Receptors In Central Nervous System Research Articles

Chapter 12 - Anti-NMDAR encephalitis and other glutamate and GABA receptor antibody encephalopathies

Over the last few year, antibodies to various central nervous system receptors, particularly the glutamate and γ-aminobutyric acid (GABA) receptors, have been found to be associated with autoimmune neurologic disorders. The receptors include the N-methyl-d-aspartate receptor (NMDAR), the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), the metabotropic glutamate receptors (mGluRs), and GABA type A and B receptors (respectively GABAAR and GABABR). Compared to the previously described paraneoplastic antibodies directed at intracellular targets, the patients with receptor antibodies are often younger, they less frequently have malignancies, and they respond better to immunotherapy. Many of the patients have limbic encephalitis with amnesia, disorientation, seizures, and psychological or psychiatric symptoms, but those with NMDAR antibodies usually develop a more widespread form of encephalitis, often leading to a decrease in consciousness and requirement for long-term intensive care treatment. The autoantibodies bind directly to the synaptic or extrasynaptic receptors on the membrane surface, and have direct effects on signal transduction in central synapses. These conditions are very important to recognize as the symptoms and complications can be fatal when not treated in time, whereas with immunotherapy many patients recover considerably.

Preliminary semi-field study on the effect of the neonicotinoid containing seed dressings to honeybees as pollinator in sunflower

The key of the success of the neonicotinoid-type insecticides is that they have the greatest affinity to the nicotinic acetylcholine receptors of the insect central nervous system. They block them irreversibly, eventually, they cause the destruction of pests insects. Ultimately, they affect the healthy functioning of ecosystems: their effect also can be extended to plant visitor pollinators – bees, butterflies, hoverflies, etc. –, causing poisoning-, health- and behaviour-changing symptoms. In 2013, we investigated the effect of the residues of a neonicotinoid seed treatment of sunflower's among semi-field conditions More than 19 000 died individuals were collected during the measurements. On the basis of the results it can be stated that the literature known symptoms required about two weeks to appear on bees. The result have underlined the relevancy of our examinations to interrelation of beekeeping and modern crop systems.

A study of pyrazines in cigarettes and how additives might be used to enhance tobacco addiction

BackgroundNicotine is known as the drug that is responsible for the addicted behaviour of tobacco users, but it has poor reinforcing effects when administered alone. Tobacco product design features enhance...

Constipation enhances the propensity to seizure in pentylenetetrazole-induced seizure models of mice

Epilepsy is characterized by spontaneous recurrent seizures and represents one of the most frequent neurological diseases, affecting about 60 million people worldwide. The cellular and neurocircuit bases of epilepsy are poorly understood. Constipation is a common gastrointestinal disorder characterized by symptoms such as straining, hard stool, and infrequent defecation. Population-based studies have shown that the prevalence of constipation is up to 30% of the population in developed countries. The causal link between seizure and constipation is a common belief among patients and physicians, but there are no scientific data to support this association. The current investigation evaluated the effects of constipation induced by loperamide (a peripheral μ-opioid receptor agonist without effect on central nervous system receptors) and clidinium (a quaternary amine antimuscarinic agent with reduced central nervous system effects) on two different seizure models of mice: (1) myoclonic, clonic, and generalized tonic seizures and death induced by intraperitoneal administration of pentylenetetrazole and (2) clonic seizure threshold induced by intravenous infusion of pentylenetetrazole. We demonstrated that the measured intestinal transit (%intestinal transit) decreased after loperamide or clidinium treatment for 3days. Constipation in mice which was induced by loperamide or clonidine caused a decrease in threshold to clonic seizure in the intravenous pentylenetetrazole seizure model. Moreover loperamide- or clidinium-induced constipation decreased latencies to, clonic, and tonic seizures and death in the intraperitoneal pentylenetetrazole model of mice. Serum ammonia levels were slightly elevated in both loperamide- and clidinium-treated mice. In conclusion, loperamide- or clidinium-induced constipated mice are more prone to seizure which might confirm the belief of patients and physicians about constipation as a trigger of seizure.

