Receptors In Central Nervous System Research Articles

Further evidence of anxiety- and depression-like behavior for total genetic ablation of cannabinoid receptor type 1

Cannabinoid receptor type 1 (CB1R) is the most abundant cannabinoid receptor in central nervous system. Clinical studies and animal models have shown that the attenuation of endocannabinoid system signaling correlates with the development of psychiatric disorders such as anxiety, depression and schizophrenia. In the present work, multiple behavioral tests were performed to evaluate behaviors related to anxiety and depression in CB1R+/− and CB1R−/−. CB1R+/− mice had anxiety-related behavior similar to wild type (CB1R+/+) mice, whereas CB1R−/− mice displayed an anxious-like phenotype, which indicates that lower expression of CB1R is sufficient to maintain the neural circuits modulating anxiety. In addition, CB1R−/− mice exhibited alterations in risk assessment and less exploration, locomotion, grooming, body weight and appetite. These phenotypic characteristics observed in CB1R−/− mice could be associated with symptoms observed in human psychiatric disorders such as depression. A better knowledge of the neuromodulatory role of CB1R may contribute to understand scope and limitations of the development of medical treatments.

Coronaviruses and the central nervous system

Seven coronavirus (CoV) species are known human pathogens: the epidemic viruses SARS-CoV, SARS-CoV-2, and MERS-CoV and those continuously circulating in human populations since initial isolation: HCoV-OC43, HCoV-229E, HCoV-HKU1, and HCoV-NL63. All have associations with human central nervous system (CNS) dysfunction. In infants and young children, the most common CNS phenomena are febrile seizures; in adults, non-focal abnormalities that may be either neurologic or constitutional. Neurotropism and neurovirulence are dependent in part on CNS expression of cell surface receptors mediating viral entry, and host immune response. In adults, CNS receptors for epidemic viruses are largely expressed on brain vasculature, whereas receptors for less pathogenic viruses are present in vasculature, brain parenchyma, and olfactory neuroepithelium, dependent upon viral species. Human coronaviruses can infect circulating mononuclear cells, but meningoencephalitis is rare. Well-documented human neuropathologies are infrequent and, for SARS, MERS, and COVID-19, can entail cerebrovascular accidents originating extrinsically to brain. There is evidence of neuronal infection in the absence of inflammatory infiltrates with SARS-CoV, and CSF studies of rare patients with seizures have demonstrated virus but no pleocytosis. In contrast to human disease, animal models of neuropathogenesis are well developed, and pathologies including demyelination, neuronal necrosis, and meningoencephalitis are seen with both native CoVs as well as human CoVs inoculated into nasal cavities or brain. This review covers basic CoV biology pertinent to CNS disease; the spectrum of clinical abnormalities encountered in infants, children, and adults; and the evidence for CoV infection of human brain, with reference to pertinent animal models of neuropathogenesis.

Advances in Neurobiology and Pharmacology of GPR12.

GPR12 is a G protein-coupled orphan receptor genetically related to type 1 and type 2 cannabinoid receptors (CB1 and CB2) which are ancient proteins expressed all over the body. Both cannabinoid receptors, but especially CB1, are involved in neurodevelopment and cognitive processes such as learning, memory, brain reward, coordination, etc. GPR12 shares with CB1 that both are mainly expressed into the brain. Regrettably, very little is known about physiology of GPR12. Concerning its pharmacology, GPR12 seems to be endogenously activated by the lysophospholipids sphingosine-1-phosphate (S1P) and sphingosyl-phosphorylcholine (SPC). Exogenously, GPR12 is a target for the phytocannabinoid cannabidiol (CBD). Functionally, GPR12 seems to be related to neurogenesis and neural inflammation, but its relationship with cognitive functions remains to be characterized. Although GPR12 was initially suggested to be a cannabinoid receptor, it does not meet the five criteria proposed in 2010 by the International Union of Basic and Clinical Pharmacology (IUPHAR). In this review, we analyze all the direct available information in PubMed database about expression, function, and pharmacology of this receptor in central nervous system (CNS) trying to provide a broad overview of its current and prospective neurophysiology. Moreover, in this mini-review we highlight the need to produce more relevant data about the functions of GPR12 in CNS. Hence, this work should motivate further research in this field.

