Dopaminergic Properties Research Articles

A Study of Prevalence of Sexual Dysfunction in Patients Receiving Psychotropic Drugs

Background: Sexual dysfunction is the most common side effect associated with psychotropic drugs. It is a threat to patient’s quality of life and a major reason for non –compliance. Psychotropic agents can impair the sexual response in different ways due to their neurobiological mode of action. Prevalence rates of sexual side effects are extraordinarily difficult to estimate due to a variety of factors, such as the effect of the disorder being treated, co morbid disorders and baseline sexual dysfunction. Objectives: To study the association between sexual dysfunction and psychotropic drugs in patients using various psychotropic drugs like antidepressants, anti-psychotics, anti-cravings and anxiolytics. Methods: A cross sectional study was done among 200 patients. A self-designed semi structured questionnaire consisting of socio demographic details, relevant psychiatric history and Psychotropic – Related Sexual dysfunction questionnaire (PR Sex DQ – SALSEX) was used. The obtained data was entered in MS excel and analysed using SPSS software Results: Among 200 patients ,62.5% of males and 38.5% of females felt that their psychiatric medications were causing sexual side effects. Out of them 41.7% of men and 30.03 % of women. Conclusion: The most relevant groups for impairment are antidepressants and antipsychotics due to the serotonin agonistic and anti – dopaminergic properties as well as the prolactin increasing characteristics. The treatment of psychiatric disorders should follow a comprehensive treatment plan that anticipates a likely sexual dysfunction at the initiation of treatment.

Psychiatric Manifestations Secondary to the use of a Dopaminergic Agonist Antiparkinsonian: A Case Report

Psychiatric disorders in Parkinson's disease can be classified into two opposing categories: hypodopaminergic if related to dopaminergic denervation and hyperdopaminergic if related to dopaminergic treatment. In this context the aim of this clinical case study is to present the psychiatric manifestations due to the use of a dopaminergic agonist anti parkinsonian (piribedil). We report the clinical case of a 55-year-old patient, hypertensive on Amlodipine, suffering from a parkinsonian disorder for 4 years; presenting to the psychiatric consultation at Ibn Nafis Hospital for a behavioural disorder following the introduction of Piribedil (antiparkinsonian dopaminergic agonist). Most of the psychic side effects of antiparkinsonian drugs are linked to their central dopaminergic properties. These effects are secondary to excessive stimulation of mesocorticolimbic dopamine receptors and/or serotonin hyperactivity.

Effects of the antipsychotic quetiapine on sleep and breathing: a review of clinical findings and potential mechanisms.

Quetiapine is an antipsychotic medication indicated for schizophrenia and bipolar disorder. However, quetiapine also has hypnotic properties and as such is increasingly being prescribed at low doses 'off-label' in people with insomnia symptoms. Pharmacologically, in addition to its dopaminergic properties, quetiapine also modulates multiple other transmitter systems involved in sleep/wake modulation and potentially breathing. However, very little is known about the impact of quetiapine on obstructive sleep apnoea (OSA), OSA endotypes including chemosensitivity, and control of breathing. Given that many people with insomnia also have undiagnosed OSA, it is important to understand the effects of quetiapine on OSA and its mechanisms. Accordingly, this concise review covers the existing knowledge on the effects of quetiapine on sleep and breathing. Further, we highlight the pharmacodynamics of quetiapine and its potential to alter key OSA endotypes to provide potential mechanistic insight. Finally, an agenda for future research priorities is proposed to fill the current key knowledge gaps.

Huitlacoche (Ustilago maydis), an Iconic Mexican Fungal Resource: Biocultural Importance, Nutritional Content, Bioactive Compounds, and Potential Biotechnological Applications.