Sigma-2 receptor ligands: neurobiological effects.

Sigma-2 receptor is a widely distributed protein, which can modulate cell proliferation and involved in the pathogenesis of tumor. Photoaffinity labelling techniques testified that its molecular size is about 18 kDa. Recent studies indicated that sigma-2 receptor modulates the cytosolic Ca2+ concentration, dopaminergic transmission, and cocaine-induced addiction behavior. Some sigma-2 receptor ligands (ditolylguanidine, afobazole, etc) display the neuroprotective effect. Although sigma-2 receptor hasn't been cloned, tens of sigma-2 receptor ligands, which demonstrate high affinity and selectivity, have been identified in the past decade. In this review, we mainly focus on these series of selective sigma-2 receptor ligands, their neuropsychological effects, and molecular probes for tracing sigma-2 receptors in central nervous system.

Validation of [(11) C]ORM-13070 as a PET tracer for alpha2c -adrenoceptors in the human brain.

This study explored the use of the α2C -adrenoceptor PET tracer [(11) C]ORM-13070 to monitor α2C -AR occupancy in the human brain. The subtype-nonselective α2 -AR antagonist atipamezole was administered to eight healthy volunteer subjects to determine its efficacy and potency (Emax and EC50 ) at inhibiting tracer uptake. We also explored whether the tracer could reveal changes in the synaptic concentrations of endogenous noradrenaline in the brain, in response to several pharmacological and sensory challenge conditions. We assessed occupancy from the bound-to-free ratio measured during 5-30 min post injection. Based on extrapolation of one-site binding, the maximal extent of inhibition of striatal [(11) C]ORM-13070 uptake (Emax ) achievable by atipamezole was 78% (95% CI 69-87%) in the caudate nucleus and 65% (53-77%) in the putamen. The EC50 estimates of atipamezole (1.6 and 2.5 ng/ml, respectively) were in agreement with the drug's affinity to α2C -ARs. These findings represent clear support for the use of [(11) C]ORM-13070 for monitoring drug occupancy of α2C -ARs in the living human brain. Three of the employed noradrenaline challenges were associated with small, approximately 10-16% average reductions in tracer uptake in the dorsal striatum (atomoxetine, ketamine, and the cold pressor test; P < 0.05 for all), but insulin-induced hypoglycemia did not affect tracer uptake. The tracer is suitable for studying central nervous system receptor occupancy by α2C -AR ligands in human subjects. [(11) C]ORM-13070 also holds potential as a tool for in vivo monitoring of synaptic concentrations of noradrenaline, but this remains to be further evaluated in future studies.

Histopathological, ultrastructural, and immunohistochemical assessment of hippocampus structures of rats exposed to TCDD and high doses of tocopherol and acetylsalicylic acid.

The effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on central nervous system consists of changing expression of estrogen receptors, whereas the result of chronic inflammatory reaction caused by dioxin is occurrence of destructive changes in various organs connected with disturbed metabolism of connective tissue and damage of cells. The aim of the study was to determine the effect of dioxins on function, ultrastructure, and cytological and histological structure of hippocampus, particularly on expression of estrogen receptors in central nervous system as well as to define protective influence of tocopherol (TCP) and acetylsalicylic acid (ASA) on the decrease in activity of proinflammatory effects in central nervous system. It was shown that TCDD contributes to destructive and inflammatory changes along with demyelization of myelin sheaths and atrophy of estrogen receptors in hippocampus. Dioxin contributes to atrophy of estrogen receptors in hippocampus, in which also destructive and inflammatory changes were found along with demyelination of myelin sheaths. Histopathological and ultrastructural image of hippocampus areas in rats, in which both TCP and ASA were used, is characterized by poorly expressed degenerative changes and smaller inflammatory reactivity. Using both TCP and ASA has a protective effect on functions of central nervous system.

Novel 2,4-disubstituted pyrimidines as potent, selective, and cell-permeable inhibitors of neuronal nitric oxide synthase.

