RESUMEN
Alterations of the microbiota-gut-brain axis has been associated with intestinal and neuronal inflammation in Parkinson's disease (PD). The aim of this work was to study some mechanisms associated with the neuroprotective effect of a combination (MIX) of lactic acid bacteria (LAB) composed by Lactiplantibacillus plantarum CRL2130 (riboflavin overproducing strain), Streptococcus thermophilus CRL808 (folate producer strain), and CRL807 (immunomodulatory strain) in cell cultures and in a chronic model of parkinsonism induced with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in aged mice, and under levodopa-benserazide treatment. In vitro, N2a differentiated neurons were exposed to the neurotoxin 1-methyl-4-phenylpyridinium (MPP+) and treated with intracellular bacterial extracts or with conditioned media from BV-2 cells exposed to the bacterial extracts. In vivo, motor skills, tyrosine hydrolase (TH) in brain and cytokine concentrations in serum and in brain were evaluated. The study of the faecal microbiota and the histology of the small intestine was also performed. The results showed that the neuroprotective effect associated with LAB MIX administration did not interfere with levodopa-benserazide treatment. This effect could be associated with the antioxidant and immunomodulatory potential of the LAB selected in the MIX, and was associated with the significant improvement in the motor tests and a higher number of TH + cells in the brain. In addition, LAB MIX administration was associated with modulation of the immune response. LAB administration decreased intestinal damage with an increase in the villus length /crypt depth ratio. Finally, the administration of the LAB MIX in combination with levodopa-benserazide treatment was able to partially revert the intestinal dysbiosis observed in the model, showing greater similarity to the profiles of healthy controls, and highlighting the increase in the Lactobacillaceae family. Different mechanisms of action would be related to the protective effect of the selected LAB combination which has the potential to be evaluated as an adjuvant for conventional PD therapies.
Asunto(s)
Benserazida , Levodopa , Ratones Endogámicos C57BL , Fármacos Neuroprotectores , Trastornos Parkinsonianos , Animales , Levodopa/farmacología , Benserazida/farmacología , Benserazida/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/farmacología , Trastornos Parkinsonianos/tratamiento farmacológico , Trastornos Parkinsonianos/metabolismo , Masculino , Ratones , Combinación de Medicamentos , Microbioma Gastrointestinal/efectos de los fármacos , Modelos Animales de Enfermedad , Lactobacillales , Probióticos/uso terapéutico , Antiparkinsonianos/farmacología , Antiparkinsonianos/uso terapéutico , Streptococcus thermophilus/efectos de los fármacosRESUMEN
Adolescence is a phase of substantial changes in the brain, characterized by maturational remodeling of many systems. This remodeling allows functional plasticity to adapt to a changing environment. The dopaminergic system is under morphological and physiological changes during this phase. In the present study, we investigated if changes in the dopaminergic tone alter mice behavior in a receptor and sex-specific manner, specifically at the beginning of the puberty period. We administered L-Dopa, SKF-38393 (D1 dopamine receptor agonist), and Quinpirole (D2 dopamine receptor agonist) and tested male and female mice's motor, anxiety- and depressive-like behavior. While females displayed an impaired exploratory drive, males presented an intense depressive-like response. Our results provide insights into the function of dopaminergic development in adolescent behavior and highlight the importance of studies in this time window with male and female subjects.
Asunto(s)
Agonistas de Dopamina , Levodopa , Humanos , Ratones , Masculino , Femenino , Animales , Adolescente , Quinpirol/farmacología , Levodopa/farmacología , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Agonistas de Dopamina/farmacología , Dopaminérgicos/farmacología , Ergolinas/farmacología , Receptores de Dopamina D1 , Dopamina , Ansiedad/tratamiento farmacológicoRESUMEN
Parkinson's Disease (PD), treated with the dopamine precursor l-3,4-dihydroxyphenylalanine (L-DOPA), displays motor and non-motor orofacial manifestations. We investigated the pathophysiologic mechanisms of the lateral pterygoid muscles (LPMs) and the trigeminal system related to PD-induced orofacial manifestations. A PD rat model was produced by unilateral injection of 6-hydroxydopamine into the medial forebrain bundle. Abnormal involuntary movements (dyskinesia) and nociceptive responses were determined. We analyzed the immunodetection of Fos-B and microglia/astrocytes in trigeminal and facial nuclei and morphological markers in the LPMs. Hyperalgesia response was increased in hemiparkinsonian and dyskinetic rats. Hemiparkinsonism increased slow skeletal myosin fibers in the LPMs, while in the dyskinetic ones, these fibers decreased in the contralateral side of the lesion. Bilateral increased glycolytic metabolism and an inflammatory muscle profile were detected in dyskinetic rats. There was increased Fos-B expression in the spinal nucleus of lesioned rats and in the motor and facial nucleus in L-DOPA-induced dyskinetic rats in the contralateral side of the lesion. Glial cells were increased in the facial nucleus on the contralateral side of the lesion. Overall, spinal trigeminal nucleus activation may be associated with orofacial sensorial impairment in Parkinsonian rats, while a fatigue profile on LPMs is suggested in L-DOPA-induced dyskinesia when the motor and facial nucleus are activated.