Worldwide, the fungus known as huitlacoche (Ustilago maydis (DC.) Corda) is a phytopathogen of maize plants that causes important economic losses in different countries. Conversely, it is an iconic edible fungus of Mexican culture and cuisine, and it has high commercial value in the domestic market, though recently there has been a growing interest in the international market. Huitlacoche is an excellent source of nutritional compounds such as protein, dietary fiber, fatty acids, minerals, and vitamins. It is also an important source of bioactive compounds with health-enhancing properties. Furthermore, scientific evidence shows that extracts or compounds isolated from huitlacoche have antioxidant, antimicrobial, anti-inflammatory, antimutagenic, antiplatelet, and dopaminergic properties. Additionally, the technological uses of huitlacoche include stabilizing and capping agents for inorganic nanoparticle synthesis, removing heavy metals from aqueous media, having biocontrol properties for wine production, and containing biosurfactant compounds and enzymes with potential industrial applications. Furthermore, huitlacoche has been used as a functional ingredient to develop foods with potential health-promoting benefits. The present review focuses on the biocultural importance, nutritional content, and phytochemical profile of huitlacoche and its related biological properties as a strategy to contribute to global food security through food diversification; moreover, the biotechnological uses of huitlacoche are also discussed with the aim of contributing to the use, propagation, and conservation of this valuable but overlooked fungal resource.

Impulse control disorders associated with dopaminergic drugs: A disproportionality analysis using vigibase

BackgroundDopamine receptor agonist drugs, which are used, for example, to treat Parkinson's disease (PD), increase the risk for impulse control disorders (ICDs), potentially resulting in devastating psychosocial consequences. It is unknown whether other drugs with dopaminergic properties also increase the risk for ICDs. This study assesses the disproportionality of reporting ICDs between drugs with dopaminergic properties and selected non-dopaminergic drugs. MethodsA case/non-case disproportionality analysis was performed, using data from VigiBase (1968–2020). Reports on ICDs as suspected adverse drug reactions (ADRs) were cases (n=852), and those with ADRs other than ICDs were non-cases (n=281,720). Relative reporting frequencies were expressed as adjusted reporting odds ratios (aRORs). Within the dopamine receptor agonists, the relationship between reporting odds ratios and dopamine receptor occupancy was explored. ResultsA high disproportionality was found for reporting ICDs for all dopaminergic drugs (aROR 20.4 [95% CI 17.4–24.1]) compared to non-dopaminergic drugs. In pharmacotherapeutic subgroups, a high disproportionality was found for primary dopaminergic agents used in PD (aROR 52.1 [95% CI 44.1–61.5]), and to a lesser extent for ADHD psychostimulants and antidepressants (aROR 5.8 [95% 4.1–8.3] and aROR 3.9 [95% CI 2.9–5.6], respectively). There was no difference in reporting by consumers and healthcare professionals. The highest disproportionality was found for the dopamine receptor agonists pramipexole and ropinirole. ConclusionsA signal of disproportion in ICD occurrence was found among all investigated drugs with dopaminergic properties, highlighting the importance of counselling and monitoring for ICDs when prescribing dopaminergic drugs.

Efficacy of Addition of Atomoxetine to Speech Therapy in Stuttering Severity of Children Aged 4-12 Years: A Double-Blind Randomized ControlledTrial.

Objectives Stuttering is a common problem at all ages that is required to be treated since childhood. Atomoxetine is currently used for the treatment of attention deficit hyperactivity disorder (ADHD). It can be effective for the treatment of stuttering due to its selective inhibition of norepinephrine reuptake and dopaminergic properties. Therefore, this randomized controlled trial aimed to evaluate the effect of atomoxetine on children’s stuttering.Materials & MethodsThe children aged 4-12 years and diagnosed with stuttering, referred to Pediatric Neurology and Psychology clinics , were randomly divided into experimental (n=50) and control (n=50) groups. One group received atomoxetine plus speech therapy, and the other group received only speech therapy. Both groups completed the Stuttering Severity Instrument-Fourth Edition at the baseline (on the first visit) and 3 months after the intervention. The results were compared between the two groups using SPSS software (version 21).ResultsMost of the children (67%) were male. Moreover, 24%, 46%, and 30% of the subjects were within the age ranges of < 60, 60-95, and > 95 months, respectively. Nearly half of the patients (52%) had a positive family history of stuttering. Stuttering severity was the highest within the age range of 60-95 months, in left-handed children, in those who used formula, and in those who felt insecure in the family; however, there was no difference in stuttering severity based on child’s gender, concomitant ADHD, multilingualism, facial or movement tics, sleeping hours, and using teats. The mean stuttering severity reduced in both groups (P<0.001), with a greater decrease in the experimental group, compared to that of the control group (P=0.011).ConclusionAtomoxetine plus speech therapy is effective for the treatment of children’s stuttering and can be used as a complementary treatment strategy in such patients.

