Dopamine agonist therapy in Parkinson's disease: Spanish expert consensus on its use in different clinical situations.

BACKGROUND: Different types of therapies were proven effective for the medical management of motor and non-motor symptoms in Parkinson's disease (PD). We aimed to gain consensus on the dopamine agonist (DA) therapy use in different clinical scenarios of Parkinson's disease (PD) patients. METHODS: This consensus study was based on the nominal group technique. Initially, a consensus group comprising 12 expert neurologists in the PD field identified the topics to be addressed and elaborated different evidence-based preliminary statements. Next, a panel of 48 Spanish neurologists expressed their opinion on an internet-based systematic voting program. Finally, initial ideas were reviewed and rewritten according to panel contribution and were ranked by the consensus group using a Likert-type scale. The analysis of data was carried out by using a combination of both qualitative and quantitative methods. The consensus was achieved if the statement reached ≥ 3.5 points in the voting process. RESULTS: The consensus group produced 76 real-world recommendations. The topics addressed included 12 statements related to DA therapy in early PD, 20 statements concerning DA treatment strategy in patients with motor complications, 11 statements associated with DA drugs and their side effects, and 33 statements regarding DA therapy in specific clinical scenarios. The consensus group did not reach a consensus on 15 statements. CONCLUSION: The findings from this consensus method represent an exploratory step to help clinicians and patients in the appropriate use of DA in different stages and clinical situations of PD.

Correlación entre la expresión del receptor dopaminérgico D2 y presencia de movimientos involuntarios anormales (MIA) en un modelo de disquinesia en ratas Wistar hemiparkinsonizadas / Correlation between dopamine receptor D2 expression and presence of abnormal involuntary movements in Wistar rats with hemiparkinsonism and dyskinesia

La enfermedad de Parkinson (EP) se caracteriza por una serie de deficiencias motoras que son tratadas comúnmente con L-DOPA; sin embargo, tras un uso crónico se desarrollan disquinesias inducidas por L-DOPA (DIL). Por otra parte, el origen de las DIL no está del todo claro, pero se asocia con alteración en receptores dopaminérgicos, donde los receptores D2 (RD2) han sido poco estudiados. El presente trabajo buscó: 1) desarrollar y estandarizar un modelo experimental de disquinesia con L-DOPA en ratas hemiparkinsonizadas, y 2) evaluar la correlación entre la expresión del RD2 y la manifestación de movimientos involuntarios anormales (MIA). Se utilizaron 21 ratas Wistar macho asignadas a 3 grupos: control intacto, lesionados (con la neurotoxina 6-OHDA) y lesionados disquinéticos (inyectados con L-DOPA durante 19 días). Los reactivos biológicos se sometieron a pruebas comportamentales para evaluar el deterioro sensoriomotor. Los animales del grupo disquinético desarrollaron de forma gradual MIA durante el tratamiento, siendo mayores los MIA de miembro anterior y menores los de tipo locomotor (p < 0,05). Todos los MIA fueron significativamente evidentes a partir del día 5 y se mantuvieron hasta el último día de inyección. Además, se pudo evidenciar incremento en la densidad del RD2 en el estriado y el cerebro anterior medial en los grupos lesionados con respecto al control, así como también una posible asociación entre la expresión del RD2 y MIA de tipo locomotor. Por lo que concluimos que el RD2 está implicado en el fenómeno disquinético generado con la L-DOPA. (AU)

Parkinson's disease (PD) is characterised by motor alterations, which are commonly treated with L-DOPA. However, long-term L-DOPA use may cause dyskinesia. Although the pathogenic mechanism of L-DOPA-induced dyskinesia is unclear, the condition has been associated with alterations in dopamine receptors, among which D2 receptors (D2R) have received little attention. This study aims to: (i) develop and standardise an experimental model of L-DOPA-induced dyskinesia in rats with hemiparkinsonism; and (ii) evaluate the correlation between D2R expression and presence of abnormal involuntary movements (AIM). We allocated 21 male Wistar rats into 3 groups: intact controls, lesioned rats (with neurotoxin 6-OHDA), and dyskinetic rats (injected with L-DOPA for 19 days). Sensorimotor impairment was assessed with behavioural tests. Dyskinetic rats gradually developed AIMs during the treatment period; front leg AIMs were more severe and locomotor AIMs less severe (P < .05). All AIMs were significantly evident from day 5 and persisted until the last day of injection. D2R density was greater in the striatum and the medial anterior brain of the lesioned and dyskinetic rats than in those of controls. Our results suggest an association between D2R expression and locomotor AIMs. We conclude that RD2 is involved in L-DOPA-induced dyskinesia. (AU)

Correlation between dopamine receptor D2 expression and presence of abnormal involuntary movements in Wistar rats with hemiparkinsonism and dyskinesia. / Correlación entre la expresión del receptor dopaminérgico D2 y presencia de movimientos involuntarios anormales (MIA) en un modelo de disquinesia en ratas Wistar hemiparkinsonizadas.