Asunto(s)
Discinesia Inducida por Medicamentos , Enfermedad de Parkinson , Trastornos Parkinsonianos , Ratas , Animales , Levodopa/farmacología , Discinesia Inducida por Medicamentos/metabolismo , Cuerpo Estriado/metabolismo , Trastornos Parkinsonianos/metabolismo , Enfermedad de Parkinson/metabolismo , Oxidopamina/efectos adversos , Tronco Encefálico/metabolismo , Modelos Animales de Enfermedad , Antiparkinsonianos/efectos adversosRESUMEN
Motor deficits observed in Parkinson's disease (PD) are caused by the loss of dopaminergic neurons and the subsequent dopamine depletion in different brain areas. The most common therapy to treat motor symptoms for patients with this disorder is the systemic intake of L-DOPA that increases dopamine levels in all the brain, making it difficult to discern the main locus of dopaminergic action in the alleviation of motor control. Caged compounds are molecules with the ability to release neuromodulators locally in temporary controlled conditions using light. In the present study, we measured the turning behavior of unilateral dopamine-depleted mice before and after dopamine uncaging. The optical delivery of dopamine in the striatum of lesioned mice produced contralateral turning behavior that resembled, to a lesser extent, the contralateral turning behavior evoked by a systemic injection of apomorphine. Contralateral turning behavior induced by dopamine uncaging was temporarily tied to the transient elevation of dopamine concentration and was reversed when dopamine decreased to pathological levels. Remarkably, contralateral turning behavior was tuned by changing the power and frequency of light stimulation, opening the possibility to modulate dopamine fluctuations using different light stimulation protocols. Moreover, striatal dopamine uncaging recapitulated the motor effects of a low concentration of systemic L-DOPA, but with better temporal control of dopamine levels. Finally, dopamine uncaging reduced the pathological synchronization of striatal neuronal ensembles that characterize unilateral dopamine-depleted mice. We conclude that optical delivery of dopamine in the striatum resembles the motor effects induced by systemic injection of dopaminergic agonists in unilateral dopamine-depleted mice. Future experiments using this approach could help to elucidate the role of dopamine in different brain nuclei in normal and pathological conditions.
Asunto(s)
Dopamina , Enfermedad de Parkinson , Animales , Ratones , Enfermedad de Parkinson/tratamiento farmacológico , Levodopa/farmacología , Levodopa/uso terapéutico , Cuerpo Estriado , NeostriadoRESUMEN
OBJECTIVE: To develop N-(levodopa) chitosan derivatives through click chemistry to study their effect in brain cells.Significance: This study presents a proof-of-concept that macromolecules such as N-(Levodopa) chitosan derivatives traverse brain cell membranes and induce biomedical functionalities. METHODS: Through click chemistry, we developed N-(levodopa) chitosan derivatives. They were physically and chemically characterized by FT-IR, 1H-NMR, TGA and Dynamic Light Scattering analyses. Solution and nanoparticles of N-(levodopa) chitosan derivatives were tested in primary cell cultures from the postnatal rat olfactory bulb, substantia nigra and corpus callosum. Ca2+ imaging and UPLC experiments were used to investigate if the biomaterial modulated the brain cell physiology. RESULTS: N-(levodopa) chitosan derivatives induced intracellular Ca2+ responses in primary cell cultures of the rat brain. UPLC experiments indicated that levodopa attached to chitosan was converted into dopamine by brain cells. CONCLUSION: The present study shows that N-(levodopa) chitosan may be useful to develop new treatment strategies, which could serve as molecular reservoirs of biomedical drugs to treat degenerative disorders of the nervous system.
Asunto(s)
Quitosano , Levodopa , Ratas , Animales , Levodopa/farmacología , Quitosano/química , Química Clic/métodos , Espectroscopía Infrarroja por Transformada de Fourier , EncéfaloRESUMEN
BACKGROUND: In advanced stages of Parkinson's disease (PD), dyskinesia and motor fluctuations become seriously debilitating and therapeutic options become scarce. Aberrant activity of striatal cholinergic interneurons (SCIN) has been shown to be critical to PD and dyskinesia, but the systemic administration of cholinergic medications can exacerbate extrastriatal-related symptoms. Thus, targeting the mechanisms causing pathological SCIN activity in severe PD with motor fluctuations and dyskinesia is a promising therapeutic alternative. METHODS: We used ex vivo electrophysiological recordings combined with pharmacology to study the alterations in intracellular signaling that contribute to the altered SCIN physiology observed in the 6-hydroxydopamine mouse model of PD treated with levodopa. RESULTS: The altered phenotypes of SCIN of parkinsonian mice during the "off levodopa" state resulting from aberrant Kir/leak and Kv1.3 currents can be rapidly reverted by acute inhibition of cAMP-ERK1/2 signaling. Inverse agonists that inhibit the ligand-independent activity of D5 receptors, like clozapine, restore Kv1.3 and Kir/leak currents and SCIN normal physiology in dyskinetic mice. CONCLUSION: Our work unravels a signaling pathway involved in the dysregulation of membrane currents causing SCIN hyperexcitability and burst-pause activity in parkinsonian mice treated with levodopa (l-dopa). These changes persist during off-medication periods due to tonic mechanisms that can be acutely reversed by pharmacological interventions. Thus, targeting the D5-cAMP-ERK1/2 signaling pathway selectively in SCIN may have therapeutic effects in PD and dyskinesia by restoring the normal SCIN function. © 2022 International Parkinson and Movement Disorder Society.