Selective inhibition of neuronal nitric oxide synthase (nNOS) is an important therapeutic approach to target neurodegenerative disorders. However, the majority of the nNOS inhibitors developed are arginine mimetics and, therefore, suffer from poor bioavailability. We designed a novel strategy to combine a more pharmacokinetically favorable 2-imidazolylpyrimidine head with promising structural components from previous inhibitors. In conjunction with extensive structure–activity studies, several highly potent and selective inhibitors of nNOS were discovered. X-ray crystallographic analysis reveals that these type II inhibitors utilize the same hydrophobic pocket to gain strong inhibitory potency (13), as well as high isoform selectivity. Interestingly, select compounds from this series (9) showed good permeability and low efflux in a Caco-2 assay, suggesting potential oral bioavailability, and exhibited minimal off-target binding to 50 central nervous system receptors. Furthermore, even with heme-coordinating groups in the molecule, modifying other pharmacophoric fragments minimized undesirable inhibition of cytochrome P450s from human liver microsomes.

Suvorexant: something new for sleep?

Orexin, also called hypocretin, is a neuropeptide that acts on central nervous system receptors to promote arousal. Suvorexant, its receptor antagonist, generates interest as a medication to treat insomnia. Suvorexant helps in decreasing wakefulness by counteracting orexin activity. Its low side effect potential may offer considerable benefit. Compared with other sleep aids, diminished drowsiness and less cognitive dysfunction is an advantage. Now approved for clinical use, an apparent lack of rebound insomnia or drug dependence potential might make suvorexant a good choice pharmacotherapy for patients with insomnia.

Some Remembrances of D. J. Brown by a Colleague

Gordon B. Barlin (Ph.D. (ANU); D.Sc. (Sydney)) worked for approximately 40 years in the John Curtin School of Medical Research, ANU, on the syntheses of nitrogen heterocyclic compounds and the examination of their physico-chemical and biological properties, including tautomerism, kinetics of nucleophilic substitution, enhancement of anticancer activity by phleomycin, new potential antimalarials, and an extensive study of substituted imidazo[1,2-b]pyridazines for interaction with central and peripheral nervous system receptors.

Interaction of metal ions with neurotransmitter receptors and potential role in neurodiseases.

There is increasing evidence that toxic metals play a role in diseases of unknown etiology. Their action is often mediated by membrane proteins, and in particular neurotransmitter receptors. This brief review will describe recent findings on the direct interaction of metal ions with ionotropic γ-aminobutyric acid (GABAA) and glutamate receptors, the main inhibitory and excitatory neurotransmitter receptors in the mammalian central nervous system, respectively. Both hyper and hypo function of these receptors are involved in neurological and psychotic syndromes and modulation by metal ions is an important pharmacological issue. The focus will be on three xenobiotic metals, lead (Pb), cadmium (Cd) and nickel (Ni) that have no biological function and whose presence in living organisms is only detrimental, and two trace metals, zinc (Zn) and copper (Cu), which are essential for several enzymatic functions, but can mediate toxic actions if deregulated. Despite limited access to the brain and tight control by metalloproteins, exogenous metals interfere with receptor performances by mimicking physiological ions and occupying one or more modulatory sites on the protein. These interactions will be discussed as a potential cause of neuronal dysfunction.

Functional adaptation of presynaptic chemokine receptors in EAE mouse central nervous system.

