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Titulo - Tesis defendidas

Doctoral theses defended

Tabla Tesis - Farmacología

 

Current doctoral programme

Previous doctoral programmes

Doctoral theses defended

10 72

Extraordinary Doctoral Awards

- 3

PhDs in cotutelle

1 -

International doctoral theses

8 23

Industrial doctorates

- -

 

XSL Content

Defended thesis of current programme

Pharmacological characterization of prostaglandin E2 EP receptors in the rodent brain: functional studies in locus coeruleus neurons and the preBötzinger complex.

NAZABAL GAZTAÑAGA, AMAIA

Directors:
MENDIGUREN ORDORICA, AITZIBER;
PINEDA ORTIZ, JOSEBA GOTZON
Mentions:
Cum Laude Distinction
International Thesis
Grade:
Excellent Cum Laude
Year:
2019
Abstract:

This work focuses on the study of the neuropharmacological mechanisms underlying prostaglandin E2 (PGE2) receptor (EP) activation in locus coeruleus (LC) neurons and the preBötzinger complex (preBötC). PGE2 is an inflammatory mediator synthesized by the brain constitutive cyclooxygenase (COX) enzyme, whose activity is blocked by the nonsteroidal anti-inflammatory drugs (NSAIDs). PGE2 binds to G protein-coupled EP1-4 receptors (EP1 to Gq, EP2 and EP4 to Gs, and EP3 to Gi/o). Activation of EP receptors by PGE2 has been shown to modulate synaptic transmission and neuronal activity in various brain regions. The noradrenergic nucleus LC, which is involved in the regulation of the sleep-wake cycle, arousal, cognition, pain, and reward behavior, expresses EP2, EP3, and EP4 receptors, but their functional role remains unexplored. Therefore, we aimed to characterize the EP2, EP3, and EP4 receptors pharmacologically in the rat LC by extracellular electrophysiological recordings in acute slices. On the other hand, the inspiratory pattern is generated by the preBötC, whose inspiratory neurons express ¿-opioid receptors (MOR) and respond to PGE2. Thus, administration of opioids produces respiratory depression while PGE2 increases the frequency of sighs and induces gasps under hypoxic circumstances. However, the possible interaction between both systems to cause major respiratory disturbances remains to be elucidated. For this purpose, we also examined the interaction between opioids and PGE2 in the mice preBötC by live time-lapse calcium imaging in organotypic slice cultures.

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Characterization of an animal model of cognitive impairment associated with schizophrenia. Effets of alpha2-adrenoceptor compounds.

PEREZ DEL PALOMAR ASIN, BLANCA

Directors:
MEANA MARTINEZ, JOSE JAVIER;
ORTEGA CALVO, JORGE
Mentions:
Cum Laude Distinction
International Thesis
Grade:
Excellent Cum Laude
Year:
2019
Abstract:

Schizophrenia is a multi multifaceted, heterogeneous, chronic and debilitating disorder triggered by a series of interacting genetic, developmental and environmental factors. Cognitive impairment is considered a core feature of this disorder and highly dependent on the correct functioning of the prefrontal cortex, however, current antipsychotics lack efficacy for treating this condition. Prenatal exposure to infection is contemplated as one the most significant environmental risk factors for developing schizophrenia in the offspring. In this context, maternal immune activation animal models produce neurochemical and behavioral alterations considered relevant for the study of schizophrenia dysfunctions. The first part of this thesis consists of a neurochemical and behavioral characterization of an animal model of cognitive impairment associated with schizophrenia by the administration of the immunostimulant agent Poly (I:C). The second part involves the study of the effects of ¿2-adrenoceptor compounds on cognitive performance in the offspring. Finally, selective targeting of the locus coeruleus-prefrontal cortex circuit by different optogenetic approaches was performed. The Poly (I:C) animal model shows a catecholaminergic hypofunction in the prefrontal cortex with marked cognitive deficits, which are reversed by the administration of ¿2A-adrenoceptor agonist guanfacine and the ¿2C-adrenoceptor antagonist MK-912. These results support the important role of the noradrenergic system in the prefrontal cortex-dependent cognitive functions and the Poly (I:C) animal model as a promising translational model of cognitive impairment associated with schizophrenia.