Asunto(s)
Discinesia Inducida por Medicamentos , Enfermedad de Parkinson , Animales , Antiparkinsonianos/farmacología , Antiparkinsonianos/uso terapéutico , Colinérgicos/metabolismo , Colinérgicos/farmacología , Colinérgicos/uso terapéutico , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Discinesia Inducida por Medicamentos/patología , Interneuronas/metabolismo , Levodopa/farmacología , Levodopa/uso terapéutico , Ratones , Oxidopamina/toxicidadRESUMEN
Paraquat (1,10-dimethyl-4,4-bipyridinium dichloride; PQ) is a free-radical producing herbicide that affects cell membranes and can upset the environmental balance of microorganisms present in soil, such as Cryptococcus spp. This study aimed to evaluate the in vitro activity of PQ against Cryptococcus spp. in planktonic and biofilm forms, as well as the protective effect of antioxidant agents against the antifungal effect of PQ and the kinetics of melanin production in response to PQ. Susceptibility to PQ was evaluated by microdilution. Cryptococcus sp. strains exposed to PQ were grown in media with ascorbic acid (AA) and glutathione (GSH). Melanin production was assessed in the presence of l-3,4-dihydroxyphenylalanine (l-DOPA) + PQ. The minimum inhibitory concentration of PQ against Cryptococcus spp. ranged from 8 to 256 µg/mL. Furthermore, PQ reduced biofilm formation. AA and GSH restored the fungal growth of Cryptococcus spp. exposed to PQ. In addition, l-DOPA + PQ delayed melanin production by 24 and 48 h for C. deuterogattii and C. neoformans sensu lato, respectively, suggesting that PQ induces a fitness trade-off in melanin production. Taken together, our data suggest that the antifungal effect of PQ against Cryptococcus spp. possibly exerts selective pressures interfering with biofilm formation and melanin production by these yeasts.
Asunto(s)
Cryptococcus gattii , Cryptococcus neoformans , Herbicidas , Antifúngicos/metabolismo , Antifúngicos/farmacología , Cryptococcus gattii/metabolismo , Cryptococcus neoformans/metabolismo , Herbicidas/metabolismo , Herbicidas/farmacología , Levodopa/metabolismo , Levodopa/farmacología , Melaninas/metabolismo , Melaninas/farmacología , Pruebas de Sensibilidad Microbiana , Paraquat/metabolismo , Paraquat/farmacologíaRESUMEN
Levodopa is a cornerstone in Parkinson's disease treatment. Beneficial effects are mainly by binding on D2 receptors. Docking simulations of a set of compounds including well-known D2-ligands and a pool of Boron-Containing Compounds (BCC), particularly boroxazolidones with a tri/tetra-coordinated boron atom, were performed on the D2 Dopamine receptor (D2DR). Theoretical results yielded higher affinity of the compound DPBX, a Dopaboroxazolidone, than levodopa on D2DR. Essential interactions with residues in the third and sixth transmembrane domains of the D2DR appear to be crucial to induce and stabilize interactions in the active receptor state. Results from a motor performance evaluation of a murine model of Parkinson's disease agree with theoretical results, as DPBX showed similar efficacy to that of levodopa for diminishing MPTP-induced parkinsonism. This beneficial effect was disrupted with prior Risperidone (D2DR antagonist) administration, supporting the role of D2DR in the biological effect of DPBX. In addition, DPBX limited neuronal loss in substantia nigra in a similar manner to that of levodopa administration.
Asunto(s)
Levodopa , Enfermedad de Parkinson , Animales , Boro , Levodopa/farmacología , Levodopa/uso terapéutico , Ratones , Enfermedad de Parkinson/tratamiento farmacológicoRESUMEN
The dopaminergic system of zebrafish is complex and the numerous pathways and receptors in the central nervous system (CNS) are being extensively studied. A critical factor for the synthesis, activation and release of catecholamines (CAs) is the presence of tyrosine hydroxylase, an enzyme which converts L-tyrosine into levodopa. Levodopa thus is the intermediary in the synthesis of dopamine (DA) and norepinephrine (NE) and promotes its release; therefore, CAs play an important role in the CNS with hormonal functions. Here, we use levodopa/carbidopa to clarify the involvement of the dopaminergic pathway in the stress response in zebrafish submitted to an acute stress challenge. Acute stress was induced by chasing fish with a net for 2 min and assessed by measuring whole-body cortisol levels. Two experiments were carried out, the first with exposure to levodopa/carbidopa and the second with exposure to AMPT and levodopa/carbidopa. Levodopa/carbidopa balances the stress response through its action on the zebrafish hypothalamic-pituitary-adrenal (HPA) axis. Changes in cortisol levels suggest that DA was related to the balance of the stress response and that NE decreased this response. These effects were specific to stress since levodopa/carbidopa did not induce changes in cortisol in non-stressed fish.