In cortical synaptosomes of Experimental Autoimmune Encephalomyelitis (EAE) mice at the early stage of disease (13 days post immunization, d.p.i.), the Regulated upon Activation Normal T cell Expressed and Secreted (RANTES, CCL5)-mediated control of [3H]D-aspartate ([3H]D-ASP) exocytosis elicited by a mild depolarizing stimulus (12 mM KCl) shifted from inhibition to facilitation. By using selective antagonists for the chemokine receptor (CCR) 1, 3, and 5 subtypes, we found that the pharmacological profile of the receptor(s) accounting for CCL5-mediated effect was unaltered when compared to control. Inasmuch, CCR protein expression was unaltered. This studies was not extended at 21 d.p.i. since, at this stage, CCL5 failed to affect [3H]D-ASP exocytosis. At 13 d.p.i., the expression of CCR proteins was largely conserved when compared to control. In spinal cord synaptosomes of EAE mice at 21 d.p.i., when presynaptic defects became evident, the [3H]D-ASP exocytosis elicited by 15 mM KCl was significantly increased when compared to control and it was significantly potentiated by 1 nM CCL5. The antagonist pharmacological profile and the western blot analysis of the CCR proteins unveiled that the receptor repertoire involved was unmodified. Differently from controls, however, the CCR1 antagonist BX513 efficiently inhibited on its own [3H]D-ASP exocytosis suggesting that this receptor could have adopted an active conformation. Altogether, our observations favor the use of CCR antagonists to the cure of neurological symptoms in patients suffering from demyelinating syndrome.

Czynniki ryzyka zaburzeń lękowych u dzieci

Anxiety disorders are common; lifetime prevalence for the group of disorders is estimated to be as high as 25%. The main question is What is the relative contribution of genetics and environment to etiology of anxiety disorders? The anxiety disorders are not, from a genetic perspective, etiologically homogeneous. Structural equation modeling provides estimates of variance in liability to a disorder that is attributable to additive genetic, common familial environmental, and individual-specific environmental factors. Familial aggregation that largely results from genetic risk factors has been documented for all of the major anxiety disorders. Genes predispose to two broad groups of disorders dichotomized as panic-generalized-agoraphobic anxiety versus specific phobias. The candidate genes are the ones encoding the central and peripheral nervous system receptors and transporters. Trauma in childhood disposes to further anxiety disorders through the hyperactivity of the HPA axis and the hypersecretion of CRF. Traumatic experience in developmental age leads to neurobiochemical changes in brain, typical for panic disorder or PTSD. Behavioral inhibition in early childhood is a predictor of further anxiety disorders. Some types of parental behaviors and family environment can lead to them, as well as improper interactions between parents and child.

Central antinociception induced by ketamine is mediated by endogenous opioids and μ- and δ-opioid receptors

It is generally believed that NMDA receptor antagonism accounts for most of the anesthetic and analgesic effects of ketamine, however, it interacts at multiple sites in the central nervous system, including NMDA and non-NMDA glutamate receptors, nicotinic and muscarinic cholinergic receptors, and adrenergic and opioid receptors. Interestingly, it was shown that at supraspinal sites, ketamine interacts with the μ-opioid system and causes supraspinal antinociception. In this study, we investigated the involvement of endogenous opioids in ketamine-induced central antinociception. The nociceptive threshold for thermal stimulation was measured in Swiss mice using the tail-flick test. The drugs were administered via the intracerebroventricular route. Our results demonstrated that the opioid receptor antagonist naloxone, the μ-opioid receptor antagonist clocinnamox and the δ-opioid receptor antagonist naltrindole, but not the κ-opioid receptor antagonist nor-binaltorphimine, antagonized ketamine-induced central antinociception in a dose-dependent manner. Additionally, the administration of the aminopeptidase inhibitor bestatin significantly enhanced low-dose ketamine-induced central antinociception. These data provide evidence for the involvement of endogenous opioids and μ- and δ-opioid receptors in ketamine-induced central antinociception. In contrast, κ-opioid receptors not appear to be involved in this effect.