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Pharmacometric analysis of the in vitro activity of echinocandins, amphotericin B and isavuconazole against Candida Auris

CABALLERO CUENCA, UNAI

Directors:
JAUREGUIZAR ALBONIGAMAYOR, NEREA
Mentions:
Cum Laude Distinction
International Thesis
Grade:
Excellent Cum Laude
Year:
2021
Abstract:

C. auris is a multidrug-resistant fungal pathogen that has recently emerged globally as a cause of life-threatening invasive infections. Despite the increasing concern on the reduced treatment options of C. auris infections, very few studies have investigated the in vitro time-kill activity of antifungal drugs against this species. Furthermore, PK/PD models, valuable tools to better characterise the activity of antimicrobial agents, are still lacking for this species. The overall aim of this Doctoral Thesis was to evaluate the in vitro activity of antifungal drugs belonging to the three main classes against C. auris, in monotherapy and in combinations, and to develop pharmacometric models for describing and predicting the activity of the drugs. In this work, Amphotericin B showed concentration-dependent fungicidal activity against C. auris in time-kill assays. Conversely, neither isavuconazole nor the echinocandins showed fungicidal or fungistatic against C. auris. The combination of amphotericin B with anidulafungin or caspofungin significantly enhanced the activity of the drugs compared to monotherapy. The interaction of isavuconazole and anidulafungin, caspofungin or micafungin was also deemed synergistic. The developed PK/PD models successfully characterised both monotherapy and isavuconazole plus echinocandin activity. Model-based simulations pointed out that amphotericin B susceptibility breakpoint for C. auris may be lower than the currently suggested one and that high dosing combination therapy of isavuconazole plus caspofungin or anidulafungin would be effective for the treatment of C. auris fungaemia.

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Fosfolipasa Cß1a/b-ren papera giza jatorrizko NTera2/D1 zelulen ziklo zelularraren G1 fasearen modulazioan. Ekintza mekanismo potentziala desberdintze neuronala zuzentzeko.

ISASTI IRIBAR, AMAIA

Directors:
GARCIA DEL CAÑO, GONTZAL;
LOPEZ DE JESUS, MAIDER
Grade:
Excellent
Year:
2021
Abstract:

Egun, ezaguna da Fosfolipasa C ß1 (PLCß1) hainbat zelulen desberdintze prozesuan inplikaturik dagoela, baita zelula neuronalen desberdintze prozesuan ere. Haatik, desberdintze neuronala bideratzeko PLCß1-aren ekintza mekanismoa aztertzen duten ikerketa gutxi burutu dira. Lan honetan, PLCß1-ak NTera2/D1 (NT2) zelulen ziklo zelularraren G1 fasea modulatu dezakela frogatu dugu eta modulazio hau, NT2 zelulen desberdintze neuronala bideratzeko mekanismoa izan daitekela proposatu dugu. Bestetik, PLCß1-ak zuzendutako NT2 zelulen desberdintze prozesuan sakondu dugu, bere bi splincing aldaerek eta zelula barneko kokapenak prozesu hau baldintzatu dezaketen aztertu baitugu. Azkenik, Saguen Helduaroko Hipokanpoko Ama Zelula Neuronalen desberdintzapen prozesuan PLCß1-ren mRNA eta proteina mailen igoera gertatzen dela frogatu dugu.

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Sphingosine 1-phosphate (S1P) system in healthy brain and alzheimer¿s disease

MARTINEZ GARDEZABAL, JONATAN

Directors:
MANUEL VICENTE, IVAN;
RODRIGUEZ PUERTAS, RAFAEL
Mentions:
Cum Laude Distinction
International Thesis
Grade:
Excellent Cum Laude
Year:
2021
Abstract:

The physiological consequences of the super-specialization of the lipids in the different regions and cellular types of the central nervous system (CNS), remain largely being a mystery. In fact, the so-called neurolipids, which possess agonistic or neuromodulatory properties, play an essential role both in health and in pathological conditions. Thus, the lysophospholipid sphingosine 1-phosphate (S1P) system is one of these neurolipids involved in immune responses and cell survival functions. However, the S1P systems in CNS is not fully elucidated. Then, the present research study evaluates the S1P system in healthy brain and AD. In this sense, the anatomical distribution of functional coupling of G¿i/o proteins to S1P1 receptor in postmortem human brain samples and rodent models showed that S1P1 receptor could be one of the most abundant and/or efficient GPCR coupled to G¿i/o proteins in the brain and consequently signaling and regulating multiple biological processes. Moreover, the present results, indicate that is preferably the use of rat models to the study of S1P1 receptors activity in human neurodegenerative diseases, such as Alzheimer¿s disease. The S1P1 receptor activity during the AD progression in postmortem human brain samples indicated that the S1P1 receptor signaling was decreased in superficial layers of the frontal cortex during the initial stages. In contrast, the activities of both S1P1 and CB1 receptors, were increased at the initial stages of the disease in the internal layers of the frontal cortex that could be related to neuroprotection. Furthermore, the activity of the S1P1 receptor in the underlying cortical white matter was increased during the initial and intermediate stages of the disease. Finally, the activities of both, S1P1 and CB1 receptors, were reduced in the hippocampus at the most severe stages of the disease indicating the continuation of the brain impairment. Lipidomic evaluation of human plasma samples from mild cognitive impairment (MCI) and AD patients to identify biomarkers for early diagnosis. To sum up, the MCI patients showed a decrease in some lipid species such as TG in general, PC and PE containing linoleic acid, and some Cer. In contrast, the AD patients showed increase in some PE compared to MCI patients, but other lipid species, such as PC and SM, were decreased. Moreover, the changes in AD patients respect to control patients were mainly focused on Cer, SM and PC. The functionality of S1P1 receptors in the CNS of 3xTg-AD mice model of familial AD showed a decrease in some areas of the olfactory bulb, in the nucleus basalis magnocellularis, basolateral amygdaloid nucleus, fimbria and molecular layer of the hippocampal dentate gyrus, the substantia nigra and in the ventral tegmental area. All this changes could be related to the learning and memory impairment and the fear and anxiety behavior in this model. On the other hand, the activity of the S1P1 receptor in the CNS of sporadic AD by cholinergic basalocortical lesion showed an increase in the basolateral amygdaloid nucleus and the piriform cortex in layers I and II that could be related to the rearrangement at the projection areas. Conversely, a decrease was observed in the nucleus basalis magnocellularis and the corpus callosum associated to the apoptotic processes that follow the injury in this area. The analysis of the relationship between the S1P and cannabinoid systems indicated a possible crosstalk of both systems. S1P1 ¿selective¿ compounds have also certain affinity for CB1 receptors and the S1P1 activity is regulated after in vivo cannabinoid treatments, indicating a crosslink between S1P and eCB systems. The MALDI-IMS technique allows us to obtain extensive information for the field of lipidomics, demonstrating the relevance of the super-specialization of lipids in the different regions of the CNS. Moreover, the ¿Lipotype¿ of the different cells that are present in the brain, such as neurons, astrocytes, microglia, oligodendrocytes or ependymocytes, allows us to associate the functions performed by each of these cells with the lipids that compose them. Additionally, the implementation of new techniques of matrix deposition, allows to increase the power of this technique by obtaining the distribution of signaling molecules such as S1P or 2-AG, or even other molecules that otherwise could not be identified. In summary, the S1P system represents a promising target since is related to important physiological functions that in pathological situations may be disturbed, offering an opportunity to modify the progression of such pathologies that include the Alzheimer¿s disease.

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Neurophysiology of non-motor complications in Parkinson¿s diseas: role of the locus coeruleus.

PAREDES RODRIGUEZ, ELENA

Directors:
MIGUELEZ PALOMO, CRISTINA;
UGEDO URRUELA, LUISA
Mentions:
Cum Laude Distinction
International Thesis
Grade:
Excellent Cum Laude
Year:
2020
Abstract:

La enfermedad de Parkinson es un trastorno neurodegenerativo, definido inicialmente por sus síntomas motores. Sin embargo, hoy en día la probabilidad de que se trate de un trastorno complejo en lugar de una enfermedad puramente motora es ampliamente aceptada. Una de las primeras áreas afectadas en esta enfermedad es el locus coeruleus (LC). Este núcleo proporciona extensa inervación noradrenérgica a todo el cerebro, incluida la corteza prefrontal, y desempeña un papel neuromodulador fundamental participando en la respuesta al estrés, memoria emocional y control de las funciones motoras, sensoriales y autonómicas. Dada la estrecha relación del sistema noradrenérgico con la enfermedad de Parkinson, y los trastornos ansiosos y de percepción dolorosa, el objetivo global de este estudio fue investigar el impacto de la degeneración dopaminérgica en la función de las neuronas del LC y sus posibles consecuencias comportamentales. En resumen, el presente estudio demuestra que el déficit dopaminérgico influye de manera significativa en el sistema noradrenérgico. La pérdida persistente de dopamina conduce a la hipoactividad y la hiperexcitabilidad del LC, junto a una comunicación disfuncional entre este núcleo y la corteza prefrontal. Estos cambios fueron estudiados mediante técnicas electrofisiológicos e histoquímicos in vivo y ex vivo. Además, el reemplazo dopaminérgico ha demostrado restaurar el patrón oscilatorio del LC y su actividad tónica y fásica. Este hallazgo confirma que los cambios observados en las ratas parkinsonianas se debieron directamente a la pérdida dopaminérgica y enfatiza la implicación del sistema dopaminérgico en la modulación del LC. Sin embargo, las modificaciones observadas en el LC tienen un impacto discreto en el comportamiento nociceptivo y ansioso.

