Meccanismo d'azione del Pramipexolo nella terapia della malattia di Parkinson

Pramipexole (PPX) is a dopamine (DA) D3 and D2 receptors agonist widely used alone or in combination with levodopa as Dopamine Replacement Therapy in Parkinson’s disease. In clinical and preclinical studies, PPX improved motor deficits, this evidence led to lowering daily dose of levodopa, delaying the motor side effects associated with its use. Recently, PPX administration has been associated to the development of addictive-like behaviors related to the DA Dysregulation Syndrome, particularly in a subpopulation of treated patients, characterized by impulsive-compulsive personality traits as well as previous addiction’s experience. Based on these evidences, the aim of this study was twofold: first to investigate the pharmacological action of PPX, using a unilateral model of Parkinson’s disease in which 6-OHDA was injected in the medial forebrain bundle. After two weeks, we tested in primed and naive rats, the ability of three different doses of PPX (0,035; 0,1 and 0,35 mg/kg s.c.), to induce contralateral turning behavior as well c-fos expression after pretreatment of DA D1 antagonist SCH 39166. Next, we checked the ability of PPX to induce contralateral rotations after D2 (eticlopride) and D3 (S33084) DA antagonist pretreatment. In order to investigate the role of PPX (0,05 mg/kg s.c.) in behavioral sensitization, we tested its effect with S33084 pretreatment in levodopa sensitized rats. Second, we assessed the correlation between PPX treatment, Parkinson’s disease and the onset of DA Dysregulation Syndrome on Conditioned Place Preference (CPP) paradigm. To do this, 6-OHDA was injected bilaterally in DA striatal terminals, in three different strains of rat: the addiction prone Lewis (LEW), the addiction resistant Fisher 344 (F344) inbred strains, and the Sprague Dawley (SD) outbred strain. Furthermore, to test its rewarding properties, PPX was directly infused in the nucleus accumbens shell (NAc), a DA mesolimbic region known to be involved in the rewarding effects of drugs of abuse, in healthy rats belonging to the above mentioned strains. We discovered that in primed rats, PPX (0,35 mg/kg s.c.) induced turning behavior that was increased by SCH 39166 pretreatment (0,1 mg/kg s.c.). No effect was seen in naive rats both for turning behavior and c-fos expression. D2 receptors antagonist eticlopride (0,1 mg/kg s.c.) reduced PPX-induced turning behavior more than D3 receptors antagonist S33084 (0,5 mg/kg s.c.), also a previous levodopa sensitization increased PPX-induced turning behavior on its first administration. This suggests that PPX’s action could be related to D2 stimulation, and it seems to require a previous D1/D2 stimulation to observe a behavioral outcome. PPX (1 mg/kg s.c.) was able to induce a significant CPP in SD and LEW lesioned rats but not in F344 and control rats, and the persistence of preference was stronger in LEW than in SD rats. When injected into the NAc shell, PPX (5 μg/0.5 μl) induced CPP in all rat strains, but the persistence of its effect was more strong in LEW compared to SD and F344 rats. These results suggest that the parkinsonian state might be more sensitive to the rewarding properties of PPX, which do not seem entirely influenced by phenotype

Beta-diversity and stressor specific index reveal patterns of macroinvertebrate community response to sediment flushing

Abstract Anthropogenic increase of fine sediment loading is one of the main pressures for rivers worldwide. Particularly, Alpine streams are increasingly facing this issue due to sediment flushing operations from hydropower reservoirs, aimed at recovering storage for preserving electricity generation. Although Controlled Sediment Flushing Operations (CSFOs) are becoming increasingly frequent, ecological indicators to adequately assess and monitor their impact on the stream ecosystem have been poorly developed. In this work, we aimed to perform a screening of currently available biomonitoring tools to evaluate the CSFO effects on the riverine biota and adequately assess its recovery, starting from the recognition of the main ecological mechanisms triggered by the mentioned activities on benthic macroinvertebrate communities. We used two independent datasets concerning two reservoirs in the central Italian Alps to investigate the temporal effects of CSFOs repeated for four consecutive years (case-study I), and the impact of a single CSFO at a seasonal scale through a before/after-control/impact approach (case-study II). Initially, we quantified the CSFO impact on the richness and beta-diversity of macroinvertebrate communities by combining multivariate and univariate statistical techniques. Then, we compared the performance of the Siltation Index for LoTic EcoSystems (SILTES), recently developed for detecting siltation impact in Alpine streams, with that of the generic index currently adopted to assess the ecological status (sensu Water Framework Directive) of the Italian rivers, and of another sediment-specific index, but developed for a different bio-geographical area. The analysis of the two case-studies demonstrated that the nestedness (i.e. taxa loss) is the primary source of biological impairment caused by CSFOs. Moreover, we found that SILTES was more effective than the other indices because of its strong correlation with the nestedness, and since it properly discriminated impaired and pristine conditions, at both multi-annual and seasonal scale. In the first case-study, a threshold in the temporal trend of this index was detected, indicating a recovery within three months. In the second one, SILTES showed a recovery to pre-event seasonal values after nine months from the CSFO, due to larger and more persistent sediment deposition. This study demonstrates that SILTES could be adopted as a benchmark to improve the management of CSFOs from an ecological viewpoint. Our findings can be extended to the management of other sediment-related activities affecting mountainous streams worldwide, and, more generally, the adopted approach can be replicated for developing new ecological tools to manage other disturbances to river environments

