RESUMO
Parkinson's disease (PD) is one of the most rapidly growing neurological disorders [...].
Assuntos
Doença de Parkinson , HumanosRESUMO
The mechanism of nigral dopaminergic neuronal degeneration in Parkinson's disease (PD) is unknown. One of the pathological characteristics of the disease is the deposition of α-synuclein (α-syn) that occurs in the brain from both familial and sporadic PD patients. This paper constitutes a narrative review that takes advantage of information related to genes (SNCA, LRRK2, GBA, UCHL1, VPS35, PRKN, PINK1, ATP13A2, PLA2G6, DNAJC6, SYNJ1, DJ-1/PARK7 and FBXO7) involved in familial cases of Parkinson's disease (PD) to explore their usefulness in deciphering the origin of dopaminergic denervation in many types of PD. Direct or functional interactions between genes or gene products are evaluated using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. The rationale is to propose a map of the interactions between SNCA, the gene encoding for α-syn that aggregates in PD, and other genes, the mutations of which lead to early-onset PD. The map contrasts with the findings obtained using animal models that are the knockout of one of those genes or that express the mutated human gene. From combining in silico data from STRING-based assays with in vitro and in vivo data in transgenic animals, two likely mechanisms appeared: (i) the processing of native α-syn is altered due to the mutation of genes involved in vesicular trafficking and protein processing, or (ii) α-syn mutants alter the mechanisms necessary for the correct vesicular trafficking and protein processing. Mitochondria are a common denominator since both mechanisms require extra energy production, and the energy for the survival of neurons is obtained mainly from the complete oxidation of glucose. Dopamine itself can result in an additional burden to the mitochondria of dopaminergic neurons because its handling produces free radicals. Drugs acting on G protein-coupled receptors (GPCRs) in the mitochondria of neurons may hopefully end up targeting those receptors to reduce oxidative burden and increase mitochondrial performance. In summary, the analysis of the data of genes related to familial PD provides relevant information on the etiology of sporadic cases and might suggest new therapeutic approaches.
Assuntos
Doença de Parkinson/genética , Animais , Animais Geneticamente Modificados , Neurônios Dopaminérgicos/metabolismo , Humanos , Doença de Parkinson/metabolismo , Substância Negra/metabolismo , alfa-Sinucleína/metabolismoRESUMO
Rhes is one of the most interesting genes regulated by thyroid hormones that, through the inhibition of the striatal cAMP/PKA pathway, acts as a modulator of dopamine neurotransmission. Rhes mRNA is expressed at high levels in the dorsal striatum, with a medial-to-lateral expression gradient reflecting that of both dopamine D2 and adenosine A2A receptors. Rhes transcript is also present in the hippocampus, cerebral cortex, olfactory tubercle and bulb, substantia nigra pars compacta (SNc) and ventral tegmental area of the rodent brain. In line with Rhes-dependent regulation of dopaminergic transmission, data showed that lack of Rhes enhanced cocaine- and amphetamine-induced motor stimulation in mice. Previous studies showed that pharmacological depletion of dopamine significantly reduces Rhes mRNA levels in rodents, non-human primates and Parkinson's disease (PD) patients, suggesting a link between dopaminergic innervation and physiological Rhes mRNA expression. Rhes protein binds to and activates striatal mTORC1, and modulates L-DOPA-induced dyskinesia in PD rodent models. Finally, Rhes is involved in the survival of mouse midbrain dopaminergic neurons of SNc, thus pointing towards a Rhes-dependent modulation of autophagy and mitophagy processes, and encouraging further investigations about mechanisms underlying dysfunctions of the nigrostriatal system.