Parkinson's disease (PD) is characterised by motor alterations, which are commonly treated with L-DOPA. However, long-term L-DOPA use may cause dyskinesia. Although the pathogenic mechanism of L-DOPA-induced dyskinesia is unclear, the condition has been associated with alterations in dopamine receptors, among which D2 receptors (D2R) have received little attention. This study aims to: (i)develop and standardise an experimental model of L-DOPA-induced dyskinesia in rats with hemiparkinsonism; and (ii)evaluate the correlation between D2R expression and presence of abnormal involuntary movements (AIM). We allocated 21 male Wistar rats into 3 groups: intact controls, lesioned rats (with neurotoxin 6-OHDA), and dyskinetic rats (injected with L-DOPA for 19 days). Sensorimotor impairment was assessed with behavioural tests. Dyskinetic rats gradually developed AIMs during the treatment period; front leg AIMs were more severe and locomotor AIMs less severe (P<.05). All AIMs were significantly evident from day 5 and persisted until the last day of injection. D2R density was greater in the striatum and the medial anterior brain of the lesioned and dyskinetic rats than in those of controls. Our results suggest an association between D2R expression and locomotor AIMs. We conclude that RD2 is involved in L-DOPA-induced dyskinesia.

Our experience in prolactinomas larger than 60mm.

INTRODUCTION: Giant prolactinomas (tumor size larger than 40mm) are a rare entity of benign nature. Prolactinomas larger than 60mm are usually underrepresented in published studies and their clinical presentation, outcomes and management might be different from smaller giant prolactinomas. PATIENTS AND METHODS: We retrospective collected data from patients with prolactinomas larger than 60mm in maximum diameter and prolactin (PRL) serum levels higher than 21,200µIU/mL in our series of prolactinomas (283). Data were collected from January 2012 to December 2017. We included three patients with prolactinomas larger than 60mm. RESULTS: At diagnosis, two patients presented neurological symptoms and one nasal protrusion. All patients received medical treatment with dopamine agonists. No surgical procedure was performed. Median prolactin levels at diagnosis was 108,180 [52,594-514,984]µIU/mL. Medical treatment achieved a marked reduction (>99%) in prolactin levels in all cases. Tumor size reduction (higher than 33%) was observed in all cases. In one patient cerebrospinal fluid (CSF) leak was observed after tumor shrinkage. CONCLUSIONS: Dopamine agonists appear to be an effective and safe first-line treatment in prolactinomas larger than 60mm even in life-threatening situations. More studies with a higher number of patients are necessary to obtain enough data to make major recommendations.

O uso do cloridrato de piridoxina para induzir estro em cadelas / The use of pyridoxine chloridrate to induce estrus in female dogs

Os agonistas dopaminérgicos são utilizados para induzir estro em cadelas, pois atuam na síntese e liberação de prolactina. Objetivou-se avaliar o efeito da piridoxina como indutor de estro em cadelas por agir na neurotransmissão dopaminérgica. Foram selecionadas 40 cadelas em anestro, divididas em quatro grupos experimentais, tratadas com 10mg/kg/dia (G1) e 50mg/kg/dia (G2) de cloridrato de piridoxina, 5µg/kg/dia (G3) de cabergolina e grupo controle/placebo (G4) por até 20 dias. Foram realizadas citologias vaginais a cada 24h para acompanhamento do ciclo estral e análises hormonais (FSH, LH e PRL) no dia zero e 120h do início do tratamento. As cadelas do G3 (100%) manifestaram proestro após 12 dias de tratamento aproximadamente, tempo inferior aos demais grupos (P<0,05). Apenas uma cadela do G1 e uma do G2 ficaram gestantes contra oito fêmeas do G3 e nenhuma do G4 (P<0,05). As concentrações plasmáticas de prolactina foram reduzidas nas fêmeas do G2 e G3 (P<0,05). As demais avaliações hormonais não sofreram influência do tratamento (P>0,05). O cloridrato de piridoxina foi ineficiente para induzir estro em cadelas, mas foi capaz de suprimir a prolactina, de forma semelhante à cabergolina, quando utilizado na dose de 50mg/kg/dia.(AU)

Dopaminergic agonists are used to induce estrus in female dogs as they act in the synthesis and release of prolactin. The objective of this study was to evaluate the effect of pyridoxine as an inducer of estrus by acting on dopaminergic neurotransmission. A total of 40 female dogs in anestrous were divided into four experimental groups treated with 10mg/kg/day (G1) and 50mg/kg/day (G2) of pyridoxine hydrochloride, 5µg/kg/day (G3) of cabergoline and control group/placebo (G4) for up to 20 days. Vaginal cytologies were performed every 24h for follow-up of the estrous cycle and hormonal analyzes (FSH, LH and PRL) on day zero and 120 hours after the start of treatment. The female dogs from G3 (100%) showed proestrus after 12 days of treatment, less time than the other groups (P< 0.05). Only one female from G1 and one from G2 were pregnant against eight from G3 and none from G4 (P< 0.05). Plasma concentrations of prolactin were reduced by treatment in females from G2 and G3 (P< 0.05). The other hormonal evaluations were not influenced by the treatment (P> 0.05). Pyridoxine chloridrate was inefficient to induce estrus in female dogs but was able to suppress prolactin when used at a dose of 50mg/kg/day.(AU)

Resolution of headache after reduction of prolactin levels in hyperprolactinemic patients / Resolução de cefaleia após redução dos níveis de prolactina em pacientes com hiperprolactinemia