Current research opportunities for potential phytotherapeutic agents for the treatment of pathologies of the female reproductive system

Introduction and aim. Herbal medicine is prescribed for various disorders of the menstrual cycle (uterine bleeding, dysmenorrhea), for the treatment of premenstrual and climacteric syndromes, inflammatory diseases of the genital organs, mastopathy and mastalgia and other pathological conditions. The aim of the study is to analysis and generalization of data from professional literature and own experience in the treatment of patients with pathologies of the female reproductive system by phytotherapeutic methods, taking into account the influence of medicinal plants on various links in the pathogenesis of the disease, as well as making recommendations for improvement and prospects for the use of phytotherapy in the treatment of this pathology. Material and methods. To make an analysis of literary sources of domestic and foreign authors about usage of medicinal plants for the treatment of pathologies of the female reproductive system. Analysis of the literature. In the treatment of primary (spasmodic) dysmenorrhea, herbal remedies with an antispasmodic, analgesic, hormone-mimetic effects are prescribed. It can be Chamomile (Matricaria chamomilla L.), Achillea millefolium, commonly known as yarrow, Viburnum, Shepherd’s purse (Capsella bursa-pastoris), Greater celandine, Atropa belladonna, Hyoscyamus niger, commonly known as henbane, black henbane, or stinking nightshade and Abraham’s tree. Many plants have bactericidal activity, and this property is used in the treatment of inflammatory diseases of the mucous membranes and skin. Such properties are possessed by flowers of Chamomile (Matricaria chamomilla L.), Calendula officinalis, infusion of Medicinal sage (Salvia officinalis L.). For the treatment of functional hyperprolactinemia phytopreparations are also successfully used. It is known that the medicinal plant Vitex agnus castus has dopaminergic properties, selectively blocking prolactin synthesis, and reduces follicle stimulating hormone levels. Strychnos ignatia, Caulophyllum thalictroides, European cyclamen, Lilium tigrinum, Iris versicolor provide a complex effect on the female body, effectively reduces the level of prolactin and the severity of mastalgia, which is confirmed not only by clinical data, but also by mammography data in fibrocystic breast disease. For the treatment of climacteric syndrome, a large number of medicinal plants are used, in particular, the most popular is the Cimicifuga racemose. Conclusion. The effectiveness of phytotherapeutic drugs has been verified by many clinical trials. Modern phytotherapy is becoming more widespread in clinical practice, as an alternative to drug treatment.

Cabergoline in Treatment of Methamphetamine-Dependent Patients and Its Effect on Serum Level of Glial Cell-Derived Neurotrophic Factor: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

Background: Methamphetamine use disorder is an important public health problem, especially in the younger generation, and associated with various psychiatric, cognitive, social, economic, and legal issues. Cabergoline, a drug with dopaminergic properties and long half-life, has been considered for the treatment of stimulant dependence. The systemic use of cabergoline has been shown to increase glial cell-derived neurotrophic factor (GDNF) expression. Objective: In this study, we investigated the effects of cabergoline on the serum level of GDNF and its effect on abstaining from methamphetamine in individuals treated for methamphetamine use disorder. Method: Sixty male subjects with methamphetamine use disorder were randomly assigned to 2 groups receiving cabergoline and placebo, respectively. During a 12-week follow-up, we compared the serum level of GDNF, urine test results for methamphetamine use, and depression scale between the 2 groups. Results: We found that serum GDNF was lower in subjects who used methamphetamine than healthy subjects (p < 0.0001). However, the serum level of GDNF was not associated with cabergoline use. The rising number of cases testing positive in the placebo group showed a trend resulting in no significant difference between cases testing positive and negative (p = 0.585) at the end of week 12. In the verum group, however, the significantly high number of cases who tested negative – sober – for substances observed in early stages (weeks 7–8) continued to remain significantly higher till the end of the study (p = 0.043), resembling an association between treatment with cabergoline and remaining sober. Although reduced during treatment, recovery from depression was not associated with cabergoline treatment. Conclusion: The findings of this study confirmed the effect of cabergoline in reducing methamphetamine use. However, a serum level of the GDNF increase, as seen in animal studies, was not associated with cabergoline treatment of human subjects. This study was registered at the Iranian Registry of Clinical Trials (TRN:IRCT2015050422077N1, October 06, 2015, https://en.irct.ir/trial/19134).