Altering the Open vs. Closed State Balance of the GLIC Ligand-Gated Ion Channel through Mutagenesis Enables Molecular Simulation of the Reversible Gating Process

The prokaryotic Gloeobacter violaceus pentameric ligand-gated ion channel (GLIC) is an important template for studies of Cys-loop receptors in the human central nervous system. It is also a key model system to understand the transitions and stabilization of different conformations of membrane proteins through allosteric modulation - a ligand that opens the channel can either stabilize the open state, or destabilize the closed one. Capturing these processes on the molecular level will not only enable us to understand gating, but also make it possible to predict functional responses rather than merely binding properties. Over the last years, we have studied mutants of the GLIC channel that make it more similar to the human Cys-loop receptors both experimentally and in simulations, and shown how this provides evidence for a dual allosteric modulation mechanism with separate inhibitory and potentiating binding sites. Here, I will present our new results on mutations in the central GLIC pore. By modifying the hydrophobicity of one or several residues in the pore it is possible to alter the pore hydration level, which in turn has paramount effects on the conformation - molecular simulations show that it is possible to stabilize the channel either in the open or closed conformation independent of pH. By using ensemble molecular dynamics simulations covering several tens of microseconds, we show that it is possible to reversibly simulate transitions between conformations that are shown to actually conduct ions or block the current in simulations. In vivo electrophysiology and single-channel recordings on the mutants confirm this influence on the kinetics, and provide us with a way to couple molecular-level dynamics and kinetics to the experimentally observed equilibrium and transitions between conformations.

Clinical features of organophosphate poisoning: A review of different classification systems and approaches.

Purpose:The typical toxidrome in organophosphate (OP) poisoning comprises of the Salivation, Lacrimation, Urination, Defecation, Gastric cramps, Emesis (SLUDGE) symptoms. However, several other manifestations are described. We review the spectrum of symptoms and signs in OP poisoning as well as the different approaches to clinical features in these patients.Materials and Methods:Articles were obtained by electronic search of PubMed® between 1966 and April 2014 using the search terms organophosphorus compounds or phosphoric acid esters AND poison or poisoning AND manifestations.Results:Of the 5026 articles on OP poisoning, 2584 articles pertained to human poisoning; 452 articles focusing on clinical manifestations in human OP poisoning were retrieved for detailed evaluation. In addition to the traditional approach of symptoms and signs of OP poisoning as peripheral (muscarinic, nicotinic) and central nervous system receptor stimulation, symptoms were alternatively approached using a time-based classification. In this, symptom onset was categorized as acute (within 24-h), delayed (24-h to 2-week) or late (beyond 2-week). Although most symptoms occur with minutes or hours following acute exposure, delayed onset symptoms occurring after a period of minimal or mild symptoms, may impact treatment and timing of the discharge following acute exposure. Symptoms and signs were also viewed as an organ specific as cardiovascular, respiratory or neurological manifestations. An organ specific approach enables focused management of individual organ dysfunction that may vary with different OP compounds.Conclusions:Different approaches to the symptoms and signs in OP poisoning may better our understanding of the underlying mechanism that in turn may assist with the management of acutely poisoned patients.

Cerebral mechanisms of general anesthesia

How does general anesthesia (GA) work? Anesthetics are pharmacological agents that target specific central nervous system receptors. Once they bind to their brain receptors, anesthetics modulate remote brain areas and end up interfering with global neuronal networks, leading to a controlled and reversible loss of consciousness. This remarkable manipulation of consciousness allows millions of people every year to undergo surgery safely most of the time. However, despite all the progress that has been made, we still lack a clear and comprehensive insight into the specific neurophysiological mechanisms of GA, from the molecular level to the global brain propagation. During the last decade, the exponential progress in neuroscience and neuro-imaging led to a significant step in the understanding of the neural correlates of consciousness, with direct consequences for clinical anesthesia. Far from shutting down all brain activity, anesthetics lead to a shift in the brain state to a distinct, highly specific and complex state, which is being increasingly characterized by modern neuro-imaging techniques. There are several clinical consequences and challenges that are arising from the current efforts to dissect GA mechanisms: the improvement of anesthetic depth monitoring, the characterization and avoidance of intra-operative awareness and post-anesthesia cognitive disorders, and the development of future generations of anesthetics.