Optimal Sequencing and Predictive Biomarkers in Patients with Advanced Prostate Cancer

SIMPLE SUMMARY: Several strategies have demonstrated the ability to improve the survival of patients with both metastatic and nonmetastatic prostate cancer. The old backbone of androgen-deprivation monotherapy has been disrupted in the hormone-sensitive setting, and several options have been introduced for the management of the castration-resistant disease. However, no optimal sequencing is still defined, and few randomized comparisons are currently available to identify the approach that maximizes the long-term benefit for these patients. This comprehensive review aims at resuming the current evidence on this topic to help physicians during the treatment choice for patients with advanced prostate cancer. ABSTRACT: The treatment landscape of advanced prostate cancer has completely changed during the last decades. Chemotherapy (docetaxel, cabazitaxel), androgen-receptor signaling inhibitors (ARSi) (abiraterone acetate, enzalutamide), and radium-223 have revolutionized the management of metastatic castration-resistant prostate cancer (mCRPC). Lutetium-177–PSMA-617 is also going to become another treatment option for these patients. In addition, docetaxel, abiraterone acetate, apalutamide, enzalutamide, and radiotherapy to primary tumor have demonstrated the ability to significantly prolong the survival of patients with metastatic hormone-sensitive prostate cancer (mHSPC). Finally, apalutamide, enzalutamide, and darolutamide have recently provided impactful data in patients with nonmetastatic castration-resistant disease (nmCRPC). However, which is the best treatment sequence for patients with advanced prostate cancer? This comprehensive review aims at discussing the available literature data to identify the optimal sequencing approaches in patients with prostate cancer at different disease stages. Our work also highlights the potential impact of predictive biomarkers in treatment sequencing and exploring the role of specific agents (i.e., olaparib, rucaparib, talazoparib, niraparib, and ipatasertib) in biomarker-selected populations of patients with prostate cancer (i.e., those harboring alterations in DNA damage and response genes or PTEN)

LA ANTICIPACIÓN COMO PROCESO PERCEPTIVO MOTOR QUE INTERVIENE EN El APRENDIZAJE DE LAS HABILIDADES ABIERTAS

In the following article, we have uied to make a revlSlon of the different investigations where it is shown how perceptive processes, as the one of anticipation, intervene making better the learuing process of open abilities. For this purpose, different kinds of anticipation have been mixed and exposed, standing out the role tbat this process plays in the performance of this kind of abilities. Lastly, different methodologies, for the study of the anticipation during the performance of open character abilities, have been mixed, more concretely, the last line of investigation by the Group of Investigation of Human Movement Analysis, where this perceptive process in the improvement of the execution of open abilities, such as a penalty in football, or the block action in volley-ball, have been applied, found in both cases, positive.En el presente artículo hemos querido realizar una revisión de diferentes investigaciones donde se muestra el efecto del entrenamiento de procesos perceptivos como el de anticipación en la mejora del aprendizaje de habilidades abiertas. Para ello, se han aunado y expuesto diferentes tipos de anticipación, destacand o el papel que juega este proceso durante la ejecución de este tipo de habilidades. Por último, se han reunido distintas metodologías llevadas a cabo para el estudio de la anticipación durante la ejecución de habilidades de carácter abierto y en concreto la última línea de investigación llevada a cabo por el Grupo de Investigación de Análisis del Movimiento Humano, donde se ha aplicado este proceso perceptivo en la mejora de la ejecución de habilidades abiertas como son el lanzamiento de un penalti en fútbol, o la acción de bloqueo en voleibol, encontrando, en ambos casos, resultados positivos