Excessive Activation of NMDA Receptors in the Pathogenesis of Multiple Peripheral Organs via Mitochondrial Dysfunction, Oxidative Stress, and Inflammation

It has been well-acknowledged that N-methyl-D-aspartate receptors (NMDARs) in central nervous system play an important role in both physiological functions of neurons and the pathophysiological progression of various neurodegenerative diseases. Besides, the receptors have also been found to present extensively in peripheral organs, such as lungs, kidneys, heart, and pancreas. Under various pathological conditions, peripheral NMDARs are upregulated and excessively activated, initiating calcium influx and intracellular calcium overloading. Subsequently, mitochondrial dysfunction, oxidative stress, and pro-inflammatory signaling pathway activation ultimately aggravate tissue damage and organ dysfunction. In addition, excessive activation of NMDARs also directly initiates mitochondrial apoptosis in many organs. Here, we discuss pathophysiological roles of NMDARs in cardiovascular system, lungs, kidneys, and pancreas.

Impairment of Synaptic Plasticity by Cannabis, Δ9-THC, and Synthetic Cannabinoids.

The ability of neurons to dynamically and flexibly encode synaptic inputs via short- and long-term plasticity is critical to an organism's ability to learn and adapt to the environment. Whereas synaptic plasticity may be encoded by pre- or postsynaptic mechanisms, current evidence suggests that optimization of learning requires both forms of plasticity. Endogenous cannabinoids (eCBs) play critical roles in modulating synaptic transmission via activation of cannabinoid CB1 receptors (CB1Rs) in many central nervous system (CNS) regions, and the eCB system has been implicated, either directly or indirectly, in several forms of synaptic plasticity. Because of this, perturbations within the eCB signaling system can lead to impairments in a variety of learned behaviors. One agent of altered eCB signaling is exposure to "exogenous cannabinoids" such as the primary psychoactive constituent of cannabis, Δ9-THC, or illicit synthetic cannabinoids that in many cases have higher potency and efficacy than Δ9-THC. Thus, by targeting the eCB system, these agonists can produce widespread impairment of synaptic plasticity by disrupting ongoing eCB function. Here, we review studies in which Δ9-THC and synthetic cannabinoids impair synaptic plasticity in a variety of neuronal circuits and examine evidence that this contributes to their well-documented ability to disrupt cognition and behavior.

The use of olanzapine as an antiemetic in palliative medicine: a systematic review of the literature

BackgroundOlanzapine is an atypical antipsychotic that has affinity for many central nervous system receptors. Its efficacy is supported by several studies in the prevention and treatment of chemotherapy-induced nausea and vomiting. No recommendations exist on the antiemetic use of olanzapine in the palliative care setting. The aim of this work is to complete the initial work of Fonte et al. published in 2015, to determine whether the literature supports the use of olanzapine as an antiemetic in palliative situations and, in practice, to propose a therapeutic schema adapted to the palliative setting.MethodsSystematic review of the literature according to the PRISMA criteria. We searched the PubMed, Cochrane, RefDoc, EMBase databases and the gray literature databases. The bibliographic search was conducted between November 2016 and August 2017.ResultsThirteen articles were included: 2 case studies, 3 case series, 3 retrospective studies, 2 prospective studies, 2 literature reviews. All studies concluded on the efficacy of olanzapine as an antiemetic in the palliative care setting. No serious adverse effects were reported. Based on the data from the literature review, we propose a therapeutic scheme adapted to the palliative care context.ConclusionAction of olanzapine on many receptors and its tolerance profile make it an interesting antiemetic treatment in palliative medicine. But to date, studies are scarce and have a low statistical power. Further investigation is therefore needed to determine the benefit of this treatment in palliative care patients, compared to usual treatments.