Abstract Prolactin (PRL) secreting adenomas are associated with high incidence of headache. The role of hyperprolactinemia in the headache context is not clear, nor is the effect of its treatment on headache. Methods: The present longitudinal study evaluated hyperprolactinemic patients (69), in terms of presence and characteristics of headache before and after hyperprolactinemia treatment. Results: Headache was reported by 45 (65.2%) patients, independent of the etiology of hyperprolactinemia. The migraine phenotype was the most prevalent (66.6%). Medications used in the treatment of headache not changed during the study. The first line of treatment of hyperprolactinemia was dopaminergic agonists. In the last reevaluation, PRL level under treatment was within the reference range in 54.7% of the cases, and it was observed complete or partial resolution of the headache in 75% of the cases. The median PRL at this time in patients with complete headache resolution was 17 ng/mL, in those who reported partial recovery was 21 ng/mL, and in those in whom the headache did not change was 66 ng/mL, with a significant difference between the group with complete headache resolution vs. the group with unchanged headache (p=0.022). In the cases with complete headache resolution, the median fall on PRL levels was 89% and in those cases with partial headache resolution 86%, both significantly different (p<0.001) from the fall in the cases with an unchanged headache. Conclusion: Data allow us to conclude that, in this series, in the majority of cases the reduction in the level of PRL was followe3d by cessation or relief of the pain.

Resumo Os adenomas secretores de prolactina (PRL) estão associados à alta incidência de cefaleia. O papel da hiperprolactinemia no contexto da dor de cabeça não está claro, nem o efeito da redução dos níveis da PRL na cefaleia. Métodos: O presente estudo longitudinal avaliou pacientes hiperprolactinêmicos (69), quanto à presença e às características da cefaleia antes e após o tratamento da hiperprolactinemia. Resultados: Cefaleia foi relatada por 45 (65,2%) pacientes, independente da etiologia da hiperprolactinemia. O fenótipo de enxaqueca foi mais prevalente (66,6%). Os medicamentos usados ​​no tratamento da cefaleia não foram alterados durante o estudo. A primeira linha de tratamento da hiperprolactinemia foram os agonistas dopaminérgicos. Na última reavaliação, o nível de PRL sob tratamento estava dentro da faixa de referência em 54,7% dos casos, observando-se resolução completa ou parcial da cefaleia em 75% dos casos. A mediana de PRL neste momento em pacientes com resolução completa da cefaleia foi de 17 ng/mL, nos que relataram recuperação parcial foi de 21 ng/mL, e naqueles em que a cefaleia não se alterou foi de 66 ng/mL, com uma diferença significativa entre o grupo com resolução completa da cefaleia versus o grupo com cefaleia inalterada (p=0,022). Nos casos com resolução completa da cefaleia, a queda mediana nos níveis de PRL foi de 89% e nos casos com resolução parcial de cefaleia de 86%, ambos significativamente diferentes (p<0,001) da queda nos casos com cefaleia inalterada. Conclusão: Os dados permitem concluir que, nesta série, na maioria dos casos, a redução do nível de PRL foi seguida pela cessação ou alívio da dor.

Preventive effects of Topiramate on methylphenidate induced behavioral disorders / Efectos preventivos de topiramato en los trastornos del comportamiento inducidos por metilfenidato

Neuronal cell damage is often caused by prolonged misuse of Methylphenidate (MPH). Topiramate (TPM) carries neuroprotective properties but its assumed mechanism remains unclear. The present study evaluates in vivo role of various doses of TPM and its mechanism against MPH-induced motor activity and related behavior disorder. Thus, we used domoic acid (DOM), bicuculline (BIC), Ketamine (KET), Yohimibine (YOH) and Haloperidole (HAL) as AMPA/kainite, GABAA, NMDA, ɑ2 adrenergic and D2 of dopamine receptor antagonists respectively. Open Field Test (OFT), Elevated Plus Maze (EPM) and Forced Swim Test (FST) were used to study motor activity, anxiety and depression level. TPM (100 and 120 mg/kg) reduced MPH-induced rise and inhibited MPH-induced promotion in motor activity disturbance, anxiety and depression. Pretreatment of animals with KET, HAL, YOH and BIC inhibited TPM- improves anxiety and depression through the interacting with Dopaminergic, GABAA, NMDA and ɑ2-adrenergic receptors.

El daño a las células neuronales a menudo es causado por el uso prolongado de metilfenidato (MPH). El topiramato (TPM) tiene propiedades neuroprotectoras, pero su mecanismo de acción no es claro. El presente estudio evalúa el papel in vivo de varias dosis de TPM y su mecanismo contra la actividad motora inducida por MPH y el trastorno de comportamiento relacionado. Utilizamos ácido domoico (DOM), bicuculina (BIC), ketamina (KET), yohimbina (YOH) y haloperidol (HAL), así como antagonistas AMPA/kainato, GABAA, NMDA, ɑ2-adrenérgico y D2 dopaminérgicos, respectivamente. Se utilizaron las pruebas de campo abierto (OFT), elevación de laberinto (EPM) y natación forzada (FST) para estudiar la actividad motora, la ansiedad y el nivel de depresión. El TPM (100 y 120 mg/kg) redujo el aumento inducido por MPH e inhibió la promoción inducida por MPH en la alteración de la actividad motora, la ansiedad y la depresión. El tratamiento previo de animales con KET, HAL, YOH y BIC inhibió el TPM, mejora la ansiedad y la depresión a través de la interacción con los receptores dopaminérgicos, GABAA, NMDA y ɑ2-adrenérgico.