Grafts Derived from an α-Synuclein Triplication Patient Mediate Functional Recovery but Develop Disease-Associated Pathology in the 6-OHDA Model of Parkinson's Disease.

Background:Human induced pluripotent stem cells (hiPSCs) have been proposed as an alternative source for cell replacement therapy for Parkinson’s disease (PD) and they provide the option of using the patient’s own cells. A few studies have investigated transplantation of patient-derived dopaminergic (DA) neurons in preclinical models; however, little is known about the long-term integrity and function of grafts derived from patients with PD.Objective:To assess the viability and function of DA neuron grafts derived from a patient hiPSC line with an α-synuclein gene triplication (AST18), using a clinical grade human embryonic stem cell (hESC) line (RC17) as a reference control.Methods:Cells were differentiated into ventral mesencephalic (VM)-patterned DA progenitors using an established GMP protocol. The progenitors were then either terminally differentiated to mature DA neurons in vitro or transplanted into 6-hydroxydopamine (6-OHDA) lesioned rats and their survival, maturation, function, and propensity to develop α-synuclein related pathology, were assessed in vivo.Results:Both cell lines generated functional neurons with DA properties in vitro. AST18-derived VM progenitor cells survived transplantation and matured into neuron-rich grafts similar to the RC17 cells. After 24 weeks, both cell lines produced DA-rich grafts that mediated full functional recovery; however, pathological changes were only observed in grafts derived from the α-synuclein triplication patient line.Conclusion:This data shows proof-of-principle for survival and functional recovery with familial PD patient-derived cells in the 6-OHDA model of PD. However, signs of slowly developing pathology warrants further investigation before use of autologous grafts in patients.

Dopamine-Related Measurements From Both IPSC-Derived Dopaminergic Neurons and [18F]-FDOPA PET in Patients With Gaucher Disease With and Without Parkinsonism

Derivation of dopaminergic neurons from patients' induced pluripotent stem-cells (iPSCs) can enhance our understanding of the biology of dopamine-related illnesses, such as schizophrenia and Parkinson disease (PD), and provide transformative information for biological psychiatry research. However, whether dopaminergic properties of these neurons capture interindividual variation in central dopamine functioning is unknown. [18F]-FDOPA PET measures presynaptic dopamine synthesis capacity and vesicular storage, identifying hallmark diminished striatal dopaminergic content in idiopathic PD. Since mutations in GBA1, the gene implicated in Gaucher disease (GD), are an important risk factor for parkinsonism, we evaluated individuals with both GD and a family history of PD, testing for correspondence between dopamine-related measurements from both iPSC-derived neurons and molecular neuroimaging of the living brain.

A short history of the 5-HT2C receptor: from the choroid plexus to depression, obesity and addiction treatment.