Asunto(s)
Glándulas Suprarrenales/efectos de los fármacos , Carbidopa/farmacología , Agonistas de Dopamina/farmacología , Dopamina/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Levodopa/farmacología , Estrés Fisiológico , Pez Cebra/metabolismo , Glándulas Suprarrenales/metabolismo , Animales , Neuronas Dopaminérgicas/metabolismo , Combinación de Medicamentos , Inhibidores Enzimáticos/farmacología , Femenino , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisario/metabolismo , Masculino , Tirosina 3-Monooxigenasa/antagonistas & inhibidores , Tirosina 3-Monooxigenasa/metabolismo , Proteínas de Pez Cebra/antagonistas & inhibidores , Proteínas de Pez Cebra/metabolismo , alfa-Metiltirosina/farmacologíaRESUMEN
BACKGROUND: Enhanced striatal cholinergic interneuron activity contributes to the striatal hypercholinergic state in Parkinson's disease (PD) and to levodopa-induced dyskinesia. In severe PD, dyskinesia and motor fluctuations become seriously debilitating, and the therapeutic strategies become scarce. Given that the systemic administration of anticholinergics can exacerbate extrastriatal-related symptoms, targeting cholinergic interneurons is a promising therapeutic alternative. Therefore, unraveling the mechanisms causing pathological cholinergic interneuron activity in severe PD with motor fluctuations and dyskinesia may provide new molecular therapeutic targets. METHODS: We used ex vivo electrophysiological recordings combined with pharmacological and morphological studies to investigate the intrinsic alterations of cholinergic interneurons in the 6-hydroxydopamine mouse model of PD treated with levodopa. RESULTS: Cholinergic interneurons exhibit pathological burst-pause activity in the parkinsonian "off levodopa" state. This is mediated by a persistent ligand-independent activity of dopamine D1/D5 receptor signaling, involving a cyclic adenosine monophosphate (cAMP) pathway. Dysregulation of membrane ion channels that results in increased inward-rectifier potassium type 2 (Kir2) and decreased leak currents causes the burst pause activity, which can be dampened by pharmacological inhibition of intracellular cAMP. A single challenge with a dyskinetogenic dose of levodopa is sufficient to induce persistent cholinergic interneuron burst-pause firing. CONCLUSION: Our data unravel a mechanism causing aberrant cholinergic interneuron burst-pause activity in parkinsonian mice treated with levodopa. Targeting D5-cAMP signaling and the regulation of Kir2 and leak channels may alleviate parkinsonism and dyskinesia by restoring normal cholinergic interneuron function. © 2021 International Parkinson and Movement Disorder Society.
Asunto(s)
Cuerpo Estriado , Levodopa , Animales , Colinérgicos/farmacología , Interneuronas , Levodopa/farmacología , Ratones , Oxidopamina/toxicidadRESUMEN
Background. Although dopaminergic medication improves dual task walking in people with Parkinson disease (PD), the underlying neural mechanisms are not yet fully understood. As prefrontal cognitive resources are involved in dual task walking, evaluation of the prefrontal cortex (PFC) is required. Objective. To investigate the effect of dopaminergic medication on PFC activity and gait parameters during dual task walking in people with PD. Methods. A total of 20 individuals with PD (69.8 ± 5.9 years) and 30 healthy older people (68.0 ± 5.6 years) performed 2 walking conditions: single and dual task (walking while performing a digit vigilance task). A mobile functional near infrared spectroscopy system and an electronic sensor carpet were used to analyze PFC activation and gait parameters, respectively. Relative concentrations of oxygenated hemoglobin (HbO2) from the left and right PFC were measured. Results. People with PD in the off state did not present changes in HbO2 level in the left PFC across walking conditions. In contrast, in the on state, they presented increased HbO2 levels during dual task compared with single task. Regardless of medication state, people with PD presented increased HbO2 levels in the right PFC during dual task walking compared with single task. The control group demonstrated increased PFC activity in both hemispheres during dual task compared with single task. People with PD showed increases in both step length and velocity in the on state compared with the off state. Conclusions. PD limits the activation of the left PFC during dual task walking, and dopaminergic medication facilitates its recruitment.