Neuroprotective potential of polydatin against motor abnormalities and dopaminergic neuronal loss in rotenone induced Parkinson model / Potencial neuroprotector de la polidatina contra las anomalías motoras y la pérdida neuronal dopaminérgica en un modelo de Parkinson inducido por la rotenona

Among the neurodegenerative disorders, Parkinson disease (PD) is ranked as second most common. The pathological hallmark is selective degeneration of the dopaminergic neurons in the nigro-striatal regions of brain with appearance of the Lewy bodies. Present study explores the neuro-protective potential of polydatin in terms of amelioration of degeneration of dopaminergic neurons in nigro-striatal regions of brain and distorted neuromotor behavior in the rotenone model of Parkinson's disease. Thirty-six male Sprague Dawley rats were divided into three groups. Group A (control), Group B (rotenone treated) and Group C (rotenone+polydatin treated). Rotenone was administrated intraperitoneally (i.p) at a dose of 3 mg/kg/body weight while polydatin was given i.p. at a dose of 50 mg/ kg/body weight for four weeks. Then, animals were sacrificed; substantia nigra (SN) & striatum isolated from brain and five micron thick sections were prepared. Cresyl violet (CV), H&E and Immuno-histochemical staining using anti-TH antibody was done. Motor behavior was assessed weekly throughout the experiment using five different methods. Rotenone treated parkinsonian animals showed deterioration of motor behavior, weight loss, loss of dopaminergic neurons and diminished immune-reactivity in the sections from the nigrostriatal regions of these animals Polydatin+rotenone treatment showed contradicting effects to parkinsonism, with amelioration in weight loss, neuro-motor behavior, dopaminergic loss and immune-reactivity against dopaminergic neurons. Present study revealed a neuro-protective potential of polydatin in animal model of PD by ameliorating the neuro-motor abnormalities and degeneration of dopaminergic neurons in nigrostriatal regions.

Entre los trastornos neurodegenerativos, la enfermedad de Parkinson (EP) se clasifica como la segunda más común. El sello patológico es la degeneración selectiva de las neuronas dopaminérgicas en las regiones nigro-estriatales del cerebro, con la aparición de los cuerpos de Lewy. El presente estudio explora el potencial de protección neuronal de la polidatina en términos de la mejora de la degeneración de las neuronas dopaminérgicas en las regiones nigro-estriatales del cerebro y el comportamiento neuromotor distorsionado en el modelo de rotenona de la enfermedad de Parkinson. Treinta y seis ratas macho Sprague Dawley se dividieron en tres grupos: Grupo A (control), Grupo B (tratado con rotenona) y Grupo C (tratamiento con rotenona + polidatina). La rotenona se administró por vía intraperitoneal (i.p.) a una dosis de 3 mg/kg/peso corporal, mientras que la polidatina se administró i.p. a una dosis de 50 mg/kg/ peso corporal durante cuatro semanas. Posteriormente, los animales fueron sacrificados. Se aislaron la substantia nigra (SN) y cuerpo estriado de los cerebros y se realizaron secciones de cinco micras de espesor. Se realizó una tinción de violeta de cresilo (CV), H&E y tinción inmunohistoquímica usando anticuerpo anti-TH. El comportamiento motriz se evaluó semanalmente durante todo el experimento utilizando cinco métodos diferentes. Los animales parkinsonianos tratados con rotenona mostraron deterioro del comportamiento motriz, pérdida de peso, pérdida de neuronas dopaminérgicas y disminución de la reactividad inmune en las secciones de las regiones nigroestriadas. El tratamiento con polidatina + rotenona mostró efectos contrarios al parkinsonismo, con mejoría en la pérdida de peso, en el comportamiento motor, en la pérdida dopaminérgica y en la reactividad inmune contra las neuronas dopaminérgicas. El presente estudio reveló un potencial de protección neuronal de la polidatina en el modelo animal de la EP al mejorar las anomalías neuro-motoras y la degeneración de las neuronas dopaminérgicas en las regiones nigroestriatales.

Pharmacological treatment with cabergoline in three cats with acromegaly / Tratamiento farmacológico con cabergolina en tres gatos con acromegalia / Tratamento farmacológico com cabergolina em três gatos com acromegalia

Abstract Anamnesis: Three cats diagnosed with diabetes mellitus (DM) were referred for examination due to the presence of insulin resistance signs, which included polyuria, polydipsia, polyphagia and high fructosamine levels, even with insulin glargine doses greater than 2 U/Kg/application. Clinical and laboratory findings: All patients had enlarged facial features along with increased interdental space. The biochemical tests revealed high IGF-1 concentrations. The magnetic resonance imaging displayed enlarged pituitary gland in one of the cats and images compatible with a pituitary macroadenoma in the other two. Acromegaly was the final diagnosis. Treatment approach: Oral cabergoline at 10 µg/Kg every 48 h was administered. Conclusion: The treatment with cabergoline successfully decreased IGF-1 concentrations and all insulin resistance signs, and it enhanced glycemic control for the DM in the three cats. Our results suggest cabergoline could be used for the treatment of acromegaly in cats.