Suppressed Prazosin‐Sensitive Cardiovascular Regulation in Central Nervous System During Early Sepsis

Sepsis is the main cause of morbidity and mortality in ICU worldwide, with a resulting mortality rate of around 30–40%. The cardiovascular system in sepsis and septic shock is depressed, resulting in fluid‐refractory hypotension and hyporeactivity to vasoactive agents. In blood pressure (BP) neural control, tonic sympathetic nerve activity (SNA) through norepinephrine (NE) release is crucial for BP maintenance. Septic shock has been associated with SNA exacerbation, resulting in pro‐inflammatory activity and increased release of catecholamines. We hypothesized that α1‐adrenergic receptors (α1AR) in central nervous system (CNS) are less sensitive for NE in early sepsis, thus affecting autonomic modulation of cardiovascular function. To evaluate this hypothesis, we assessed BP and heart rate (HR) of anesthetized male rats subjected to cecal ligation puncture (CLP) model of sepsis, which was performed 6 h before the experiments. Control experiments were conducted in naïve rats. These animals received NE, administered by intracerebroventricular (icv; 10 μg/5 μL) or intravenous (iv; 3, 10, and 30 nmol/Kg) routes. In additional experiments, prazosin (5 μg/5 μL, icv), a selective α1AR antagonist, was given 15 min before a second icv administration of NE. In our experiments CLP generated a mortality rate of 50% in 36 h. Systemic administration of NE dose‐dependently increased the mean arterial pressure (MAP) by 9.2 ± 3.3, 74.6 ± 6.6 and 83.5 ± 4.6 mmHg in control group (n = 5), and by 8.9 ± 1.8, 48.9 ± 7.2 (p < 0.05), and 72.1 ± 11.7 mmHg in CLP animals (n = 4) for doses of 3, 10 and 30 nmol/Kg, respectively. When administered by iv route, NE‐increased BP was accompanied by increased HR, with no differences between control and CLP groups. Central microinjection of NE increased MAP and decreased HR of both control and CLP groups. However, responses were significantly depressed in septic animals. For instance, icv injection of NE increased MAP by 53.6 ± 3.3 mmHg in control (n = 5), and 18.9 ± 3.9 mmHg in CLP group (n = 8, p < 0.0001). Prazosin microinjection generated a similar pattern of slight and transitory reduction in BP of both control and CLP animals. In control animals, pretreatment with prazosin reduced NE‐increased MAP to 20.3 ± 2.6 mmHg (n = 5, p < 0.0001). However, icv administered NE maintained its pressor effect by 12.7 ± 1.4 mmHg in CLP subjected rats (n = 6) even after pretreatment with prazosin. Moreover, prazosin reversed the bradycardia induced by icv NE from −41 ± 12 bpm to 11 ± 21 bpm (n = 5, p < 0.05) in control animals, but had no effects in HR of CLP group. Our results disclose that mechanisms involved in tonic SNA stimulation by NE are depressed in CLP‐subjected rats during early sepsis stages, even before the establishment of hyporesponsiveness in peripheral cardiovascular system. The lack of prazosin effects in septic animals reinforces the development of neural sympathetic α1AR dysfunction and abnormal autonomic modulation of cardiovascular function in sepsis.Support or Funding InformationFinancial Support: CNPq (Brazil), with a Ph.D. fellowship to Matsubara, N. K. This study was approved by the Animal Ethics Committee of UFSC (6327180718).

The process of somatic hypermutation increases polyreactivity for central nervous system antigens in primary central nervous system lymphoma.

The immunoglobulin (Ig) heavy and light chain variable gene mutational pattern of the B-cell receptor (BCR) in primary central nervous system lymphoma (PCNSL) cells suggests antigenic selection to drive pathogenesis and confinement to the central nervous system (CNS). This hypothesis is supported by the observation that the tumor B-cell receptor (tBCR) of PCNSL is polyreactive and may be stimulated by CNS proteins. To obtain further insight into the role of the germinal center (GC) reaction on BCR reactivity, we constructed recombinant antibodies (recAb) with Ig heavy and light chain sequences of the corresponding naïve BCR (nBCR) by reverting tBCR somatic mutations in ten PCNSL. Analysis of nBCR-derived recAb reactivity by a protein microarray and immunoprecipitation demonstrated auto- and polyreactivity in all cases. Self- /polyreactivity was not lost during the GC reaction; surprisingly, tBCR significantly increased self-/polyreactivity. In addition to proteins recognized by both the nBCR and tBCR, tBCR gained self-/polyreactivity particularly for proteins expressed in the CNS including proteins of oligodendrocytes/ myelin, the S100 protein family, and splicing factors. Thus, in PCNSL pathogenesis, a faulty GC reaction may increase self-/polyreactivity, hereby facilitating BCR signaling via multiple CNS antigens, and may ultimately foster tumor cell survival in the CNS.