Modelli di interazione spaziale: presupposti teorici e aspetti applicativi

No abstract availabl

Non‐Apoptotic Caspase‐3 Activation Mediates Early Synaptic Dysfunction of Indirect Pathway Neurons in the Parkinsonian Striatum

Non‐apoptotic caspase‐3 activation is critically involved in dendritic spine loss and synaptic dysfunction in Alzheimer’s disease. It is, however, not known whether caspase‐3 plays similar roles in other pathologies. Using a mouse model of clinically manifest Parkinson’s disease, we provide the first evidence that caspase‐3 is transiently activated in the striatum shortly after the degeneration of nigrostriatal dopaminergic projections. This caspase‐3 activation concurs with a rapid loss of dendritic spines and deficits in synaptic long‐term depression (LTD) in striatal projection neurons forming the indirect pathway. Interestingly, systemic treatment with a caspase inhibitor prevents both the spine pruning and the deficit of indirect pathway LTD without interfering with the ongoing dopaminergic degeneration. Taken together, our data identify transient and non‐apoptotic caspase activation as a critical event in the early plastic changes of indirect pathway neurons following dopamine denervation

Conditioned saccharin avoidance induced by infusion of amphetamine in the Nucleus Accumbens shell and morphine in the Ventral Tegmental Area: behavioral and biochemical study

Drugs of abuse possess the seemingly paradoxical property of conditioning rats to avoid from drinking a saccharin solution that had been predictively paired with their systemic administration (conditioned saccharin avoidance, CSA). CSA is dependent upon an intact dopamine (DA) transmission but the locus, central or peripheral, and eventually the brain area from which this effect originates and its relationship with the rewarding properties of the drug is debated. In order to clarify this issue we tested the ability of amphetamine and morphine to induce CSA after infusion at the same dose-range and in the same areas from which these drugs induce conditioned place preference (CPP). Drugs were infused intracerebrally immediately after saccharin drinking in two acquisition trials and CSA was tested on a two bottle saccharin/water choice. Amphetamine (10 and 20μg/0.5μl) induced CSA after infusion in the NAc shell but was ineffective in the NAc core. Morphine (0.5 and 1μg/0.5μl) induced CSA from the VTA at both doses tested. Amphetamine (20μg/0.5μl) and morphine (1μg/0.5μl) failed to induce CSA after infusion 1.2mm dorsal the NAc shell and the VTA respectively. Finally, morphine (1μg/0.5μl), infused in the VTA, elicited a selective increase in dialysate DA in the NAc shell. These results indicate that drugs of abuse induce CSA from the same intracerebral sites and at the same doses at which they induce CPP. These observations are consistent with the existence of a strong relationship between CSA and drug reward related to their ability to stimulate DA transmission in the NAc shell

La anticipación como proceso percetivo motor que interviene en el aprendizaje de las habilidades abiertas

En el presente artículo hemos querido realizar una revisión de diferentes investigaciones donde se muestra el efecto del entrenamiento de procesos perceptivos como el de anticipación en la mejora del aprendizaje de habilidades abiertas. Para ello, se han aunado y expuesto diferentes tipos de anticipación, destacando el papel que juega este proceso durante la ejecución de este tipo de habilidades. Por último, se han reunido distintas metodologías llevadas a cabo para el estudio de la anticipación durante la ejecución de habilidades de carácter abierto y en concreto la última línea de investigación llevada a cabo por el Grupo de Investigación de Análisis del Movimiento Humano, donde se ha aplicado este proceso perceptivo en la mejora de la ejecución de habilidades abiertas como son el lanzamiento de un penalti en fútbol, o la acción de bloqueo en voleibol, encontrando, en ambos casos, resultados positivos.In the following article, we have tried to make a revisión of the different investigations where it is shown how perceptive processes, as the one of anticipation, intervene making better the leaming process of open abilities. For this purpose, different kinds of anticipation have been mixed and exposed, standing out the role that this process plays in the performance of this kind of abüities. Lastly, different methodologies, for the study of the anticipation during the performance of open character abilities, have been mixed, more concretely, the last Une of investigation by the Group of Investigation of Human Movement Analysis, where this perceptive process in the improvement of the execution of open abilities, such as a penalty in football, or the block action in volley-ball, have been applied, found in both cases, positive.Facultad de Educación y Humanidades - Campus de Melilla (Universidad de Granada