Resumen Anamnesis: Tres gatos diagnósticados con diabetes mellitus (DM) fueron referidos para ser examinados debido a la presencia de signos de resistencia a la insulina, que incluían poliuria, polidipsia, polifagia, y de valores elevados de fructosamina, incluso con dosis de insulina glargina mayor a 2 U/Kg/aplicación. Hallazgos clínicos y de laboratorio: Los tres gatos presentaron amplios rasgos faciales con aumento de los espacios interdentales. En la bioquímica sanguínea, la concentración de IGF-1 fue hallada elevada. La imagen por resonancia magnética mostró agrandamiento de la glándula hipófisis en uno de los gatos, e imágenes compatibles con un macroadenoma de hipófisis en los otros dos. El diagnóstico final fue de acromegalia. Abordaje terapéutico: Se administraron 10 µg/Kg de cabergolina cada 48 h, via oral. Conclusión: El tratamiento con cabergolina logró disminuir las concentraciones de IGF-1 y todos los signos de resistencia a la insulina con mejor control glucémico de la DM en los tres gatos. Los anteriores hallazgos sugieren que la cabergolina es una opción viable para el tratamiento de la acromegalia en gatos.

Resumo Anamnese: Três gatos diagnosticados com diabetes mellitus (DM) foram encaminhados para exame devido à presença de sinais de resistência à insulina, que incluíram poliúria, polidipsia, polifagia e altos níveis de fructosamina, mesmo com doses de insulina glargina superiores a 2 U/Kg/aplicação. Achados clínicos e de laboratório: Os três gatos apresentavam mudanças dos rasgos faciais e aumento do espaço interdental. As provas bioquímicas revelaram altas concentrações de IGF-1. A ressonância magnética mostrou incremento do tamanho da glândula pituitária em um dos gatos e imagens compatíveis com um macroadenoma pituitário nos outros dois. Com estes dados chegou-se ao diagnóstico de acromegalia. Enfoque terapêutico: Foram dadas 10 µg/Kg de cabergolina a cada 48 h, via oral. Conclusão: O tratamento com cabergolina diminuiu com sucesso as concentrações de IGF-1 e todos os sinais de resistência à insulina e aumentou o controlo glicémico para a DM nos três gatos. Conclusões anteriores evidenciam que a cabergolina é uma opção viável para o tratamento da acromegalia em gatos.

Novedoso profármaco derivado de la lilolidina con actividad dopaminérgica central / Novel prodrug derivative from lilolidine with central dopaminergic activity

La desregulación de la neurotransmisión dopaminérgica central ha sido relacionada con enfermedades neurodegenerativas, tales como la enfermedad de Parkinson y la Corea de Huntington. En las últimas décadas son muchos los compuestos con actividad dopaminérgica central que se han diseñado, sintetizado y evaluado farmacológicamente y, a pesar de estos esfuerzos, no se ha logrado obtener un fármaco efectivo capaz de mejorar o curar estas patologías. Con el fin de contribuir en esta búsqueda primordial, en el presente trabajo se describe el diseño, la síntesis y la evaluación farmacológica del derivado de la lilolidina, clorhidrato de 6-(2-aminoindanil)-N-(2,4,5,6-tetrahidro-1H-pirrolo[3,2,1-ij]quinolina) 4 (MAIL), con el propósito de restablecer la homeostasis de la transmisión dopaminérgica en la enfermedad de Parkinson y/o la Corea de Huntington. Para ello, se utilizaron las diferentes estrategias nigroesclásicas y heterocíclicas enmarcadas en la síntesis orgánica a través de una ruta convergente. Asimismo, se realizó la evaluación farmacológica preliminar, al determinar el comportamiento estereotipado en ratas Sprague-Dawley cuando les fue administrado el derivado de la lilolidina, por las vías ICV (intracerebroventricular) e IE (intraestriatal). Los resultados obtenidos del compuesto 4 mostraron una acción central como agonista, a través de mecanismos dopaminérgicos.

Central dopaminergic neurotransmission deregulation has been related with neurodegenerative sicknesses, like Parkinson’s disease and Huntington’s Chorea. During the last decades, many compounds with dopaminergic activity have been designed, synthesized and pharmacologically evaluated, but despite all these efforts, an effective drug able to improve or cure these pathologies has not been achieved. With the purpose to contribute in this essential search, this work describes the design, synthesis and pharmacological evaluation of the lilolidine derivative, 6-(2-aminoindanyl)-N-(2,4,5,6-tetrahydro-1H-pyrrolo[3,2,1-ij]quinoline hydrochloride) 4 (MAIL), with the purpose of restoring the homeostasis of dopaminergic transmission in Parkinson’s disease and/or Huntington’s Chorea. To perform that, different organic synthesis classic and heterocyclic strategies were employed through a convergent route. Also, a preliminar pharmacological evaluation was done, where the stereotyped behavior of Sprague-Dawley rats was studied after the ICV (intracerebroventricular) and IE (intrastriatum) administration of the lilodine derivative. The results obtained of compound 4 showed a central dopaminergic agonist activity through dopaminergic mechanisms.