Asunto(s)
Dopaminérgicos/farmacología , Función Ejecutiva/efectos de los fármacos , Marcha/efectos de los fármacos , Levodopa/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Corteza Prefrontal/efectos de los fármacos , Desempeño Psicomotor/efectos de los fármacos , Anciano , Función Ejecutiva/fisiología , Femenino , Neuroimagen Funcional , Marcha/fisiología , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/fisiopatología , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/fisiopatología , Desempeño Psicomotor/fisiología , Espectroscopía Infrarroja CortaRESUMEN
Parkinson's disease is a neurodegenerative disorder that affects the central nervous system and is mainly characterized by the loss of dopaminergic neurons and pro-oxidant mechanisms. Eugenol has been widely studied due to its anti-inflammatory and antioxidant activities, making it a promising neuroprotective agent. This study aimed to investigate the effects of eugenol and its combined action with levodopa in the 6-hydroxydopamine-induced Parkinson's disease model. Wistar rats were subjected to intrastriatal injection of 6-hydroxydopamine (21 µg) and then treated with eugenol (0.1, 1, or 10 mg/kg), levodopa (25 mg/kg) or their combination (eugenol 10 mg/kg + levodopa 12.5 mg/kg) orally for 14 days. On the 14th day, the animals were subjected to behavioural tests, and after euthanization and dissection of the brain areas, neurochemical analyses were performed. The results showed that eugenol reduced the oxidative stress and behavioural disturbances induced by 6-hydroxydopamine. The eugenol and levodopa combination was more effective in some behavioural parameters and body-weight gain in addition to promoting an increase in reduced glutathione levels compared to levodopa alone. Thus, the neuroprotective activity of eugenol was observed against motor and neurochemical disorders. Additionally, the eugenol and levodopa combination was promising when compared to conventional treatment.
Asunto(s)
Eugenol/farmacología , Levodopa/farmacología , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Animales , Conducta Animal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Modelos Animales de Enfermedad , Glutatión/efectos de los fármacos , Glutatión/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Masculino , Actividad Motora/efectos de los fármacos , Nitritos/metabolismo , Estrés Oxidativo/efectos de los fármacos , Oxidopamina/farmacología , Ratas , Ratas WistarRESUMEN
We explored the origin of the impaired control of action stability in Parkinson's disease (PD) by testing levodopa-naïve PD patients to disambiguate effects of PD from possible effects of long-term exposure to levodopa. Thirteen levodopa-naïve PD patients and 13 controls performed single- and multi-finger force production tasks, including producing a self-paced quick force pulse into a target. A subgroup of patients (n = 10) was re-tested about 1 h after the first dose of levodopa. Compared to controls, PD patients showed lower maximal forces and synergy indices stabilizing total force (reflecting the higher inter-trial variance component affecting total force). In addition, PD patients showed a trend toward shorter anticipatory synergy adjustments (a drop in the synergy index in preparation to a quick action) and larger non-motor equivalent finger force deviations. Lower maximal force, higher unintentional force production (enslaving) and higher inter-trial variance indices occurred in PD patients after one dosage of levodopa. We conclude that impairment in synergies is present in levodopa-naïve patients, mainly in indices reflecting stability (synergy index), but not agility (anticipatory synergy adjustments). A single dose of levodopa, however, did not improve synergy indices, as it did in PD patients on chronic anti-PD medication, suggesting a different mechanism of action. The results suggest that indices of force-stabilizing synergies may be used as an early behavioral sign of PD, although it may not be sensitive to acute drug effects in drug-naïve patients.
Asunto(s)
Antiparkinsonianos/farmacología , Dedos/fisiopatología , Levodopa/farmacología , Actividad Motora/fisiología , Enfermedad de Parkinson/fisiopatología , Desempeño Psicomotor/fisiología , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Actividad Motora/efectos de los fármacos , Enfermedad de Parkinson/tratamiento farmacológico , Desempeño Psicomotor/efectos de los fármacosRESUMEN
Parkinson's disease (PD) is a multisystem disorder that affects 2-3% of the population ≥ 65 years of age. The main pharmacologic agent use in the treatment of clinical symptoms of PD is levodopa (L-DOPA). However, the chronic use of L-DOPA might result in the emergence of motor complications such as motor fluctuation and dyskinesia. Previous studies have shown that the inter-individual variability and pharmacogenetic profile of PD patients seem to influence the occurrence of motor complications. For these reasons, the purpose of this study was to evaluate a possible relationship between DRD1 A48G and DRD3 Ser9Gly genetic variants with the occurrence of motor complications in PD patients in a Brazilian population. A total of 228 patients with idiopathic PD were enrolled. Patients were genotyped for DRD1 A48G and DRD3 Ser9Gly polymorphisms using PCR-RFLP. The univariate and multivariate analyses were performed to assess the association of these polymorphisms with the occurrence of motor fluctuation and dyskinesia in PD patients. Multiple Poisson regression analyses showed a protector effect to the occurrence of dyskinesia for individuals carrying of the DRD1 G/G genotype (PR 0.294; CI 0.09-0.87; p ≤ 0.020) after the threshold Bonferroni's. Besides, we verified risk increased to the occurrence of motor complications with daily L-DOPA dosage, disease duration, and users of rasagiline, selegiline, or entacapone (p < 0.05 for all). Our results suggest that the DRD1 A48G polymorphism and the presence of extrinsic and intrinsic factors may role an effect in the occurrence of dyskinesia in PD patients.
