Anti-parkinsonian and anti-dyskinetic profiles of two novel potent and selective nociceptin/orphanin FQ receptor agonists

Background and Purpose We previously showed that nociceptin/orphanin FQ opioid peptide (NOP) receptor agonists attenuate the expression of levodopa-induced dyskinesia in animal models of Parkinson's disease. We now investigate the efficacy of two novel, potent and chemically distinct NOP receptor agonists, AT-390 and AT-403, to improve Parkinsonian disabilities and attenuate dyskinesia development and expression. Experimental Approach Binding affinity and functional efficacy of AT-390 and AT-403 at the opioid receptors were determined in radioligand displacement assays and in GTPγS binding assays respectively, conducted in CHO cells. Their anti-Parkinsonian activity was evaluated in 6-hydroxydopamine hemi-lesioned rats whereas the anti-dyskinetic properties were assessed in 6-hydroxydopamine hemi-lesioned rats chronically treated with levodopa. The ability of AT-403 to inhibit the D1 receptor-induced phosphorylation of striatal ERK was investigated. Key Results AT-390 and AT-403 selectively improved akinesia at low doses and disrupted global motor activity at higher doses. AT-403 palliated dyskinesia expression without causing sedation in a narrow therapeutic window, whereas AT-390 delayed the appearance of abnormal involuntary movements and increased their duration at doses causing sedation. AT-403 did not prevent the priming to levodopa, although it significantly inhibited dyskinesia on the first day of administration. AT-403 reduced the ERK phosphorylation induced by SKF38393 in vitro and by levodopa in vivo. Conclusions and Implications NOP receptor stimulation can provide significant albeit mild anti-dyskinetic effect at doses not causing sedation. The therapeutic window, however, varies across compounds. AT-403 could be a potent and selective tool to investigate the role of NOP receptors in vivo

Anti-parkinsonian and anti-dyskinetic profiles of two novel potent and selective nociceptin/orphanin FQ receptor agonists

Background and Purpose We previously showed that nociceptin/orphanin FQ opioid peptide (NOP) receptor agonists attenuate the expression of levodopa-induced dyskinesia in animal models of Parkinson's disease. We now investigate the efficacy of two novel, potent and chemically distinct NOP receptor agonists, AT-390 and AT-403, to improve Parkinsonian disabilities and attenuate dyskinesia development and expression. Experimental Approach Binding affinity and functional efficacy of AT-390 and AT-403 at the opioid receptors were determined in radioligand displacement assays and in GTPγS binding assays respectively, conducted in CHO cells. Their anti-Parkinsonian activity was evaluated in 6-hydroxydopamine hemi-lesioned rats whereas the anti-dyskinetic properties were assessed in 6-hydroxydopamine hemi-lesioned rats chronically treated with levodopa. The ability of AT-403 to inhibit the D1 receptor-induced phosphorylation of striatal ERK was investigated. Key Results AT-390 and AT-403 selectively improved akinesia at low doses and disrupted global motor activity at higher doses. AT-403 palliated dyskinesia expression without causing sedation in a narrow therapeutic window, whereas AT-390 delayed the appearance of abnormal involuntary movements and increased their duration at doses causing sedation. AT-403 did not prevent the priming to levodopa, although it significantly inhibited dyskinesia on the first day of administration. AT-403 reduced the ERK phosphorylation induced by SKF38393 in vitro and by levodopa in vivo. Conclusions and Implications NOP receptor stimulation can provide significant albeit mild anti-dyskinetic effect at doses not causing sedation. The therapeutic window, however, varies across compounds. AT-403 could be a potent and selective tool to investigate the role of NOP receptors in vivo

Nuclear ERK1/2 signaling potentiation enhances neuroprotection and cognition via Importinα1/KPNA2