Polimorfismos del receptor D2 / D2 receptor polymorphisms

Los prolactinomas son tumores bien diferenciados que se originan en las células lactotropas pituitarias, una línea celular que secreta fisiológicamente prolactina (PRL). A nivel hipofisario, la dopamina está implicada en la regulación de la secreción de PRL por las células lactotropas y este efecto inhibitorio está mediado por la activación del receptor de prolactina tipo 2 (DRD2). Hay varios polimorfismos del DRD2, el primero y más estudiado es TaqI A1; está demostrado que este alelo se encuentra asociado a una reducción de la actividad cerebral dopaminérgica, además de observarse una reducción en su capacidad de unión de aproximadamente un 30%. Este alelo se ha vinculado con una menor densidad de DRD2 en el cuerpo estriado, especialmente en el putamen y caudado ventral, y la cantidad de DRD2 en portadores del alelo A1 fue un 30-40% más bajo que en los no portadores (es decir, TaqI A2 homocigotos). En la literatura, hay evidencia que apoya la posible participación de los polimorfismos DRD2 en la regulación de la secreción hormonal.

Prolactinomas are well differentiated tumours that originate in the pituitary lactotrope cells, a cell line that physiologically secretes prolactin (PRL). At pituitary level, dopamine is involved in the regulation of PRL secretion by lactotropes, and this inhibitory effect is mediated by activation of prolactin type 2 receptor (DRD2). Of the several DRD2 polymorphisms, the first and most studied is TaqI A1. It has been demonstrated that this allele is associated with a reduced dopaminergic brain activity, and a reduction in its binding capacity of approximately 30% also being observed. This allele was associated with a lower density of DRD2 in the striatum, especially in the putamen and ventral caudate. The amount of DRD2 in A1 allele carriers was 30 - 40% lower than in non-carriers (this is, TaqI A2 Homozygotes). There is evidence in the literature, that supports the possible involvement of DRD2 polymorphisms in the regulation of hormonal secretion.

Efecto de la Nicotina en un Modelo de Activación Dopaminérgica en Timing: Hacia un Modelo en Esquizofrenia / Nicotine Effect on a Model of Hyperactivation of the Dopaminergic System using a Temporal Bisection Task: Towards a Model in Schizophrenia

Resumen: La esquizofrenia es un trastorno que implica múltiples anomalías bioquímicas. Los pacientes con esquizofrenia tienen una prevalencia muy alta de tabaquismo, que se ha relacionado con el hecho de que la nicotina tiene importantes interacciones con la dopamina, siendo teóricamente capaz de reducir algunos de los síntomas positivos, negativos y cognitivos de la esquizofrenia. Sin embargo, existe controversia respecto al papel de la nicotina en la sintomatologia de los pacientes con esquizofrenia fumadores. El objetivo de la presente investigación fue evaluar el efecto de la administración de nicotina en un modelo de hiperactivación del sistema dopaminérgico, mediante una tarea de estimación temporal en animales del laboratorio. Los resultados sugieren una recuperación de las habilidades cognitivas, sin embargo el efecto procognitivo de la nicotina depende de una gran variedad de factores, incluyendo los sistemas neurales subyacentes a las tareas usadas y su interacción con otros fármacos y sistemas. Se propone que la evaluación del procesamiento de la información temporal puede servir como una herramienta en la comprensión y evaluación de los déficits cognitivos de la esquizofrenia.

Abstract: Schizophrenia is a disorder that involves multiple biochemical abnormalities. Patients with schizophrenia have a high prevalence of smoking, which has been linked with the fact that nicotine has significant interactions with dopamine, theoretically being able to reduce some of the positive, negative and cognitive symptoms of schizophrenia. However, there is controversy about the role of nicotine on symptoms of patients with schizophrenia who smoke. The objective of this research was to evaluate the effect of nicotine administration in a model of hyperactivation of the dopaminergic system using a temporal bisection task. The results suggest a recovery of cognitive skills, but the procognitive effect of nicotine depends on a variety of factors, including the underlying neural systems of the tasks and its interaction with other drugs and systems. It is proposed that the evaluation of the temporal processing of information could be a tool in the understanding and assessment of cognitive deficits of schizophrenia.

El sistema antioxidante del glutatión en la etiopatología de la disfunción nigro-estriatal / Glutathione antioxidant system in the etiopathology of nigrostriatal dysfunction

La enfermedad de Parkinson es una enfermedad neurodegenerativa crónica que afecta a las personas de la tercera edad. En una minoría de los casos la enfermedad es de origen genético pero en el resto, la causa es idiopática. En este sentido, la acumulación de los radicales libres y la pérdida de la homeostasis del glutatión se han señalado como posibles agentes causales. El presente texto se propuso revisar las evidencias experimentales que apoyan la participación de los radicales libres y la pérdida de la homeostasis del glutatión en el comienzo y la progresión de la degeneración de la substantianigrapars compacta. El estrés oxidativo en la enfermedad de Parkinson´s puede estar relacionado con las propiedades pro-oxidantes intrínsecas de la dopamina y elevadas concentraciones de hierro en la substantianigrapars compacta, que promueven la oxidación de la dopamina y la generación de especies reactivas del oxígeno. Cualquier evento que desencadene estos mecanismos, genera un daño celular. La disminución del glutatión es una de las alteraciones bioquímicas más tempranas, detectadas en asociación con la enfermedad de Parkinson y se ha relacionado con la inhibición del complejo I de la cadena de transporte mitocondrial, daño oxidativo, activación glial, entre otros que favorecen la neurodegeneración. Estas evidencias sugieren la necesidad de mantener la homeostasis del glutatión en el sistema dopaminérgico y su vínculo con la etiología de la degeneración nigro-estriatal, lo que tiene una potencial aplicación en la práctica clínica.