Asunto(s)
Enfermedad de Parkinson/genética , Polimorfismo de Nucleótido Simple , Receptores de Dopamina D1/genética , Receptores de Dopamina D3/genética , Antiparkinsonianos/farmacología , Antiparkinsonianos/uso terapéutico , Catecoles/farmacología , Catecoles/uso terapéutico , Estudios Transversales , Dopamina/fisiología , Agonistas de Dopamina/farmacología , Agonistas de Dopamina/uso terapéutico , Genotipo , Humanos , Indanos/farmacología , Indanos/uso terapéutico , Levodopa/farmacología , Levodopa/uso terapéutico , Actividad Motora , Nitrilos/farmacología , Nitrilos/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/fisiopatología , Selegilina/farmacología , Selegilina/uso terapéuticoRESUMEN
Parkinson's disease (PD) is a neurodegenerative illness presenting motor and non-motor symptoms due to the loss of dopaminergic terminals in basal ganglia, most importantly, the striatum. L-DOPA relieves many motor signs. Unfortunately, in the long term, L-DOPA use causes motor disabilities by itself and does not act in comorbid conditions such as depression. These deficiencies have led to search for drugs such as dopamine (DA) receptor agonists (DA-agonists) that allow the reduction of L-DOPA dose. Previously, we have identified the attributes of non-stimulated (resting) and cortical stimulated (active) striatal microcircuits following the activity of dozens of neurons simultaneously using calcium imaging in brain slices. We also have characterized the changes that take place in DA-depleted microcircuits in vitro. In control conditions, there is low spontaneous activity. After cortical stimulation (CtxS) sequences and alternation of neuronal ensembles activity occur, including reverberations. In contrast, DA-deprived circuits exhibit high spontaneous activity at rest, and a highly recurrent ensemble curtails alternation. Interestingly, CtxS briefly relieves these Parkinsonian signs in DA-depleted tissue. Here we compare the actions of some DA-agonists used in PD therapeutics on the pathological dynamics of DA-depleted microcircuits at rest and with CtxS; taking L-DOPA as reference. D2-class agonists better reduce the excessive spontaneous activity of DA-depleted microcircuits. All DA-agonists tend to maintain ensemble alternation seen in control circuits after CtxS. However, quantitative analyses suggest differences in their actions: in general, DA-agonists only approximate L-DOPA actions. Nonetheless no treatment, including L-DOPA, completely restores microcircuit dynamics to control conditions.
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Cuerpo Estriado/metabolismo , Agonistas de Dopamina/farmacología , Dopamina/metabolismo , Levodopa/farmacología , Red Nerviosa/metabolismo , Animales , Cuerpo Estriado/efectos de los fármacos , Evaluación Preclínica de Medicamentos/métodos , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Red Nerviosa/efectos de los fármacos , Técnicas de Cultivo de ÓrganosRESUMEN
PURPOSE: To evaluate the effect of levodopa on cochlear dynamics and on the medial olivocochlear efferent pathway of idiopathic Parkinson's disease (PD) individuals. METHODS: Individuals with and without PD, followed at a University Hospital, were submitted to Distortion Product Otoacoustic Emissions (DPOAE) and DPOAE Inhibitory Effect (OAEIE) in the presence of contralateral noise. Correlation measures between DPOAE and OAEIE results with Hoehn&Yahr (H&Y) stage, daily dose of levodopa and PD diagnosis period were established. Furthermore, electroacoustic measures were compared between individuals without and those with PD, stratified by dose of levodopa daily administered. RESULTS: Weak negative correlation between DPOAE amplitude and daily dose of levodopa was found, as well positive correlations between EIEOA with daily dose of levodopa and time of PD diagnosis, respectively. Higher DPOAE amplitude was found in individuals with PD using daily doses of levodopa ≤ 600 milligrams when compared to individuals without PD and those with PD using higher doses. EIEOA was lower in individuals using doses ≤ 600 milligrams, when compared to the other groups. CONCLUSION: Daily doses of levodopa up to 600 mg / day increase the cochlear mechanical-transducer responses in 2 and 3 kHz frequencies, while the action of olivocochlear efferent systems is reduced in this region.