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Biochemical and functional charactrization of the CB1 cannabinoid recptor coupling to Gai/l proteins in synaptosomal membranes from hippocampus and frontal cortex of cell-type-specifc mutant mouse rescue model/CB1 hartzailearen eta gai/o proteinen arteko akoplamendua: hurbilketa biokimiko eta funtxionala zelula espezifikoetan CB1 hartzailearen erreskate selektiboa duten sagu transgenikoen hipokanpo eta kortex frontaletik eratorritako sinaptosoma mintzetan.

SAUMELL ESNAOLA, MIQUEL

Directors:
BARRONDO LACARRA, SERGIO;
SALLES ALVIRA, JOAN
Mentions:
Cum Laude Distinction
International Thesis
Grade:
Excellent Cum Laude
Year:
2021
Abstract:

Egun, ezaguna da terminal sinaptiko glutamatergiko eta GABAergikoetan espresatzen den CB1 hartzailearen aktibazioak aktibitate neuronal eszitatzaile-inhibitzailearen balantzea erregulatzen duela. Horregatik, bi terminal mota hauetan aurkitzen den CB1 hartzailearen seinaleztapen kanonikoaren (G¿i/o proteinen akoplamentua) azterketa zehatza beharrezkoa da agonista kannabinoideen efektuak garunean zehar karakterizatzeko. Lan honetan, CB1 hartzailea neurona glutamatergiko edo GABAergikoetan espresatzen duen sagu transgenikoak erabiliz, kortex frontaleko eta hipokanpoko bi terminal sinaptiko hauetan CB1 hartzailearen seinaleztapen kanonikoa hartzailearen espresio mailarekin positiboki erlazionatzen dela frogatu dugu. Gainera, kolesterola CB1 hartzailearen funtzio kanonikoa negatiboki modulatzen duen konposatu alosteriko gisa identifikatu dugu.

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Characterization of buspirone effect on output basal ganglia nuclei in 6-hydroxydopamine lesioned rats with and without long-term levodopa treatment.

VEGAS SUAREZ, SERGIO

Directors:
MIGUELEZ PALOMO, CRISTINA;
UGEDO URRUELA, LUISA
Mentions:
Cum Laude Distinction
International Thesis
Grade:
Excellent Cum Laude
Year:
2020
Abstract:

La enfermad de Párkinson es un trastorno neurodegenerativo en el que varios sistemas de neurotransmisión se ven afectados. En los últimos años, numerosas evidencias clínicas y experimentales han demostrado el papel del sistema serotonérgico en el desarrollo y en los síntomas de esta enfermedad así como en las complicaciones motoras derivadas del tratamiento crónico con levodopa, conocidas como discinesias inducidas por levodopa. El objetivo de esta tesis ha sido caracterizar el efecto de la buspirona, un agonista parcial de los receptores serotoninérgicos 5-HT1A, en los principales núcleos de salida de los ganglios basales, la substantia nigra pars reticulata (SNr) y el núcleo entopeduncular (EP) mediante técnicas electrofisiológicas in vivo, un estudio histoquímico para la actividad del citocromo c oxidasa (COX) y estudios inmunohistoquímicos para el receptor 5-HT1A y el transportador de la serotonina (SERT), que fueron realizados en los ganglios basales y el núcleo dorsal del rafe. En este trabajo se ha demostrado que el efecto de la buspirona y el agonista total 5-HT1A, 8-OH-DPAT, sobre la actividad de la SNr y el EP se ve comprometido tras el déficit dopaminérgico, y está prácticamente ausente en la actividad oscilatoria entre estos núcleos y la corteza motora. Sin embargo, estos fármacos pueden normalizar la descarga en ¿burst¿ durante el parkinsonismo. Además, se ha observado un aumento generalizado de la actividad de la COX junto con cambios en la expresión del receptor 5-HT1A y del SERT en las ratas parkinsonianas tratadas o sin tratar con levodopa. Estos resultados sugieren que la actividad ¿burst¿ en modelos experimentales es importante para estudiar el efecto terapéutico de nuevos fármacos antiparkinsonianos y antidiscinéticos.