Assuntos
Neurônios Dopaminérgicos/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Doença de Parkinson/metabolismo , Animais , Autofagia , Encéfalo/metabolismo , Encéfalo/patologia , Corpo Estriado/metabolismo , Corpo Estriado/patologia , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Proteínas de Ligação ao GTP/deficiência , Proteínas de Ligação ao GTP/genética , Regulação da Expressão Gênica , Humanos , Levodopa/metabolismo , Camundongos , Camundongos Knockout , Mitofagia , Modelos Neurológicos , Degeneração Neural/genética , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Doença de Parkinson/genética , Doença de Parkinson/patologia , Transtornos Parkinsonianos/genética , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais , Transmissão SinápticaRESUMO
Ras homolog enriched in striatum (Rhes) is a protein that exerts important physiological functions and modulates psychostimulant drug effects. On this basis, the object of this study was to assess 3,4-methylenedioxymethamphetamine (MDMA) effects on microglial (CD11b) and astroglial (GFAP) activation and on dopamine neuron degeneration (TH) in wild-type (WT) and Rhes knockout (KO) male and female mice of different ages. Motor activity was also evaluated. Adult (3 months) MDMA-treated mice displayed an increase in GFAP-positive cells in striatum (STR), whereas the substantia nigra pars compacta (SNc) was affected only in male mice. In these mice, the increase of CD11b was more extensive including STR, SNc, motor cortex (CTX), ventral tegmental area (VTA), and nucleus accumbens (NAc). MDMA administration also affected TH immunoreactivity in both STR and SNc of male but not female WT and Rhes KO mice. In middle-aged mice (12 months), MDMA administration further increased GFAP and CD11b and decreased TH immunoreactivity in STR and SNc of all mice. Finally, MDMA induced a higher increase of motor activity in adult Rhes KO male, but not female mice. The results show that Rhes protein plays an important role on MDMA-mediated neuroinflammation and neurodegeneration dependent on gender and age, and confirm the important role of Rhes protein in neuroinflammatory and neurodegenerative processes.
Assuntos
Neurônios Dopaminérgicos/efeitos dos fármacos , Proteínas de Ligação ao GTP/genética , Alucinógenos/efeitos adversos , Inflamação/induzido quimicamente , N-Metil-3,4-Metilenodioxianfetamina/efeitos adversos , Doenças Neurodegenerativas/induzido quimicamente , Fatores Etários , Animais , Neurônios Dopaminérgicos/patologia , Feminino , Deleção de Genes , Inflamação/genética , Inflamação/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Fatores SexuaisRESUMO
Adenosine is an endogenous purine nucleoside that regulates several physiological functions, at the central and peripheral levels. Besides, adenosine has emerged as a major player in the regulation of motor behavior. In fact, adenosine receptors of the A2A subtype are highly enriched in the caudate-putamen, which is richly innervated by dopamine. Moreover, several studies in experimental animals have consistently demonstrated that the pharmacological antagonism of A2A receptors has a facilitatory influence on motor behavior. Taken together, these findings have envisaged A2A receptors as a promising target for symptomatic therapies aimed at ameliorating motor deficits. Accordingly, A2A receptor antagonists have been extensively studied as new agents for the treatment of Parkinson's disease (PD), the epitome of motor disorders. In this review, we provide an overview of the effects that adenosine A2A receptor antagonists elicit in rodent and primate experimental models of PD, with regard to the counteraction of motor deficits as well as to manifestation of dyskinesia and motor fluctuations. Moreover, we briefly present the results of clinical trials of A2A receptor antagonists in PD patients experiencing motor fluctuations, with particular regard to dyskinesia. Finally, we discuss the interaction between A2A receptor antagonists and serotonin receptor agonists, since combined administration of these drugs has recently emerged as a new potential therapeutic strategy in the treatment of dyskinesia.
Assuntos
Discinesia Induzida por Medicamentos/metabolismo , Doença de Parkinson/metabolismo , Receptor A2A de Adenosina/metabolismo , Animais , Antiparkinsonianos/efeitos adversos , Discinesia Induzida por Medicamentos/fisiopatologia , Humanos , Levodopa/efeitos adversos , Doença de Parkinson/fisiopatologiaRESUMO
BACKGROUND: Here we aimed to evaluate: (1) Rhes mRNA expression in mouse midbrain, (2) the effect of Rhes deletion on the number of dopamine neurons, (3) nigrostriatal-sensitive behavior during aging in knockout mice. METHODS: Radioactive in situ hybridization was assessed in adult mice. The beam-walking test was executed in 3-, 6- and 12-month-old mice. Immunohistochemistry of midbrain tyrosine hydroxylase (TH)-positive neurons was performed in 6- and 12-month-old mice. RESULTS: Rhes mRNA is expressed in TH-positive neurons of SNpc and the ventral tegmental area. Moreover, lack of Rhes leads to roughly a 20% loss of nigral TH-positive neurons in both 6- and 12-month-old mutants, when compared with their age-matched controls. Finally, lack of Rhes triggers subtle alterations in motor performance and coordination during aging. CONCLUSIONS: Our findings indicate a fine-tuning role of Rhes in regulating the number of TH-positive neurons of the substantia nigra and nigrostriatal-sensitive motor behavior during aging.
