CNS which offer distinctive opportunities to study, in vivo, the onset and progression of membrane damaging free-radical reactions within well-defined parameters of time, extent of tissue injury, correlation with changes in membrane enzymes, and correlation with readily measurable in vivo functions.