G-Protein-Coupled Receptors in CNS: A Potential Therapeutic Target for Intervention in Neurodegenerative Disorders and Associated Cognitive Deficits.

Neurodegenerative diseases are a large group of neurological disorders with diverse etiological and pathological phenomena. However, current therapeutics rely mostly on symptomatic relief while failing to target the underlying disease pathobiology. G-protein-coupled receptors (GPCRs) are one of the most frequently targeted receptors for developing novel therapeutics for central nervous system (CNS) disorders. Many currently available antipsychotic therapeutics also act as either antagonists or agonists of different GPCRs. Therefore, GPCR-based drug development is spreading widely to regulate neurodegeneration and associated cognitive deficits through the modulation of canonical and noncanonical signals. Here, GPCRs’ role in the pathophysiology of different neurodegenerative disease progressions and cognitive deficits has been highlighted, and an emphasis has been placed on the current pharmacological developments with GPCRs to provide an insight into a potential therapeutic target in the treatment of neurodegeneration.

Heterogeneous Network Model to Identify Potential Associations Between Plasmodium vivax and Human Proteins.

Integration of multiple sources and data levels provides a great insight into the complex associations between human and malaria systems. In this study, a meta-analysis framework was developed based on a heterogeneous network model for integrating human-malaria protein similarities, a human protein interaction network, and a Plasmodium vivax protein interaction network. An iterative network propagation was performed on the heterogeneous network until we obtained stabilized weights. The association scores were calculated for qualifying a novel potential human-malaria protein association. This method provided a better performance compared to random experiments. After that, the stabilized network was clustered into association modules. The potential association candidates were then thoroughly analyzed by statistical enrichment analysis with protein complexes and known drug targets. The most promising target proteins were the succinate dehydrogenase protein complex in the human citrate (TCA) cycle pathway and the nicotinic acetylcholine receptor in the human central nervous system. Promising associations and potential drug targets were also provided for further studies and designs in therapeutic approaches for malaria at a systematic level. In conclusion, this method is efficient to identify new human-malaria protein associations and can be generalized to infer other types of association studies to further advance biomedical science.

Preclinical validation of [18F]2FNQ1P as a specific PET radiotracer of 5-HT6 receptors in rat, pig, non-human primate and human brain tissue

IntroductionThe aim of this study was to perform in-vitro and in-vivo radiopharmacological characterizations of [18F]2FNQ1P, a new PET radiotracer of 5-HT6 receptors, in rat, pig, non-human primate and human tissues. The 5-HT6 receptor is one of the more recently identified serotonin receptors in central nervous system and, because of its role in memory and cognitive processes, is considered as a promising therapeutic target. MethodsIn-vitro autoradiography and saturation binding assays were performed in postmortem brain tissues from rat, pig, non-human primate and human caudate nucleus, completed by serum stability assessment in all species and cerebral radiometabolite and biodistribution studies in rat. ResultsIn all species, autoradiography data revealed high binding levels of [18F]2FNQ1P in cerebral regions with high 5-HT6 receptor density. Binding was blocked by addition of SB258585 as a specific antagonist. Binding assays provided KD and Bmax values of respectively 1.34 nM and 0.03 pmol·mg−1 in rat, 0.60 nM and 0.04 pmol·mg−1 in pig, 1.38 nM and 0.07 pmol·mg−1 in non-human primate, and 1.39 nM and 0.15 pmol·mg−1 in human caudate nucleus. In rat brain, the proportion of unmetabolized [18F]2FNQ1P was >99% 5 min after iv injection and 89% at 40 min. The biodistribution studies found maximal radioactivity in lungs and kidneys (3.5 ± 1.2% ID/g and 2.0 ± 0.7% ID/g, respectively, 15 min post-injection). ConclusionThese radiopharmacological data confirm that [18F]2FNQ1P is a specific radiotracer for molecular imaging of 5-HT6 receptors and suggest that it could be used as a radiopharmaceutical in humans.