Assuntos
Envelhecimento/metabolismo , Corpo Estriado/metabolismo , Neurônios Dopaminérgicos/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Desempenho Psicomotor/fisiologia , Substância Negra/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Animais , Comportamento Animal/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
BACKGROUND: The serotonin 5-HT1A/1B receptor agonist eltoprazine suppressed dyskinetic-like behavior in animal models of Parkinson's disease (PD) but simultaneously reduced levodopa (l-dopa)-induced motility. Moreover, adenosine A2A receptor antagonists, such as preladenant, significantly increased l-dopa efficacy in PD without exacerbating dyskinetic-like behavior. OBJECTIVES: We evaluated whether a combination of eltoprazine and preladenant may prevent or suppress l-dopa-induced dyskinesia, without impairing l-dopa's efficacy in relieving motor signs, in 2 PD models: unilateral 6-hydroxydopamine-lesioned rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. METHODS: Rotational behavior and abnormal involuntary movements, or disability and l-dopa-induced dyskinesia were evaluated in 6-hydroxydopamine-lesioned rats and MPTP-treated monkeys, respectively. Moreover, in the rodent striatum, induction of immediate-early gene zif-268, an index of long-term changes, was correlated with dyskinesia. RESULTS: In 6-hydroxydopamine-lesioned rats, combined administration of l-dopa (4 mg/kg) plus eltoprazine (0.6 mg/kg) plus preladenant (0.3 mg/kg) significantly prevented or reduced dyskinetic-like behavior without impairing motor activity. Zif-268 was increased in the striatum of rats treated with l-dopa and l-dopa plus preladenant compared with vehicle. In contrast, rats treated with eltoprazine (with or without preladenant) had lower zif-268 activation after chronic treatment in both the dyskinetic and l-dopa-non-primed groups. Moreover, acute l-dopa plus eltoprazine plus preladenant prevented worsening of motor performance (adjusting step) and sensorimotor integration deficit. Similar results were obtained in MPTP-treated monkeys, where a combination of preladenant with eltoprazine was found to counteract dyskinesia and maintain the full therapeutic effects of a low dose of l-dopa. CONCLUSIONS: Our results suggest a promising nondopaminergic pharmacological strategy for the treatment of dyskinesia in PD. © 2016 International Parkinson and Movement Disorder Society.
Assuntos
Antiparkinsonianos/farmacologia , Comportamento Animal/efeitos dos fármacos , Discinesia Induzida por Medicamentos/tratamento farmacológico , Levodopa/farmacologia , Doença de Parkinson/tratamento farmacológico , Piperazinas/farmacologia , Pirimidinas/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Triazóis/farmacologia , Animais , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/efeitos adversos , Modelos Animais de Doenças , Quimioterapia Combinada , Discinesia Induzida por Medicamentos/prevenção & controle , Feminino , Levodopa/administração & dosagem , Levodopa/efeitos adversos , Macaca fascicularis , Masculino , Piperazinas/administração & dosagem , Pirimidinas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Agonistas do Receptor de Serotonina/administração & dosagem , Triazóis/administração & dosagemRESUMO
The glutamate metabotropic receptor 5 (mGluR5) and the adenosine A2A receptor (A2A R) represent major non-dopaminergic therapeutic targets in Parkinson's disease (PD) to improve motor symptoms and slow down/revert disease progression. The 6-hydroxydopamine rat model of PD was used to determine/compare the neuroprotective and behavioral impacts of single and combined administration of one mGluR5 antagonist, 2-methyl-6-(phenylethynyl)pyridine (MPEP), and two A2A R antagonists, (E)-phosphoric acid mono-[3-[8-[2-(3-methoxyphenyl)vinyl]-7-methyl-2,6-dioxo-1-prop-2-ynyl-1,2,6,7-tetrahydropurin-3-yl]propyl] (MSX-3) and 8-ethoxy-9-ethyladenine (ANR 94). Chronic treatment with MPEP or MSX-3 alone, but not with ANR 94, reduced the toxin-induced loss of dopaminergic neurons in the substantia nigra pars compacta. Combining MSX-3 and MPEP further improved the neuroprotective effect of either antagonists. At the behavioral level, ANR 94 and MSX-3 given alone significantly potentiated L-DOPA-induced turning behavior. Combination of either A2A R antagonists with MPEP synergistically increased L-DOPA-induced turning. This effect was dose-dependent and required subthreshold drug concentration, which per se had no motor stimulating effect. Our findings suggest that co-treatment with A2A R and mGluR5 antagonists provides better therapeutic benefits than those produced by either drug alone. Our study sheds some light on the efficacy and advantages of combined non-dopaminergic PD treatment using low drug concentration and establishes the basis for in-depth studies to identify optimal doses at which these drugs reach highest efficacy. Combined treatment with low concentrations of known adenosine A2A receptor (A2A R) and metabotropic glutamate receptor (mGluR5) antagonists results in a therapeutic benefit and provides better results than those produced by either drug given alone, both in terms of motor performance and neuroprotection. Future trials should involve careful optimization of drug combinations and concentrations that may avoid the emergence of debilitating side effects and slow-down/revert disease progression.