Cell signaling is central to neuronal activity and its dysregulation may lead to neurodegeneration and cognitive decline. Here, we show that selective genetic potentiation of neuronal ERK signaling prevents cell death in vitro and in vivo in the mouse brain, while attenuation of ERK signaling does the opposite. This neuroprotective effect mediated by an enhanced nuclear ERK activity can also be induced by the novel cell penetrating peptide RB5. In vitro administration of RB5 disrupts the preferential interaction of ERK1 MAP kinase with importinα1/KPNA2 over ERK2, facilitates ERK1/2 nuclear translocation, and enhances global ERK activity. Importantly, RB5 treatment in vivo promotes neuroprotection in mouse models of Huntington's (HD), Alzheimer's (AD), and Parkinson's (PD) disease, and enhances ERK signaling in a human cellular model of HD. Additionally, RB5‐mediated potentiation of ERK nuclear signaling facilitates synaptic plasticity, enhances cognition in healthy rodents, and rescues cognitive impairments in AD and HD models. The reported molecular mechanism shared across multiple neurodegenerative disorders reveals a potential new therapeutic target approach based on the modulation of KPNA2‐ERK1/2 interactions

Modeling of the GERDA data after the upgrade

The GERDA experiment at the Gran Sasso underground laboratories is searching for neutrinoless double-beta decay in 76 Ge. In order to observe such a rare process this experiment will collect an exposure of 100 kg·y in background free condition. In 2018 many upgrades have been performed on the apparatus. In my thesis project I am studying and modeling the full-range energy spectrum acquired by the germanium detectors. All the analysis is done using bayesian statistics approach (parameter estimation, hypothesis testing, etc.). The spectrum is modeled by means of Monte Carlo simulations reproducing possible ra- dioactive isotopes, coming from U and T h chains or from cosmogenic activation, distributed in different components of the apparatus (cables, LAr, etc.) that can give significant contribution. The parameters of interest (isotopes activities, two neutrino beta decay’s half life) are then estimated from the data using Markov Chain Monte Carlo algorithms while direct screening measurements of the apparatus’ components (if available) are introduced as prior distributions in the analysis. For very high statistics gamma decay lines ( 40 K and 42 K) a detector by detector study of the number of registered counts is performed in order to get a more accurate and reliable assessment of the activities of the isotope generating these events; then they are inserted as prior distributions in the full-range fit. From this analysis it will be possible to understand the origin of the collected events, make a precise mea- surement of the half-life of the allowed two neutrino decay mode and could also give information about the purity of the materials for future experiments’ strategies. Moreover this study will help a lot the search for the neutrinoless double-beta decay in the region around Q ββ

Dosimetric evaluation of radiopharmaceuticals containing Mn radioisotopes

MultiModal Imaging is a new tool in Nuclear Medicine that allows combining images with different diagnostic contents. In order to do this it is necessary to find a radionuclide that could show both good positron-emitting nuclear properties and high paramagnetic properties: a possible isotope that satisfies these conditions is 52Mn. Goal of this work is to perform a dosimetric evaluation of radiopharmaceutocals containing manganese in order to assess the energy transferred to the human body

Neutrinoless Double Beta Decay with Germanium Detectors: 1026 yr and Beyond

In the global landscape of neutrinoless double beta (0νββ) decay search, the use of semiconductor germanium detectors provides many advantages. The excellent energy resolution, the negligible intrinsic radioactive contamination, the possibility of enriching the crystals up to 88% in the 76Ge isotope as well as the high detection efficiency, are all key ingredients for highly sensitive 0νββ decay search. The Majorana and Gerda experiments successfully implemented the use of germanium (Ge) semiconductor detectors, reaching an energy resolution of 2.53 ± 0.08 keV at the Qββ and an unprecedented low background level of 5.2×10−4 cts/(keV·kg·yr), respectively. In this paper, we will review the path of 0νββ decay search with Ge detectors from the original idea of E. Fiorini et al. in 1967, to the final recent results of the Gerda experiment setting a limit on the half-life of 76Ge 0νββ decay at T1/2>1.8×1026 yr (90% C.L.). We will then present the LEGEND project designed to reach a sensitivity to the half-life up to 1028 yr and beyond, opening the way to the exploration of the normal ordering region