OBJETIVO: Analisar o efeito da levodopa na dinâmica coclear, bem como na via eferente olivococlear medial de indivíduos com doença de Parkinson idiopática (DP). MÉTODO: Indivíduos com e sem DP, acompanhados em um hospital universitário, realizaram a pesquisa das emissões otoacústicas por produto de distorção (EOAPD) e do efeito inibitório das EOAPD (EIEOA) na presença de ruído contralateral. Foram estabelecidas as medidas de correlação entre os resultados das EOAPD e do EIEOA com estágio Hoehn&Yahr (H&Y), dose diária de levodopa e tempo de diagnóstico da DP. Além disso, as medidas eletroacústicas foram comparadas entre os indivíduos sem DP e com DP, estratificados de acordo com a dose de levodopa administrada diariamente. RESULTADOS: Foi identificada correlação fraca e negativa entre a amplitude das EOAPD com a dose diária de levodopa e correlações positivas, de força moderada e fraca, entre o EIEOA com a dose diária de levodopa e o tempo de diagnóstico da DP, respectivamente. A amplitude das EOAPD foi maior nos indivíduos com DP em uso de levodopa ≤ 600 miligramas quando comparada à de indivíduos sem DP e com DP, em uso de dose superior. Já o EIEOA foi menor nos indivíduos em uso de doses ≤ 600 miligramas, quando comparado aos demais grupos. CONCLUSÃO: Doses diárias de levodopa iguais ou inferiores a 600 mg/dia aumentam as respostas mecanotransdutoras cocleares nas frequências de 2 e 3 kHz, enquanto que a ação dos sistemas eferentes olivococleares é reduzida nesta região.
Asunto(s)
Antiparkinsonianos/farmacología , Levodopa/farmacología , Emisiones Otoacústicas Espontáneas/efectos de los fármacos , Enfermedad de Parkinson/tratamiento farmacológico , Estimulación Acústica , Adulto , Anciano , Anciano de 80 o más Años , Vías Auditivas/efectos de los fármacos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/complicacionesRESUMEN
Levodopa-induced dyskinesia (LID) is the main side effect associated with levodopa treatment and represents the biggest challenge for Parkinson's disease therapy. While the overexpression of ΔFosB transcription factor is related to the development of LID, few studies have been undertaken on fosB gene transcriptional regulation induced by levodopa in vivo. The aim of this study is to evaluate the expression of ΔFosB mRNA and FosB mRNA in the striatum after acute, chronic, and subchronic levodopa treatment in rats with unilateral 6-OHDA-lesion in the medial forebrain bundle. qRT-PCR was used to compare the levels of ΔFosB and FosB mRNA expression in the dopamine-denervated striatum following levodopa treatment. While the results obtained after a single levodopa dose indicate a significant increase of ∆FosB mRNA expression in the striatum 1 h post-injection, the levels returned to baseline values after 24 h. After subchronic levodopa treatment, the levels of ∆FosB and FosB mRNA expression were lower 1 h post-administration of levodopa in comparison with acute effect. However, after chronic levodopa treatment, ∆FosB mRNA expression in the striatum persisted in dyskinetic rats only, and positive correlation was found between the levels of ∆FosB mRNA expression 1 h after levodopa administration and the level of dyskinetic severity. In summary, acute levodopa treatment led to highly increased levels of ∆FosB mRNA expression in the striatum. While repeated administration induced a partial desensitization of the fosB gene in the striatum, it did not suppress its activity completely, which could explain why dyskinesia appears after chronic levodopa treatment.
Asunto(s)
Antiparkinsonianos/farmacología , Cuerpo Estriado/efectos de los fármacos , Levodopa/farmacología , Trastornos Parkinsonianos/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-fos/metabolismo , Animales , Cuerpo Estriado/metabolismo , Lateralidad Funcional , Expresión Génica/efectos de los fármacos , Masculino , Trastornos Parkinsonianos/metabolismo , ARN Mensajero/metabolismo , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
OBJECTIVES: The aim of this study was to evaluate a possible relationship between DRD2/ANKK1 (rs1800497) and SLC6A3/DAT1 (rs28363170) gene polymorphisms with the response to levodopa (L-DOPA)-therapy in patients with Parkinson's disease (PD). METHODS: One hundred and ninety-five patients with idiopathic PD were investigated. Patients were genotyped for rs1800497 and rs28363170 polymorphisms using PCR-RFLP. Logistic regression was performed to assess the association of polymorphisms with the occurrence of the chronic complications of L-DOPA therapy. KEY FINDINGS: Our results showed association between the occurrence of dyskinesia with an increased greater disease severity (P = 0.007), higher L-DOPA dose (P = 0.007) and use of dopamine agonist (P = 0.020). Moreover, there were significant protective effects for age (P = 0.004) and male subjects (P = 0.006). CONCLUSIONS: Clinical and demographic characteristics of Brazilian PD patients and differences in DRD2 and DAT1 genes may to determine individual variations in the therapeutic response to L-DOPA in the Brazilian PD patients.