Assuntos
Levodopa/administração & dosagem , Neurônios/patologia , Fármacos Neuroprotetores/administração & dosagem , Transtornos Parkinsonianos/tratamento farmacológico , Antagonistas de Receptores Purinérgicos P1/administração & dosagem , Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores , Adenina/administração & dosagem , Adenina/análogos & derivados , Animais , Sistemas de Liberação de Medicamentos/métodos , Sinergismo Farmacológico , Masculino , Neurônios/efeitos dos fármacos , Transtornos Parkinsonianos/patologia , Transtornos Parkinsonianos/psicologia , Piridinas/administração & dosagem , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Rotação , Resultado do Tratamento , Xantinas/administração & dosagemRESUMO
The clinical manifestation of Parkinson's disease (PD) appears when neurodegeneration is already advanced, compromising the efficacy of disease-modifying treatment approaches. Biomarkers to identify the early stages of PD are therefore of paramount importance for the advancement of the therapy of PD. In the present study, by using a mouse model of PD obtained by subchronic treatment with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and the clearance inhibitor probenecid (MPTPp), we identified prodromal markers of PD by combining in vivo positron emission tomography (PET) imaging and ex vivo immunohistochemistry. Longitudinal PET imaging of the dopamine transporter (DAT) by [18F]-N-(3-fluoropropyl)-2ß-carboxymethoxy-3ß-(4-iodophenyl) nortropane ([18F]-FP-CIT), and brain glucose metabolism by 2-deoxy-2-[18F]-fluoroglucose ([18F]-FDG) were performed before MPTPp treatment and after 1, 3, and 10 MPTPp administrations, in order to assess relation between dopamine neuron integrity and brain connectivity. The results show that in vivo [18F]-FP-CIT in the dorsal striatum was not modified after the first administration of MPTPp, tended to decrease after 3 administrations, and significantly decreased after 10 MPTPp administrations. Post-mortem immunohistochemical analyses of DAT and tyrosine hydroxylase (TH) in the striatum showed a positive correlation with [18F]-FP-CIT, confirming the validity of repeated MPTPp-treated mice as a model that can reproduce the progressive pathological changes in the early phases of PD. Analysis of [18F]-FDG uptake in several brain areas connected to the striatum showed that metabolic connectivity was progressively disrupted, starting from the first MPTPp administration, and that significant connections between cortical and subcortical regions were lost after 10 MPTPp administrations, suggesting an association between dopamine neuron degeneration and connectivity disruption in this PD model. The results of this study provide a relevant model, where new drugs that can alleviate neurodegeneration in PD could be evaluated preclinically.
Assuntos
Doença de Parkinson , Tropanos , Humanos , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/patologia , Dopamina/metabolismo , Probenecid/farmacologia , Probenecid/uso terapêutico , Neurônios Dopaminérgicos/patologia , Fluordesoxiglucose F18/uso terapêutico , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/metabolismo , Degeneração Neural/diagnóstico por imagem , Degeneração Neural/patologiaRESUMO
Clinical observations report a greater propensity to develop Parkinson's disease (PD) in amphetamine users. 3,4-Methylenedioxymethamphetamine (MDMA; "ecstasy") is an amphetamine-related drug that is largely consumed by adolescents and young adults, which may have neuroinflammatory and neurotoxic effects. Here, the objective was to evaluate in mice whether consumption of MDMA during adolescence might influence the neuroinflammatory and neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a toxin known to induce PD in humans. The activation of astroglia and microglia by glial fibrillary acidic protein (GFAP) and complement receptor type 3 (CD11b) immunohistochemistry and the degeneration of dopaminergic neurons by tyrosine hydroxylase (TH) immunohistochemistry were evaluated. MPTP (20 mg/kg × 4) was administered to mice treated from ages 8 weeks to 17 weeks with MDMA (10 mg/kg twice daily, two times a week). In mice that were chronically treated with MDMA, administration of MPTP induced a higher microglial and astroglial response in both the striatum and the substantia nigra pars compacta (SNc) compared with vehicle-treated or vehicle + MPTP-treated mice. Inflammatory changes were associated with a decrease in TH immunoreactivity in the SNc of MDMA-treated mice and with a further decrease in the striatum and the SNc of MDMA + MPTP-treated mice compared with vehicle-treated, MDMA-treated, and MPTP-treated mice. The results demonstrate that chronic administration of MDMA during late adolescence in mice exacerbates the neurodegeneration and neuroinflammation caused by MPTP, suggesting that MDMA may constitute a risk factor for dopaminergic neuron degeneration.