Air-breathing organs and Nervous control of respiration in Freshwater fishes

In fishes, exploitation of aerial gas exchange has evolved independently many times, involving a variety of airbreathing organs. Indeed, air-breathing occurs in at least 49 known families of fish (Graham, 1997). The present review examines the evolutionary implications of air-breathing organs in fishes and the morphology of the peripheral receptors and the neurotransmitter content of the cells involved in the control of air-breathing. The breathing control is influenced by feedback from peripheral and/or central nervous system receptors that respond to changes in PO2, PCO2 and/or pH. Although the specific chemoreceptors mediating the respiratory reflexes have not been conclusively identified, studies in water breathing teleosts have implicated the neuro-epithelial cells (NECs) existing in gill tissues as the O2 sensitive chemoreceptors that initiate the cardiorespiratory reflexes in aquatic vertebrates. NECs have been also reported in the specialized respiratory epithelia of accessory respiratory organs (ARO's) of some catfish species and in the gill and skin of the Channa punctatus. Unlike teleosts matching an O2oriented ventilation to ambient O2 levels, lungfishes have central and peripheral H+/CO2 receptors that control the acid-base status of the blood.

Anxiolytic Terpenoids and Aromatherapy for Anxiety and Depression.

In our society, anxiety and depression are serious health issues that affect a large proportion of the population. Unfortunately, drug therapies are not always effective and can lead to drug abuse, delay of therapeutic effect, dependence, and tolerance. Traditionally, aromatherapy has also been used for anxiety relief and mood improvement. The use of essential oils, in relieving anxiety and depression, does not have the disadvantages associated with currently used drug therapies. In-vivo studies on animal models have verified the anxiolytic effects of these essential oils and the interactions of their major components with central nervous system receptors. Therefore, it seems reasonable to argue that the modulation of glutamate and GABA neurotransmitter systems are likely to be the critical mechanisms responsible for the sedative, anxiolytic, and anticonvulsant proprieties of linalool and essential oils containing linalool in significant proportions. Popular anxiolytic essential oils are generally rich in terpenoid alcohols like linalool, geraniol and citronellol, and the monoterpene limonene (or citral). Therefore, other essential oils or formulations that contain these terpenoids as major components may serve as important aromatherapeutics for relief of anxiety.

Nonpharmacologic interventions for chronic pruritus

Chronic pruritus, traditionally defined as itch persisting for >6 weeks, is a common affliction that can be associated with cutaneous or systemic disease, or may be idiopathic in nature. It affects patients of all ages and backgrounds and seems to have no predilection for sex or socioeconomic status. The lifetime prevalence has been estimated between 22% and 26%. It accounts for millions of outpatient clinic encounters every year. Pruritus is associated with significant morbidity ranging from sleep disturbance to suicidal ideation in both pediatric and adult patients. The pathophysiology of pruritus is complex and multifactorial. An intricate and incompletely understood interplay between cytokines, sensory neurons, and a variety of cutaneous and central nervous system receptors and effector cells are responsible for the development of itch. Scores of therapies exist, with enormous variation in efficacy, for the amelioration of itch. Drugs aimed at virtually all of the aforementioned pathogenic factors in pruritus have been trialed or are being developed. Nonpharmacologic therapies for chronic pruritus encompass a variety of methods for altering itch signaling or for changing the patient’s perception of pruritus. Although some of these interventions may be used as monotherapy, they are usually best utilized in combination with more conventional pharmacologic antipruritic therapies. This review evaluates the current understanding of the mechanisms and efficacy of these nonpharmacologic interventions and serves to expand the dermatologist's armamentarium against chronic pruritus.