Parkinson's disease is a chronic neurodegenerative condition affecting elderly persons. In a minority of cases the disease has a genetic origin, but in most the cause is idiopathic. Accumulation of free radicals and loss of glutathione homeostasis have been pointed at as possible causal agents. The purpose of the study was to review experimental evidence supporting the involvement of free radicals and loss of glutathione homeostasis in the outset and progress of substantia nigra pars compacta degeneration. Oxidative stress in Parkinson's disease may be related to the intrinsic pro-oxidant properties of dopamine and high iron concentrations in the substantia nigra pars compacta, promoting dopamine oxidation and the generation of reactive oxygen species. Any event triggering these mechanisms will cause cell damage. Glutathione reduction is one of the earliest biochemical alterations detected in association with Parkinson's disease, and it has been related to the inhibition of complex I of the mitochondrial transport chain, oxidative damage and glial activation, among other factors leading to neurodegeneration. This evidence points to the need to maintain glutathione homeostasis in the dopaminergic system, as well as its relationship to the etiology of nigrostriatal degeneration, of potential application in clinical practice.

El sistema antioxidante del glutatión en la etiopatología de la disfunción nigro-estriatal / Glutathione antioxidant system in the etiopathology of nigrostriatal dysfunction

La enfermedad de Parkinson es una enfermedad neurodegenerativa crónica que afecta a las personas de la tercera edad. En una minoría de los casos la enfermedad es de origen genético pero en el resto, la causa es idiopática. En este sentido, la acumulación de los radicales libres y la pérdida de la homeostasis del glutatión se han señalado como posibles agentes causales. El presente texto se propuso revisar las evidencias experimentales que apoyan la participación de los radicales libres y la pérdida de la homeostasis del glutatión en el comienzo y la progresión de la degeneración de la substantianigrapars compacta. El estrés oxidativo en la enfermedad de Parkinson´s puede estar relacionado con las propiedades pro-oxidantes intrínsecas de la dopamina y elevadas concentraciones de hierro en la substantianigrapars compacta, que promueven la oxidación de la dopamina y la generación de especies reactivas del oxígeno. Cualquier evento que desencadene estos mecanismos, genera un daño celular. La disminución del glutatión es una de las alteraciones bioquímicas más tempranas, detectadas en asociación con la enfermedad de Parkinson y se ha relacionado con la inhibición del complejo I de la cadena de transporte mitocondrial, daño oxidativo, activación glial, entre otros que favorecen la neurodegeneración. Estas evidencias sugieren la necesidad de mantener la homeostasis del glutatión en el sistema dopaminérgico y su vínculo con la etiología de la degeneración nigro-estriatal, lo que tiene una potencial aplicación en la práctica clínica(AU)

Parkinsons disease is a chronic neurodegenerative condition affecting elderly persons. In a minority of cases the disease has a genetic origin, but in most the cause is idiopathic. Accumulation of free radicals and loss of glutathione homeostasis have been pointed at as possible causal agents. The purpose of the study was to review experimental evidence supporting the involvement of free radicals and loss of glutathione homeostasis in the outset and progress of substantia nigra pars compacta degeneration. Oxidative stress in Parkinsons disease may be related to the intrinsic pro-oxidant properties of dopamine and high iron concentrations in the substantia nigra pars compacta, promoting dopamine oxidation and the generation of reactive oxygen species. Any event triggering these mechanisms will cause cell damage. Glutathione reduction is one of the earliest biochemical alterations detected in association with Parkinsons disease, and it has been related to the inhibition of complex I of the mitochondrial transport chain, oxidative damage and glial activation, among other factors leading to neurodegeneration. This evidence points to the need to maintain glutathione homeostasis in the dopaminergic system, as well as its relationship to the etiology of nigrostriatal degeneration, of potential application in clinical practice(AU)

Prolactinoma / Prolactinoma

Os prolactinomas são os adenomas de hipófise mais comuns e frequentemente afetam mulheres jovens, em faixa etária de fertilidade. A hiperprolactinemia causa hipogonadismo, irregularidade menstrual ou amenorreia em mulheres, níveis baixos de testosterona sérica em homens e infertilidade e disfunção sexual em ambos os gêneros. Macroprolactinomas podem causar cefaleia, aliteração visual e hipopituitarismo. O tratamento clínico com agonista dopaminérgico é o padrão-ouro, sendo a cabergolina a droga de escolha por sua maior eficácia e tolerabilidade. Em cerca de 20% dos casos, o tratamento é parcial ou totalmente ineficaz, situação na qual a cirurgia, em geral por via transesfenoidal, está indicada. A radioterapia é indicada somente para controle de crescimento tumoral em casos invasivos/agressivos. Nos macroprolactinomas invasivos, a abordagem em geral necessária é a de diversas modalidades terapêuticas combinadas, incluindo debulking e drogas recém-aprovadas como a temozolamida. Com relação à gestação, a droga de escolha para induzir a ovulação ainda é a bromocriptina. Nos casos de microprolactinomas e de macroprolactinomas intrasselares, o agonista dopaminérgico pode ser suspenso após a confirmação da gestação. Nos macroprolactinomas, o manejo deve ser individualizado.