Assuntos
Inibidores da Captação Adrenérgica/toxicidade , Encéfalo/patologia , Neurônios Dopaminérgicos/patologia , Intoxicação por MPTP/patologia , N-Metil-3,4-Metilenodioxianfetamina/toxicidade , Neuroglia/metabolismo , Animais , Antígeno CD11b/metabolismo , Contagem de Células , Modelos Animais de Doenças , Sinergismo Farmacológico , Proteína Glial Fibrilar Ácida/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuroglia/efeitos dos fármacos , Fatores de Tempo , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Activation of the nuclear factor κB/c-Rel can increase neuronal resilience to pathological noxae by regulating the expression of pro-survival manganese superoxide dismutase (MnSOD, now known as SOD2) and Bcl-xL genes. We show here that c-Rel-deficient (c-rel(-/-)) mice developed a Parkinson's disease-like neuropathology with ageing. At 18 months of age, c-rel(-/-) mice exhibited a significant loss of dopaminergic neurons in the substantia nigra pars compacta, as assessed by tyrosine hydroxylase-immunoreactivity and Nissl staining. Nigral degeneration was accompanied by a significant loss of dopaminergic terminals and a significant reduction of dopamine and homovanillic acid levels in the striatum. Mice deficient of the c-Rel factor exhibited a marked immunoreactivity for fibrillary α-synuclein in the substantia nigra pars compacta as well as increased expression of divalent metal transporter 1 (DMT1) and iron staining in both the substantia nigra pars compacta and striatum. Aged c-rel(-/-) mouse brain were characterized by increased microglial reactivity in the basal ganglia, but no astrocytic reaction. In addition, c-rel(-/-) mice showed age-dependent deficits in locomotor and total activity and various gait-related deficits during a catwalk analysis that were reminiscent of bradykinesia and muscle rigidity. Both locomotor and gait-related deficits recovered in c-rel(-/-) mice treated with l-3,4-dihydroxyphenylalanine. These data suggest that c-Rel may act as a regulator of the substantia nigra pars compacta resilience to ageing and that aged c-rel(-/-) mice may be a suitable model of Parkinson's disease.
Assuntos
Envelhecimento/genética , Neurônios Dopaminérgicos/patologia , NF-kappa B/genética , Transtornos Parkinsonianos/genética , Substância Negra/patologia , Envelhecimento/metabolismo , Animais , Contagem de Células , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Ácido Homovanílico/metabolismo , Camundongos , Camundongos Knockout , Atividade Motora/genética , NF-kappa B/metabolismo , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia , Substância Negra/metabolismo , alfa-Sinucleína/metabolismoRESUMO
The dopamine neuronal loss that characterizes Parkinson's Disease (PD) is associated to changes in neurotransmitters, such as serotonin and adenosine, which contribute to the symptomatology of PD and to the onset of dyskinetic movements associated to levodopa treatment. The present review describes the role played by serotonin 5-HT1A receptors and the adenosine A2A receptors on dyskinetic movements induced by chronic levodopa in PD. The focus is on preclinical and clinical results showing the interaction between serotonin 5-HT1A receptors and other receptors such as 5-HT1B receptors and adenosine A2A receptors. 5-HT1A/1B receptor agonists and A2A receptor antagonists, administered in combination, contrast dyskinetic movements induced by chronic levodopa without impairing motor behaviour, suggesting that this drug combination might be a useful therapeutic approach for counteracting the PD motor deficits and dyskinesia associated with chronic levodopa treatment. This article is part of the Special Issue on "The receptor-receptor interaction as a new target for therapy".