This paper is a personal account on the discovery and characterization of the 5-HT2C receptor (first known as the 5-HT1C receptor) over 30years ago and how it translated into a number of unsuspected features for a G protein-coupled receptor (GPCR) and a diversity of clinical applications. The 5-HT2C receptor is one of the most intriguing members of the GPCR superfamily. Initially referred to as 5-HT1CR, the 5-HT2CR was discovered while studying the pharmacological features and the distribution of [3H]mesulergine-labelled sites, primarily in the brain using radioligand binding and slice autoradiography. Mesulergine (SDZ CU-085), was, at the time, best defined as a ligand with serotonergic and dopaminergic properties. Autoradiographic studies showed remarkably strong [3H]mesulergine-labelling to the rat choroid plexus. [3H]mesulergine-labelled sites had pharmacological properties different from, at the time, known or purported 5-HT receptors. In spite of similarities with 5-HT2 binding, the new binding site was called 5-HT1C because of its very high affinity for 5-HT itself. Within the following 10years, the 5-HT1CR (later named 5-HT2C) was extensively characterised pharmacologically, anatomically and functionally: it was one of the first 5-HT receptors to be sequenced and cloned. The 5-HT2CR is a GPCR, with a very complex gene structure. It constitutes a rarity in the GPCR family: many 5-HT2CR variants exist, especially in humans, due to RNA editing, in addition to a few 5-HT2CR splice variants. Intense research led to therapeutically active 5-HT2C receptor ligands, both antagonists (or inverse agonists) and agonists: keeping in mind that a number of antidepressants and antipsychotics are 5-HT2CR antagonists/inverse agonists. Agomelatine, a 5-HT2CR antagonist is registered for the treatment of major depression. The agonist Lorcaserin is registered for the treatment of aspects of obesity and has further potential in addiction, especially nicotine/ smoking. There is good evidence that the 5-HT2CR is involved in spinal cord injury-induced spasms of the lower limbs, which can be treated with 5-HT2CR antagonists/inverse agonists such as cyproheptadine or SB206553. The 5-HT2CR may play a role in schizophrenia and epilepsy. Vabicaserin, a 5-HT2CR agonist has been in development for the treatment of schizophrenia and obesity, but was stopped. As is common, there is potential for further indications for 5-HT2CR ligands, as suggested by a number of preclinical and/or genome-wide association studies (GWAS) on depression, suicide, sexual dysfunction, addictions and obesity. The 5-HT2CR is clearly affected by a number of established antidepressants/antipsychotics and may be one of the culprits in antipsychotic-induced weight gain.

Safinamide and glutamate release: New insights

s / Parkinsonism and Related Disorders 22 (2016) e149ee192 e177 Sciences, University of Ferrara, Ferrara, Italy; Consultant, Gallarate, Varese, Italy; RD Department of Medical Sciences, University of Ferrara, Ferrara, Italy; Consultant, Gallarate, Varese, Italy Objectives: Safinamide (Xadago®) is a novel drug recently approved as add-on therapy to levodopa in midto late-stage Parkinson's disease. Xadago® shows a unique dual mechanism of action: it has both dopaminergic properties (highly selective, potent and reversible inhibition of monoamine oxidase-B) and non-dopaminergic properties (state and usedependent sodium channel blockade causing inhibition of excessive glutamate release). The study aim was to evaluate the effect of safinamide on stimulated glutamate release in rat hippocampus at doses giving free brain concentrations able to block sodium channels and to provide a PK/PD approach to support its clinical relevance on overactive glutamate release inhibition. Methods: Glutamate release, stimulated by veratridine in the hippocampus of rats, was measured by in vivo microdialysis. Results: Safinamide was able to significantly inhibit the glutamate release in a dose-dependent manner and the relative measured free brain concentrations (0.3-2.2 mM) support the inhibition of sodium channels (2050% Ki. A functional blockade of sodium channels suggests that pharmacodynamically active concentrations of safinamide are available at the target sites in the brain: in rodents significant protection (50-70%) from convulsions was found when free brain concentration of 0.37-1.4 mM was reached. At the recommended clinical doses (50 and 100 mg) the estimated human free brain safinamide concentrations (0.21-1.92 mM) overlap the range of measured free brain concentrations effective in inhibiting overactive glutamate release in animals. Conclusions: These results clearly support the non-dopaminergic aspects of Xadago® mode of action in rats, likely relevant also in humans. P 6.004. 4I (N-(3-CHLORO-2-METHYLPHENYL) QUINOXALIN-2-CARBOXAMIDE), A NOVEL 5-HT3 RECEPTOR ANTAGONIST ALLEVIATES DEPRESSIVE BEHAVIOR EVOKED IN STREPTOZOTOCIN-INDUCED DIABETIC MICE: ROLE OF OXIDATIVE STRESS Deepali Gupta, Mahesh Radhakrishnan. Department of Pharmacy, Pilani,

Clinical pharmacology review of safinamide for the treatment of Parkinson's disease.