Asunto(s)
Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Levodopa/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Receptores de Dopamina D2/genética , Adulto , Factores de Edad , Anciano , Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/efectos adversos , Antiparkinsonianos/farmacología , Brasil , Relación Dosis-Respuesta a Droga , Femenino , Genotipo , Humanos , Levodopa/administración & dosificación , Levodopa/efectos adversos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/fisiopatología , Polimorfismo Genético , Proteínas Serina-Treonina Quinasas/genética , Índice de Severidad de la Enfermedad , Factores Sexuales , Resultado del TratamientoRESUMEN
The nitric oxide (NO) system has been proven to be a valuable modulator of L-DOPA-induced dyskinesia in Parkinsonian rodents. NO activates the enzyme soluble guanylyl cyclase and elicits the synthesis of the second-messenger cGMP. Although we have previously described the anti-dyskinetic potential of NO synthase inhibitors on L-DOPA-induced dyskinesia, the effect of soluble guanylyl cyclase inhibitors remains to be evaluated. The aim of this study was to analyze whether the clinically available non-selective inhibitor methylene blue, or the selective soluble guanylyl cyclase inhibitor ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one), could mitigate L-DOPA-induced dyskinesia in 6-hydroxydopamine-lesioned rats. Here, we demonstrated that methylene blue was able to reduce L-DOPA-induced dyskinesia incidence when chronically co-administered with L-DOPA during 3 weeks. Methylene blue chronic (but not acute) administration (2 weeks) was effective in attenuating L-DOPA-induced dyskinesia in rats rendered dyskinetic by a previous course of L-DOPA chronic treatment. Furthermore, discontinuous methylene blue treatment (e.g., co-administration of methylene blue and L-DOPA for 2 consecutive days followed by vehicle and L-DOPA co-administration for 5 days) was effective in attenuating dyskinesia. Finally, we demonstrated that microinjection of methylene blue or ODQ into the lateral ventricle effectively attenuated L-DOPA-induced dyskinesia. Taken together, these results demonstrate an important role of NO-soluble guanylyl cyclase-cGMP signaling on L-DOPA-induced dyskinesia. The clinical implications of this discovery are expected to advance the treatment options for patients with Parkinson's disease.
Asunto(s)
Antiparkinsonianos/farmacología , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Levodopa/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Animales , Reposicionamiento de Medicamentos/métodos , Oxidopamina/farmacología , Quinoxalinas/farmacología , Ratas Wistar , Transducción de Señal/efectos de los fármacosRESUMEN
RESUMO Objetivo Analisar o efeito da levodopa na dinâmica coclear, bem como na via eferente olivococlear medial de indivíduos com doença de Parkinson idiopática (DP). Método Indivíduos com e sem DP, acompanhados em um hospital universitário, realizaram a pesquisa das emissões otoacústicas por produto de distorção (EOAPD) e do efeito inibitório das EOAPD (EIEOA) na presença de ruído contralateral. Foram estabelecidas as medidas de correlação entre os resultados das EOAPD e do EIEOA com estágio Hoehn&Yahr (H&Y), dose diária de levodopa e tempo de diagnóstico da DP. Além disso, as medidas eletroacústicas foram comparadas entre os indivíduos sem DP e com DP, estratificados de acordo com a dose de levodopa administrada diariamente. Resultados Foi identificada correlação fraca e negativa entre a amplitude das EOAPD com a dose diária de levodopa e correlações positivas, de força moderada e fraca, entre o EIEOA com a dose diária de levodopa e o tempo de diagnóstico da DP, respectivamente. A amplitude das EOAPD foi maior nos indivíduos com DP em uso de levodopa ≤ 600 miligramas quando comparada à de indivíduos sem DP e com DP, em uso de dose superior. Já o EIEOA foi menor nos indivíduos em uso de doses ≤ 600 miligramas, quando comparado aos demais grupos. Conclusão Doses diárias de levodopa iguais ou inferiores a 600 mg/dia aumentam as respostas mecanotransdutoras cocleares nas frequências de 2 e 3 kHz, enquanto que a ação dos sistemas eferentes olivococleares é reduzida nesta região.
ABSTRACT Purpose To evaluate the effect of levodopa on cochlear dynamics and on the medial olivocochlear efferent pathway of idiopathic Parkinson's disease (PD) individuals. Methods Individuals with and without PD, followed at a University Hospital, were submitted to Distortion Product Otoacoustic Emissions (DPOAE) and DPOAE Inhibitory Effect (OAEIE) in the presence of contralateral noise. Correlation measures between DPOAE and OAEIE results with Hoehn&Yahr (H&Y) stage, daily dose of levodopa and PD diagnosis period were established. Furthermore, electroacoustic measures were compared between individuals without and those with PD, stratified by dose of levodopa daily administered. Results Weak negative correlation between DPOAE amplitude and daily dose of levodopa was found, as well positive correlations between EIEOA with daily dose of levodopa and time of PD diagnosis, respectively. Higher DPOAE amplitude was found in individuals with PD using daily doses of levodopa ≤ 600 milligrams when compared to individuals without PD and those with PD using higher doses. EIEOA was lower in individuals using doses ≤ 600 milligrams, when compared to the other groups. Conclusion Daily doses of levodopa up to 600 mg / day increase the cochlear mechanical-transducer responses in 2 and 3 kHz frequencies, while the action of olivocochlear efferent systems is reduced in this region.