Assuntos
Discinesia Induzida por Medicamentos , Doença de Parkinson , Humanos , Doença de Parkinson/tratamento farmacológico , Levodopa/efeitos adversos , Serotonina , Antiparkinsonianos/efeitos adversos , Discinesia Induzida por Medicamentos/tratamento farmacológicoRESUMO
Genetic background and age at first exposure have been identified as critical variables that contribute to individual vulnerability to drug addiction. Evidence shows that genetic factors may account for 40-70% of the variance in liability to addiction. Alcohol consumption by young people, especially in the form of binge-drinking, is becoming an alarming phenomenon predictive of future problems with drinking. Thus, the literature indicates the need to better understand the influence of age and genetic background on the development of alcohol dependence. To this aim, the inbred rat strains Lewis (LEW, addiction prone) and Fischer 344 (F344, addiction resistant) were used as a model of genetic vulnerability to addiction and compared with the outbred strain Sprague-Dawley (SD) in a two-bottle choice paradigm as a model of alcohol abuse. During a 9-week period, adolescent and adult male rats of the three strains were intermittently exposed to ethanol (20%) and water during three 24-h sessions/week. Adult and adolescent SD and LEW rats escalated their alcohol intake over time reaching at stable levels, while F344 rats did not escalate their intake, regardless of age at drinking onset. Among adolescents, only F344 rats consumed a higher total amount of ethanol than adults, although only SD and LEW rats escalated their intake. Adult LEW rats, albeit having a lower ethanol consumption as compared to SD rats but greater than F344, showed a more compulsive intake, consuming higher amounts of ethanol during the first hour of exposure, reaching a higher degree of ethanol preference when start drinking as adolescents. Behavioral analysis during the first hour of ethanol consumption revealed significant strain differences, among which noticeable the lack of sedative effect in the LEW strain, at variance with F344 and SD strains, and highest indices of withdrawal (most notable jumping) in LEW rats during the first hour of abstinence days. The present results underscore the importance of individual genetic background and early onset of alcohol use in the progression toward abuse and development of alcohol addiction.
RESUMO
Grape pomaces have recently received great attention for their richness in polyphenols, compounds known to exert anti-inflammatory and antioxidant effects. These pomaces, however, have low brain bioavailability when administered orally due to their extensive degradation in the gastrointestinal tract. To overcome this problem, Nasco pomace extract was incorporated into a novel nanovesicle system called nutriosomes, composed of phospholipids (S75) and water-soluble maltodextrin (Nutriose® FM06). Nutriosomes were small, homogeneously dispersed, had negative zeta potential, and were biocompatible with intestinal epithelial cells (Caco-2). Nasco pomace extract resulted rich in antioxidant polyphenols (gallic acid, catechin, epicatechin, procyanidin B2, and quercetin). To investigate the neuroprotective effect of Nasco pomace in the subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD), Nasco nutriosomes or Nasco suspension was administered intragastrically and their neuroprotective effects were evaluated. Degeneration of nigro-striatal dopaminergic neurons induced by subacute MPTP treatment, the pathological hallmark of PD, was assessed through immunohistochemical evaluation of tyrosine hydroxylase (TH) in the caudate-putamen (CPu) and substantia nigra pars compacta (SNc), and the dopamine transporter (DAT) in CPu. Immunohistochemical analysis revealed that Nasco nutriosomes significantly prevented the reduction in TH- and DAT-positive fibres in CPu, and the number of TH-positive cells in SNc following subacute MPTP treatment, while Nasco suspension counteracted MPTP toxicity exclusively in SNc. Overall, these results highlight the therapeutic effects of Nasco pomace extract when administered in a nutriosome formulation in the subacute MPTP mouse model of PD and validate the effectiveness of the nutriosome preparation over suspension as an innovative nano-drug delivery system for in vivo administration.
Assuntos
Amiloidose Familiar/patologia , Dermoscopia/métodos , Doença Granulomatosa Crônica/patologia , Dermatopatias Genéticas/patologia , Amiloidose Familiar/diagnóstico , Biópsia por Agulha , Diagnóstico Diferencial , Feminino , Doença Granulomatosa Crônica/diagnóstico , Humanos , Imuno-Histoquímica , Perna (Membro) , Pessoa de Meia-Idade , Dermatopatias Genéticas/diagnósticoRESUMO
Several lines of evidence have strongly implicated neuroinflammation in Parkinson's disease (PD) progression and l-dopa-induced dyskinesia. The present study investigated whether early subchronic pretreatment with the serotonin 5-HT1A/1B receptor agonist eltoprazine plus the adenosine A2A receptor antagonist preladenant counteracted l-dopa-induced abnormal involuntary movements (AIMs, index of dyskinesia), and neuroinflammation, in unilateral 6-hydroxydopamine(6-OHDA)-lesioned rat model of PD. The immunoreactivity of glial fibrillary acidic protein (GFAP), and the colocalization of ionized calcium binding adaptor molecule-1 (IBA-1), with interleukin (IL)-1ß, tumor-necrosis-factor-α (TNF-α) and IL-10 were evaluated in the denervated caudate-putamen (CPu) and substantia nigra pars-compacta (SNc). The combined subchronic pretreatment with l-dopa plus eltoprazine and preladenant reduced AIMs induced by acute l-dopa challenge in these rats and decreased GFAP and IBA-1 immunoreactivity induced by the drug in both CPu and SNc, with reduction in IL-1ß in IBA-1-positive cells in both CPu and SNc, and in TNF-α in IBA-1-positive cells in SNc. Moreover, a significant increase in IL-10 in IBA-1-positive cells was observed in SNc. Evaluation of immediate early-gene zif-268 (index of neuronal activation) after l-dopa challenge, showed an increase in its expression in denervated CPu of rats pretreated with l-dopa or l-dopa plus preladenant compared with vehicle, whereas rats pretreated with eltoprazine, with or without preladenant, had lower zif-268 expression. Finally, tyrosine hydroxylase and dopamine transporter examined to evaluate neurodegeneration, showed a significant equal decrease in all experimental groups. The present findings suggest that combination of l-dopa with eltoprazine and preladenant may be promising therapeutic strategy for delaying the onset of dyskinesia, preserving l-dopa efficacy and reducing neuroinflammation markers in nigrostriatal system of 6-OHDA-lesioned rats.