Prolactinomas are the most common pituitary adenomas that affect young women at fertile age. Hyperprolactinemia causes hypogonadism, menstrual irregularities or amenorrhea in women, low serum testosterone levels in men, and infertility and sexual dysfunction in both men and women. Macroprolactinomas may cause cephalea, visual disturbance, and hypopituitarism. Clinical treatment with dopamine agonists is the gold standard, with cabergoline as the first choice due to its greater efficiency and tolerability. In about 20% of the cases, treatment is partially or completely ineffective, a situation in which surgery, in general by transsphenoidal route, is indicated. Radiotherapy is indicated only in the control of tumor growth in invasive/aggressive cases. In invasive macroprolactinoma, the necessary approach, in general, is the combination of several therapeutic modalities, including debulking and recently-approved drugs, such as temozolamide. As for pregnancy, the drug of choice to induce ovulation still is bromocriptine. In the cases of microprolactinomas and intrasselar macroprolactinomas, the treatment with dopaminergic agonists may be suspended after pregnancy is confirmed. In macroprolactinomas, management should be individualized.

Dopamine transporter imaging in clinically unclear cases of parkinsonism and the importance of Scans Without Evidence of Dopaminergic Deficit (SWEDDs) / Neuroimagem do transportador de dopamina em casos de parkinsonismo clinicamente indefinidos e a importância dos SWEDDs (exames sem evidência de déficit dopaminérgico)

The clinical diagnosis of Parkinson's disease (PD) is susceptible to misdiagnosis, especially in the earlier stages of the disease. Recently, in vivo imaging techniques assessing the presynaptic dopamine transporter (DAT) have emerged as a useful tool in PD diagnosis, improving its accuracy. OBJECTIVE: It was to illustrate the clinical usefulness of a brain single-photon emission computed tomography (SPECT) DAT ligand, and highlight relevant aspects of scans without evidence of dopaminergic deficit (SWEDDs) in this context. CASES: We described four representative patients with clinically unclear parkinsonian syndromes who underwent [99mTc]-TRODAT-1 SPECT and reviewed the clinical implications. CONCLUSION: DAT-SPECT is an important, cost-effective, technique for the differential diagnosis of parkinsonian syndromes. Additionally, SWEDD cases present clinical and paraclinical peculiarities that may retrospectively identify them as essential/dystonic tremor. The lack of histopathological data limits further conclusions.

O diagnóstico clínico da doença de Parkinson (DP) pode estar sujeito a erros especialmente nas fases iniciais da doença. Recentemente, técnicas de imagem in vivo que avaliam o transportador de dopamina pré-sináptico (DAT) surgiram como uma ferramenta empregada no diagnóstico da DP, melhorando sua acurácia. OBJETIVO: Foi demonstrar a utilização clínica de um traçador de tomografia computadorizada por emissão de fóton único (SPECT) e destacar importantes aspectos dos casos de SWEDDs (exames sem evidência de déficit dopaminérgico) neste contexto. CASOS: Descrevemos quatro pacientes representativos de síndromes parkinsonianas clinicamente incertas submetidos a [99mTc]-TRODAT-1 SPECT e revisamos suas implicações. CONCLUSÃO: O DAT-SPECT é uma técnica importante e eficiente para o diagnóstico diferencial das síndromes parkinsonianas. Além disso, os casos de SWEDDs apresentam peculiaridades clínicas e paraclínicas que podem retrospectivamente identificá-los como tremor essencial ou tremor distônico. As conclusões têm alcance limitado pela falta de dados histopatológicos.

Agonistas dopaminérgicos para prolactinomas: quando, quanto e por quanto tempo? / Dopamine agonists for prolactinomas: when, how much and how long?

Os prolactinomas são os tumores hipofisários mais comuns e têm como tratamento de escolha os agonistas dopaminérgicos, que propiciam normalização dos níveis de prolactina, redução tumoral e reversão da galactorreia e das manifestações do hipogonadismo na maioria dos casos. A cabergolina é preferível a bromocriptina por ser mais eficaz e mais bem tolerada. Todo macroprolactinoma, a princípio, deve ser tratado, e a terapia dos microprolactinomas pode ser reservada para casos de amenorreia, galactorreia incômoda, distúrbios sexuais ou infertilidade. Ainda existem controvérsias sobre a dose máxima desses medicamentos e sobre a duração ideal do tratamento. Sugerem os autores sua suspensão depois de 24 meses, caso tenha havido normalização dos níveis de prolactina, particularmente quando a ressonância magnética hipofisária não revele anormalidade.

Prolactinomas are the most common hipophisary tumors. Their treatment of choice are dopamine agonists that provide in most cases normalization of prolactin levels, tumor reduction and reversal of both galactorrhea and hypogonadism symptoms. Cabergoline is preferable to bromocriptine because it is more effective and better tolerated. While all macroprolactinomas, a priori, should be treated, the therapy of microprolactinomas can be reserved for cases of amenorrhea, bothersome galactorrhea, sexual disturbances or infertility. There is still controversy about the maximum dose of dopamine agonists and the ideal duration of treatment. The authors suggest treatment withdrawal after 24 months if there has been normalization of prolactin levels, particularly in patients with normal pituitary magnetic resonance findings.