Repurposing of Iloperidone: Antihypertensive and ocular hypotensive activity in animals

PurposeIloperidone, second generation antipsychotic drug, reported in clinical trial to produce orthostatic hypotension as side effect. It was claimed to be antagonistic at alpha adrenergic receptor in central nervous system. We evaluated effect of Iloperidone on peripheral alpha 1 adrenoreceptor by in silico and in vitro methods while in vivo hypotensive, antihypertensive and ocular hypotensive activity was evaluated in animals. MethodsPharmacological activity prediction of Iloperidone was done using PASSOnline and SwissTargetPrediction softwares and molecular docking with Alpha 1A adrenoreceptor using AutoDock Vina. Hypotensive activity in normotensive and antihypertensive activity against DOCA-salt induced hypertension in rats were evaluated at doses 0.03 mg/Kg and 0.1 mg/Kg, i.p of Iloperidone. Blood pressure was measured by invasive blood pressure measurement technique using PowerLab 4/30 and intraocular pressure was measured using digital tonometer. ResultsIloperidone (0.1 mg/Kg) showed significant decrease in blood pressure (38.96 ± 1.1%) in normotensive rats, while in DOCA salt induced hypertensive rats, systolic blood pressure was found to be decreased by 29.04 ± 1.45% and 31.43 ± 1.21% in 0.03 mg/Kg and 0.1 mg/Kg treated rats respectively. Iloperidone prevented rise in systolic BP with adrenaline. Intraocular pressure was found to be decreased by 36.66 ± 3.15% in rabbits after 1 h of instillation of 0.1% Iloperidone. ConclusionIloperidone exerted hypotensive and/or anti-hypertensive activity in rats and ocular hypotensive activity in rabbits.

CB1 and LPA1 Receptors Relationship in the Mouse Central Nervous System

Neurolipids are a class of bioactive lipids that are produced locally through specific biosynthetic pathways in response to extracellular stimuli. Neurolipids are important endogenous regulators of neural cell proliferation, differentiation, oxidative stress, inflammation and apoptosis. Endocannabinoids (eCBs) and lysophosphatidic acid (LPA) are examples of this type of molecule and are involved in neuroprotection. The present study analyzes a possible relationship of the main receptor subtypes for both neurolipid systems that are present in the central nervous system, the CB1 and LPA1 receptors, by using brain slices from CB1 KO mice and LPA1-null mice. Receptor-mediated G protein activation and glycerophospholipid regulation of potential precursors of their endogenous neurotransmitters were measured by two different in vitro imaging techniques, functional autoradiography and imaging mass spectrometry (IMS), respectively. Possible crosstalk between CB1 and LPA1 receptors was identified in specific areas of the brain, such as the amygdala, where LPA1 receptor activity is upregulated in CB1 KO mice. More evidence of an interaction between both systems was that the CB1-mediated activity was clearly increased in the prefrontal cortex and cerebellum of LPA1-null mice. The eCB system was specifically over-activated in regions where LPA1 has an important signaling role during embryonic development. The modifications on phospholipids (PLs) observed in these genetically modified mice by using the IMS technique indicated the regulation of some of the PL precursors of both LPA and eCBs in specific brain areas. For example, phosphatidylcholine (PC) (36:1) was detected as a potential LPA precursor, and phosphatidylethanolamine (PE) (40:6) and PE (p18:0/22:6) as potential eCB precursors. The absence of the main cerebral receptors for LPA or eCB systems is able to induce modulation on the other at the levels of both signaling and synthesis of endogenous neurotransmitters, indicating adaptive responses between both systems during prenatal and/or postnatal development.

Concatenated γ-aminobutyric acid type A receptors revisited: Finding order in chaos.