Assuntos
Antagonistas do Receptor A2 de Adenosina/farmacologia , Antiparkinsonianos/efeitos adversos , Discinesia Induzida por Medicamentos/fisiopatologia , Levodopa/efeitos adversos , Transtornos Parkinsonianos/fisiopatologia , Piperazinas/farmacologia , Pirimidinas/farmacologia , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Triazóis/farmacologia , Animais , Proteínas de Ligação ao Cálcio/efeitos dos fármacos , Proteínas de Ligação ao Cálcio/metabolismo , Núcleo Caudado/efeitos dos fármacos , Núcleo Caudado/metabolismo , Discinesia Induzida por Medicamentos/etiologia , Discinesia Induzida por Medicamentos/metabolismo , Proteína Glial Fibrilar Ácida/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Interleucina-10/metabolismo , Interleucina-1beta/efeitos dos fármacos , Interleucina-1beta/metabolismo , Proteínas dos Microfilamentos/efeitos dos fármacos , Proteínas dos Microfilamentos/metabolismo , Doenças Neuroinflamatórias/metabolismo , Oxidopamina/toxicidade , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/metabolismo , Parte Compacta da Substância Negra/efeitos dos fármacos , Parte Compacta da Substância Negra/metabolismo , Putamen/efeitos dos fármacos , Putamen/metabolismo , Ratos , Receptor 5-HT1A de Serotonina , Receptor 5-HT1B de Serotonina , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
While Parkinson's disease (PD) is traditionally characterized by dopaminergic neuron degeneration, several neurotransmitters and neuromodulators besides dopamine are also involved in the onset and progression of the disease and its symptoms. The other principal neurotransmitters/neuromodulators known to control basal ganglia functions and, in particular, motor functions, are GABA, glutamate, serotonin (5-HT), noradrenaline, acetylcholine, adenosine and endocannabinoids. Among these, adenosine is the most relevant, acting through its adenosine A2A receptor. Work in experimental models of PD has established the effects of A2A receptor antagonists, including the alleviation of disrupted dopamine functions and improved efficacy of dopamine replacement therapy. Moreover, positive interactions between A2A receptor antagonists and both D2 and D1 receptor agonists have been described in vitro at the receptor-receptor level or in more complex in vivo models of PD, respectively. In addition, the interactions between A2A receptor antagonists and glutamate ionotropic GluN2B-containing N-Methyl-d-aspartic acid receptors, or metabotropic glutamate (mGlu) receptors, including both mGlu5 receptor inhibitors and mGlu4 receptor activators, have been reported in both in vitro and in vivo animal models of PD, as have positive interactions between A2A and endocannabinoid CB1 receptor antagonists. At the same time, a combination of A2A receptor antagonists and 5-HT1A-5-HT1B receptor agonists have been described to modulate the expression of dyskinesia induced by chronic dopamine replacement therapy.