Safinamide (Xadago™) is an oral α-aminoamide derivative marketed for the treatment of Parkinson's disease (PD). The drug has both dopaminergic properties, namely highly selective and reversible inhibition of monoamine oxidase B, and nondopamimetic properties, namely selective sodium channel blockade and calcium channel modulation, with consequent inhibition of excessive glutamate release. In 2014, safinamide was approved in the European Economic Area, as "an add-on therapy to stable dose levodopa, alone or in combination with other PD therapies in mid- to late-stage-fluctuating PD patients." In addition, evidence has been provided for safinamide in the treatment of motor symptoms in early PD patients. This article summarizes the pharmacological properties, development program, clinical indications for PD treatment, stratified according to several disease's stages and the safety profile of safinamide. A meta-analysis of the most frequent adverse events among Phase III trials has been also performed.

Silicon surface biofunctionalization with dopaminergic tetrahydroisoquinoline derivatives

In this work we grafted vinyl- and azido-terminated tetrahydroisoquinolines (compounds 1 and 2, respectively) onto HSi(111) silicon wafers obtaining highly stable modified surfaces. A double bond was incorporated into the tetrahydroisoquinoline structure of 1 to be immobilized by a light induced hydrosilylation reaction on hydrogen-terminated Si(111). The best results were obtained employing a polar solvent (DMSO), rather than a non-polar solvent (toluene). The azide derivative 2 was grafted onto alkenyl-terminated silicon substrates with copper-catalyzed azide-alkyne cycloaddition (CuAAC). Atomic force microscopy (AFM), contact angle goniometry (CA) and X-ray photoemission spectroscopy (XPS) were used to demonstrate the incorporation of 1 and 2 into the surfaces, study the morphology of the modified surfaces and to calculate the yield of grafting and surface coverage. CA measurements showed the increase in the surface hydrophobicity when 1 or 2 were incorporated into the surface. Moreover, compounds 1 and 2 were prepared starting from 1-(p-nitrophenyl)tetrahydroisoquinoline 3 under smooth conditions and in good yields. The structures of 1 and 2 were designed with a reduced A-ring, two substituents at positions C-6 and C-7, an N-methyl group and a phenyl moiety at C-1 in order to provide a high affinity against dopaminergic receptors. Moreover, O-demethylation of 1 was carried out once it was adsorbed onto the surface by treatment with BBr3. The method presented constitutes a simple, easily reproducible and high yielding approach for grafting complex organic biomolecules with dopaminergic properties onto silicon surfaces.

Optogenetics and the circuit dynamics of psychiatric disease.

Optogenetics and the circuit dynamics of psychiatric disease.

Safinamide: first global approval.

Safinamide (Xadago(®)) is an oral α-aminoamide derivative developed by Newron for the treatment of Parkinson's disease (PD). The drug has both dopaminergic properties (highly selective and reversible inhibition of monoamine oxidase-B) and non-dopaminergic properties (selective sodium channel blockade and calcium channel modulation, with consequent inhibition of excessive glutamate release). Safinamide is approved in the EU, Iceland, Lichtenstein and Norway, as an add-on therapy to stable-dose levodopa, alone or in combination with other PD therapies in mid- to late-stage fluctuating PD patients; regulatory submissions have also been filed in the USA and Switzerland for its use in this indication. Additional submissions have been made in the USA, Iceland, Lichtenstein, Norway and Switzerland for early-stage PD. Safinamide has also undergone phase II investigation in PD patients with drug-induced dyskinesia (France, Germany, Austria, Canada and South Africa) or cognitive impairment (USA and Spain). This article summarizes the milestones in the development of safinamide leading to its first approval for PD.

Pyrolysed 3D‐Carbon Scaffolds Induce Spontaneous Differentiation of Human Neural Stem Cells and Facilitate Real‐Time Dopamine Detection

Structurally patterned pyrolysed three‐dimensional carbon scaffolds (p3D‐carbon) are fabricated and applied for differentiation of human neural stem cells (hNSCs) developed for cell replacement therapy and sensing of released dopamine. In the absence of differentiation factors (DF) the pyrolysed carbon material induces spontaneous hNSC differentiation into mature dopamine‐producing neurons and the 3D‐topography promotes neurite elongation. In the presence and absence of DF, ≈73–82% of the hNSCs obtain dopaminergic properties on pyrolysed carbon, a to‐date unseen efficiency in both two‐dimensional (2D) and 3D environment. Due to conductive properties and 3D environment, the p3D‐carbon serves as a neurotransmitter trap, enabling electrochemical detection of a significantly larger dopamine fraction released by the hNSC derived neurons than on conventional 2D electrodes. This is the first study of its kind, presenting new conductive 3D scaffolds that provide highly efficient hNSC differentiation to dopaminergic phenotype combined with real‐time in situ confirmation of the fate of the hNSC‐derived neurons.