Protective effect of moxonidine on ischemia/reperfusion-induced acute kidney injury through α2/imidazoline I1 receptor

Enhancement of renal sympathetic nerve activity during renal ischemia and norepinephrine overflow from the kidney after reperfusion play important roles in the development of ischemic acute kidney injury. Recently, we have found that moxonidine, an α2/imidazoline Ι1-receptor agonist, has preventive effects on ischemic acute kidney injury by suppressing the excitation of renal sympathetic nervous system after reperfusion. In the present study, to clarify the renoprotective mechanisms of moxonidine (360nmol/kg, i.v.) against ischemic acute kidney injury, we investigated the effect of intravenous (i.v.) and intracerebroventricular (i.c.v.) injection of efaroxan, an α2/Ι1 receptor antagonist, on the moxonidine-exhibited actions. Ischemic acute kidney injury was induced by clamping the left renal artery and vein for 45min followed by reperfusion, 2 weeks after contralateral nephrectomy. The suppressive effect of moxonidine on enhanced renal sympathetic nerve activity during renal ischemia was not observed in the rat treated with either i.v. (360nmol/kg) or i.c.v. (36nmol/kg) of efaroxan. Furthermore, i.v. injection of efaroxan eliminated the preventive effect of moxonidine on ischemia/reperfusion-induced kidney injury and norepinephrine overflow, and i.c.v. injection of efaroxan did not completely inhibit the moxonidine's effects. These results indicate that moxonidine prevents the ischemic kidney injury by sympathoinhibitory effect probably via α2/Ι1 receptors in central nervous system and by suppressing the norepinephrine overflow through α2/Ι1 receptors on sympathetic nerve endings.

Acidic biphenyl derivatives: Synthesis and biological activity of a new series of potent 5-HT4 receptor antagonists

Serotonin (5-hydroxytryptamine, 5-HT) is an important signaling molecule in the central nervous system (CNS) and in non-neuronal tissues and organs. Serotonin mediates a positive chronotropic and inotropic response through 5-HT4 receptors in the atrium and ventricle of the heart. Recent investigations have revealed increased expression of the 5-HT4(b) isoform in cardiomyocytes of chronic arrhythmic and failing hearts, and that the use of 5-HT4 receptor antagonists may be beneficial for treating these conditions. The 5-HT4 receptor possesses a transmembrane (TM) binding site important for ligand affinity and recognition, as well as a capacity to accommodate bulky ligands. A new series of peripherally-acting 5-HT4 receptor antagonists were prepared by combining the acidic biphenyl group from the class of angiotensin II receptor blockers (ARBs) with the SB207266 (piboserod) scaffold. The new compounds were pharmacologically evaluated and carboxylic acid 21 was identified as a potent and promising 5-HT4 receptor antagonist with moderate affinity for the AT1 receptor. The permeability of carboxylic acid 21 in a Caco-2 assay was low and the corresponding prodrug esters 23a–f were therefore prepared. The pharmacokinetics of methyl ester 20 and n-butyl ester 23c were evaluated in a rat model, revealing incomplete metabolism to carboxylic acid 21. However, methyl ester 20 is a potent 5-HT4 receptor antagonist with binding affinities in the low picomolar range. Methyl ester 20 has promising oral bioavailability and pharmacokinetics and may target 5-HT4 receptors in both CNS and peripheral organs.

Evaluation and management of children and adolescents with gender identification and transgender disorders

Gender identity development is poorly understood but impacted by central nervous system (CNS) factors, genes, gonadal hormones and receptors, genitalia, and social/environmental factors. Gender identity disorder (GID) is the diagnostic term to describe persons discontent with the sex they were assigned at birth and/or the gender roles associated with that sex. It is crucial that the diagnosis be verified as persistent, since gender confusion among those young persists among only a portion. Recent publications do not yet provide an overall perspective but involve observations regarding outcome information, unusual variables, incidence of cross-gender behavior, and CNS differences related to GID and bi-gender descriptions. Approaches to therapy for GID and task force guidelines are noted. Although the concept of gender identity is a relatively new paradigm and remains an area of active and exciting investigation, findings reported here provide items of information for understanding and treatment of GIDs and illustrate the need for further research.