Assuntos
Antagonistas do Receptor A2 de Adenosina/uso terapêutico , Antiparkinsonianos/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Receptor A2A de Adenosina/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Discinesia Induzida por Medicamentos/tratamento farmacológico , Humanos , Receptor A2A de Adenosina/metabolismoRESUMO
Twelve-month-old male mice expressing the human A53T variant of α-synuclein (A53T) develop dopamine neuron degeneration, neuroinflammation, and motor deficits, along with dysfunctions of the mitochondrial Na+-Ca2+ exchanger (NCX) isoforms 1 (NCX1) and 3 (NCX3) in the nigrostriatal system. Since gender is thought to play a role in the etiology of Parkinson's disease (PD), we characterized neurochemical and behavioral alterations in 12-month-old female A53T transgenic mice. We investigated the presence of dopaminergic degeneration, astrogliosis and microgliosis using immunohistochemistry for tyrosine hydroxylase (TH), glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule-1 (IBA-1) in both the substantia nigra pars compacta (SNc) and striatum. In the same regions, we also evaluated the co-localization of NCX1 in cells positive for IBA-1 and the co-localization of NCX3 in TH-positive neurons and fibers. Furthermore, in both male and female mice, we performed motor (beam walking and pole tests) and memory [novel object recognition (NOR) and spontaneous alternation] tasks, together with tests to evaluate peripheral deficits (olfactory and stool collection tests). Female A53T transgenic mice displayed degeneration of nigral dopaminergic neurons, but neither microgliosis nor astrogliosis in the SNc and striatum. Moreover, female A53T transgenic mice displayed co-localization between NCX1 and IBA-1 positive cells in the striatum but not SNc, whereas NCX3 did not co-localize with either TH-positive terminals or neuronal bodies in the nigrostriatal system. Furthermore, female A53T transgenic mice showed increased crossing time in the beam walking test, but no impairments in the pole or memory tests, and in tests that evaluated peripheral deficits, whereas male A53T transgenic mice displayed motor, memory and peripheral deficits. Immunohistochemical and behavioral results obtained here in the female mice differ from those previously observed in males, and suggest a dissimilar influence of NCX1 and NCX3 on dopaminergic function in female and male A53T transgenic mice, strengthening the validity of these mice as a model for studying the etiological factors of PD.
RESUMO
The extended amygdala has been proposed to play an essential role in cognitive and affective processes and in neuropsychiatric disorders. In the present study, we examined the induction of Fos-like nuclei in the central amygdaloid nucleus (CeA), sublenticular extended amygdala (SLEA), interstitial nucleus of the posterior limb of the anterior commissure (IPAC), and bed nucleus of the stria terminalis (BSTL) of rodents to improve the knowledge regarding the pharmacological profile, therapeutic efficacy, and side-effects of olanzapine, an atypical antipsychotic drug and risperidone, a mixed atypical/typical antipsychotic drug in the rat brain. In addition, we evaluated the induction of Fos-like-nuclei in areas connected with these structures such as prefrontal cortex (PFCx), and nucleus accumbens shell, and in other important areas including the lateral septum and caudate-putamen that are involved in the therapeutic efficacy or side-effects of antipsychotic drugs. Fos-like-immunoreactivity induced by olanzapine and risperidone was compared with that by the atypical antipsychotic clozapine and typical antipsychotic haloperidol. Regarding the extended amygdala, and similarly to clozapine, olanzapine (5-10â¯mg/kg) and, with a lower efficacy, risperidone (1-3â¯mg/kg), induced Fos-like-nuclei in CeA, IPAC, SLEA, and BSTL. Both these drugs increased the induction of Fos-like-nuclei in PFCx, nucleus accumbens shell, lateral septum, and caudate-putamen. On the contrary, the increase of Fos-like-nuclei in the extended amygdala by haloperidol was restricted to IPAC only. These findings, consistent with the important role of extended amygdala in neuropsychiatric disorders characterized by affective disturbances, showed that olanzapine and risperidone, contrary to haloperidol, preferentially activated Fos-expression in these brain areas.
Assuntos
Antipsicóticos/farmacologia , Encéfalo/efeitos dos fármacos , Olanzapina/farmacologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Risperidona/farmacologia , Animais , Encéfalo/metabolismo , Masculino , Ratos Sprague-DawleyRESUMO
A large body of clinical evidence suggests a possible association between perinatal asphyxia and the onset of early, as well as long-term, neurological and psychiatric disorders including cognitive deficits. The present study investigated cognitive and motor function modifications in a well characterized and clinically relevant experimental rat model of human perinatal asphyxia. The results reported here show that adult rats exposed to a single (20 min) asphyctic episode at delivery displayed: (a) a deficit in non-spatial memory, assessed in a novel object recognition task; (b) an impaired motor coordination, measured by the rotarod test. On the other hand, gross motor activity and spatial memory, evaluated in both the Y maze and the Barnes maze, were not affected by perinatal asphyxia. The results of this study provide further insights into the long-term effects of perinatal asphyxia on neurobehavioural functions.