Antagonizing Nogo-receptor 1 promotes the number of cultured dopaminergic neurons and elongates their neurites

The myelin-associated protein Nogo-A and its receptor Nogo-receptor 1 (NgR1) are known as potent growth inhibitors of the adult central nervous system (CNS). Nogo-A is mostly expressed on the surface of oligodendrocytes, but is also found in neurons of the adult and developing CNS. This observation suggests that Nogo-A serves additional functions in the brain. Hence, in the present study, we investigated the effects of antagonizing NgR1 on cultured organotypic and dissociated dopaminergic neurons. For that purpose ventral mesencephalic cultures from E14 rat embryos were grown in absence or presence of the NgR1 antagonist NEP1-40 for 1 week. Treatment with NEP1-40 significantly increased cell densities of tyrosine hydroxylase-immunoreactive neurons. Moreover, organotypic ventral mesencephalic cultures displayed a significantly bigger volume after NEP1-40 treatment. Morphological analysis of tyrosine hydroxylase-positive neurons disclosed longer neurites and higher numbers of primary neurites in dissociated cultures incubated with NEP1-40, whereas soma size was not changed. In conclusion, our findings demonstrate that interfering with Nogo-A signaling by antagonizing NgR1 modulates dopaminergic neuron properties during development. These observations highlight novel aspects of the role of Nogo-A in the CNS and might have an impact in the context of Parkinson's disease.

NURR1 in Parkinson disease—from pathogenesis to therapeutic potential

In Parkinson disease (PD), affected midbrain dopamine (DA) neurons lose specific dopaminergic properties before the neurons die. How the phenotype of DA neurons is normally established and the ways in which pathology affects the maintenance of cell identity are, therefore, important considerations. Orphan nuclear receptor NURR1 (NURR1, also known as NR4A2) is involved in the differentiation of midbrain DA neurons, but also has an important role in the adult brain. Emerging evidence indicates that impaired NURR1 function might contribute to the pathogenesis of PD: NURR1 and its transcriptional targets are downregulated in midbrain DA neurons that express high levels of the disease-causing protein α-synuclein. Clinical and experimental data indicate that disrupted NURR1 function contributes to induction of DA neuron dysfunction, which is seen in early stages of PD. The likely involvement of NURR1 in the development and progression of PD makes this protein a potentially interesting target for therapeutic intervention.

Enhanced dopamine release by mesenchymal stem cells reprogrammed neuronally by the modulators of SMAD signaling, chromatin modifying enzymes, and cyclic adenosine monophosphate levels

Recently, using the chemical genetics approach for cell reprogramming, via the combination of small molecule modulators of chromatin modifying enzymes, specific SMAD signaling pathways, and cyclic adenosine monophosphate levels, we have been able to generate neuronallike cells predominantly positive to mature neuronal and dopaminergic markers. This study aimed to characterize further the dopaminergic properties of neurally induced (NI) human bone marrow-derived mesenchymal stem cells (hMSCs) and to determine whether addition of sonic hedgehog (SHH)/fibroblast growth factor 8 (FGF8) to NI medium could promote further dopaminergic maturation. Dopaminergic differentiation was evaluated by immunocytochemistry, reverse transcription-polymerase chain reaction, Western blot, and enzyme-linked immunosorbent assay. Results demonstrated that release of dopamine by NI-hMSCs differentiated with SMAD inhibitor supplementation significantly increased from picogram to nanogram levels, with a tendency of further increase when supplemented by SHH/FGF8. Direct generation of dopaminergic cells from adult hMSCs by using this reprogramming approach may have significant implications for understanding the mechanism underlying cell plasticity and may opennew potentialities for cell replacement therapies.