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Molecular mechanisms underlying cannabis abuse and schizophrenia: Focus on 5-HT2A receptors and Akt/mTOR signaling pathway.

IBARRA LECUE, INES

Directors:
CALLADO HERNANDO, LUIS FELIPE;
URIGUEN ECHEVERRIA, LEYRE
Mentions:
Cum Laude Distinction
International Thesis
Grade:
Excellent Cum Laude
Year:
2020
Abstract:

Schizophrenia is a chronic and disabling mental illness that affects around 20 million people worldwide. The etiology of the disorder is multifactorial, and different genetic and environmental factors take part in its onset and course. However, the mechanisms underlying this interaction remain poorly understood. Cannabis abuse, especially during adolescence, has been associated with an increased risk of developing schizophrenia as well as with an earlier onset. The main aim of this Thesis consisted in evaluating the molecular mechanisms underlying this relationship, with a focus in two targets previously related with schizophrenia: serotonin 2A receptors (5-HT2AR) and Akt/mTOR signaling pathway. For this purpose, we evaluated (1) the G¿ protein subunits activation exerted by three cannabinoids, including THC in mouse brain cortex, (2) chronic THC effects on psychosis-like states, cortical 5-HT2AR functionality and Akt/mTOR signaling pathway status, (3) the implication of Akt/mTOR signaling pathway in these effects, (4) the Akt/mTOR signaling pathway status in postmortem prefrontal cortex (PFC) of subjects with schizophrenia, and (5) the 5-HT2AR protein expression and Akt functional status in platelets from subjects with a cannabis use disorder, with and without schizophrenia. Most significant results from this Thesis show that chronic THC leads to hyperactive 5-HT2AR functionality in the brain cortex associated with a hyperactive Akt/mTOR signaling and psychosis-like behavior. Disruption of this signaling pathway is also evident in postmortem PFC and platelets of subjects with schizophrenia, and cannabis abuse seems to exert different effects depending on the presence of schizophrenia pathology. Together, this Doctoral Thesis suggests that 5-HT2AR and Akt/mTOR pathway are elements of an interacting mechanism involving chronic cannabis pharmacological effects and schizophrenia pathogenesis.

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Impacto de la falta de adherencia terapéutica sobre la eficacia antimicrobiana de Amoxicilina, Levofloxacino y Moxifloxacino, como probabilidad de alcanzar un índice farmacocinético-farmacodinámico, en pacientes ambulatorios con neumonía adquirida en la comunidad, teniendo en cuenta su variabilidad interindividual

CARRAL TELLITU, NEREA

Directors:
SUAREZ GONZALEZ, MARIA ELENA
Mentions:
Cum Laude Distinction
Grade:
Excellent Cum Laude
Year:
2017
Abstract:

El punto de partida para la realización de este trabajo ha sido la falta de estudios que permitan conocer las consecuencias de la falta de adherencia a la prescripción de la dosificación antimicrobiana sobre su eficacia en el tratamiento de neumonía adquirida en la comunidad en los pacientes ambulatorios. Ante la imposibilidad ética de plantear estudios clínicos controlados para evaluar este objetivo, el objetivo de nuestro trabajo ha sido evaluar las consecuencias de la falta de adherencia al tratamiento antimicrobiano empírico con Amoxicilina, Levofloxacino y Moxifloxacino, en pacientes con neumonía adquirida en la comunidad en tratamiento ambulatorio, sobre su eficacia clínica antimicrobiana, medida como probabilidad de alcanzar un determinado índice Fc-Fd basado en el análisis de sus propiedades farmacocinéticas-farmacodinámicas y teniendo en cuenta la variabilidad interindividual de los pacientes. Se han realizado estudios de simulación farmacocinética-farmacodinámica, como herramienta metodológica de trabajo, en diferentes escenarios de pacientes virtuales. Una de las consecuencia es que en zonas geográficas con baja incidencia de resistencia a S.Pneumoniae, la Amoxicilina, s, presenta clara ¿idoneidad¿ en estas poblaciones, , aun en situación de presentar baja adherencia al tratamiento.