γ-aminobutyric acid type A receptors (GABAARs), the major inhibitory neurotransmitter receptors in the mammalian central nervous system, are arguably the most challenging member of the pentameric Cys-loop receptors to study due to their heteromeric structure. When two or more subunits are expressed together in heterologous systems, receptors of variable subunit type, ratio, and orientation can form, precluding accurate interpretation of data from functional studies. Subunit concatenation is a technique that involves the linking of individual subunits and in theory allows the precise control of the uniformity of expressed receptors. In reality, the resulting concatemers from widely used constructs are flexible in their orientation and may therefore assemble with themselves or free GABAAR subunits in unexpected ways. In this study, we examine functional responses of receptors from existing concatenated constructs and describe refinements necessary to allow expression of uniform receptor populations. We find that dimers from two commonly used concatenated constructs, β-23-α and α-10-β, assemble readily in both the clockwise and the counterclockwise orientations when coexpressed with free subunits. Furthermore, we show that concatemers formed from new tetrameric α-10-β-α-β and α-10-β-α-γ constructs also assemble in both orientations with free subunits to give canonical αβγ receptors. To restrict linker flexibility, we systematically shorten linker lengths of dimeric and pentameric constructs and find optimized constructs that direct the assembly of GABAARs only in one orientation, thus eliminating the ambiguity associated with previously described concatemers. Based on our data, we revisit some noncanonical GABAAR configurations proposed in recent years and explain how the use of some concatenated constructs may have led to wrong conclusions. Our results help clarify current contradictions in the literature regarding GABAAR subunit stoichiometry and arrangement. The lessons learned from this study may guide future efforts in understanding other related heteromeric receptors.

Receptor Ligands as Helping Hands to L-DOPA in the Treatment of Parkinson's Disease.

Levodopa (LD) is the most effective drug in the treatment of Parkinson’s disease (PD). However, although it represents the “gold standard” of PD therapy, LD can cause side effects, including gastrointestinal and cardiovascular symptoms as well as transient elevated liver enzyme levels. Moreover, LD therapy leads to LD-induced dyskinesia (LID), a disabling motor complication that represents a major challenge for the clinical neurologist. Due to the many limitations associated with LD therapeutic use, other dopaminergic and non-dopaminergic drugs are being developed to optimize the treatment response. This review focuses on recent investigations about non-dopaminergic central nervous system (CNS) receptor ligands that have been identified to have therapeutic potential for the treatment of motor and non-motor symptoms of PD. In a different way, such agents may contribute to extending LD response and/or ameliorate LD-induced side effects.

Reciprocal Regulation of KCC2 Trafficking and Synaptic Activity.

The main inhibitory neurotransmitter receptors in the adult central nervous system (CNS) are type A γ-aminobutyric acid receptors (GABAARs) and glycine receptors (GlyRs). Synaptic responses mediated by GlyR and GABAAR display a hyperpolarizing shift during development. This shift relies mainly on the developmental up-regulation of the K+-Cl− co-transporter KCC2 responsible for the extrusion of Cl−. In mature neurons, altered KCC2 function—mainly through increased endocytosis—leads to the re-emergence of depolarizing GABAergic and glycinergic signaling, which promotes hyperexcitability and pathological activities. Identifying signaling pathways and molecular partners that control KCC2 surface stability thus represents a key step in the development of novel therapeutic strategies. Here, we present our current knowledge on the cellular and molecular mechanisms governing the plasma membrane turnover rate of the transporter under resting conditions and in response to synaptic activity. We also discuss the notion that KCC2 lateral diffusion is one of the first parameters modulating the transporter membrane stability, allowing for rapid adaptation of Cl− transport to changes in neuronal activity.

Evaluation of Aqueous Extract and Fractions from theSeed of Magonia Pubescens in Sleep Models, Anxiety and Depression in Mice

Many studies directly relate changes in sleep patterns to the quality of human health. Experimental studies suggest that changes in sleep may influence levels of cytokines that have massive studies related to their role in the inflammatory process. Sleep deprivation may alter the pattern of immune responses by inducing increased circulating levels of inflammatory markers such as interleukin-6 (IL-6), tumor necrosis factor (TNF-α), and C-reactive protein. Magonia pubescens (M.P.) is a typical plant of the Brazilian cerrado, popularly known as tingui or timbó do cerrado. Popular reports attest to the action of their extracts as facilitating agents in fish farms, due to their narcotic action in fish. Several plant extracts have sedative action, such as sleep inducers or mood disorders, such as anxiety and depression, as they have bioactive components capable of interacting with monoamines and their central nervous system receptors. This work evaluated the action of extracts of the seeds of M. pubescens in models of sleep, anxiety and depression in mice, the relationship of these effects with inflammatory cytokines. The seeds of M. pubescens were dried and submitted to the aqueous extraction process. The FPLC analysis of the extracts proved to be two protein populations.