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Determining the binding kinetics and signalling effects of CB1 and CB2 receptor ligands; a closer look at residence time and functional selectivity/Ligando kannabinoideen lotura-zinetikak eta seinaleztapena CB1 eta CB2 hartzaileetara lotzean; kinkapen denbora eta selktibitate funtzionala gertuagotik aztertzen.

BORREGA ROMAN, LEIRE

Directors:
BARRONDO LACARRA, SERGIO;
SALLES ALVIRA, JOAN
Mentions:
Cum Laude Distinction
International Thesis
Grade:
Excellent Cum Laude
Year:
2022
Abstract:

The CB1 and CB2 receptors are the main GPCRs of the endocannabinoid system, and regulate many important physiological processed as pain, inflammation, or behaviour. Increasing interest exist to develop new drugs targeting these receptors, as they constitute potential drug targets for many diseases as Alzheimer disease, Huntington disease, chronic pain, or inflammation. During the last decades, the interest around the binding kinetics of drugs has hugely expanded, as it has been shown to be an important determinant of in vivo drug action in many cases. Moreover, studying the kinetic interactions of drug binding to its target can also provide valuable information in order to understand the efficacy at a molecular level. In this work, we generated a novel fluorescence-based assay that allows the determination of binding association and dissociation rates of cannabinoid compounds at CB1 and CB2 receptors. Using the methodology proposed by Motulsky and Mahan, we successfully determined the kinetic parameters of seven different cannabinoid compounds at both CB1 and CB2 receptors. We also studied the efficacy of the selected cannabinoid compounds using three different assays. On one hand, we determined the coupling to miniGsi and b-arrestin 2 using BRET biosensors. On the other hand, we successfully determine the internalization that cannabinoid compounds elicited using a technique based on diffusion-enhanced resonance energy transfer (DERET). Applying the operational model of agonism (OMA) proposed by Black and Leff, the bias exerted by the compounds at both CB1 and CB2 receptors was determined for the studied responses. Finally, we explore the relationship between the efficacy elicited at the different responses with the residence time of the cannabinoid agonists.

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Cannabinoid modulation of the cortical information processing through the basal ganglia circuits in physiological and hypodopaminergic states

ANTONAZZO SOLER, MARIO

Directors:
MORERA HERRERAS, TERESA;
UGEDO URRUELA, LUISA
Mentions:
Cum Laude Distinction
International Thesis
Grade:
Excellent Cum Laude
Year:
2021
Abstract:

The basal ganglia (BG) are a network of subcortical nuclei that classically have been considered to be involved in motor behaviours, with mounting evidence in the last decades indicating that they are also involved in cognitive and emotional processing. The BG nuclei are involved in several pathologies such as Parkinson¿s disease, where the dopaminergic (DA) system, that influences BG function, is seriously affected. The endocannabinoid system, especially the CB1 receptor, is highly expressed in the BG representing a promising therapeutic target in disorders related with these structures. The objective of this thesis was to characterize the CB1 receptor modulation on the sensorimotor and medial prefrontal BG circuits, as well as the impact of DA denervation upon them, using electrophysiological techniques. In this work, cortical information cross through both BG circuits differently, in a way that was affected by DA denervation. Moreover, the CB1 receptor is able to modulate information transmission through both BG circuits differently. Further assessment on the role of the role of the CB1 receptor on these circuits revealed that it specially influences cortico-striatal transmission through the SM circuits. After DA denervation, the ability of the CB1 receptor to modulate transmission was generally lost in both circuits, although there were no changes in the density of this receptor in the BG nuclei. This data contribute to increase our understanding of BG function, and the role of the endocannabinoid system in modulating BG circuits, in physiological and hypodopaminergic states. Hence, providing further evidence on the potential of the endocannabinoid system as a pharmacological target in pathologies with BG dysfunction such as Parkinson¿s disease.

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Electrophysiological characterization of neuronal diversity in the substantia nigra pars reticulata in control and parkinsonian mice.

DELGADO ZABALZA, LORENA

Directors:
BAUFRETON , JEROME MICHEL RENE;
MIGUELEZ PALOMO, CRISTINA
Mentions:
Cotutelle PhD thesis
Cum Laude Distinction
International Thesis
Grade:
Excellent Cum Laude
Year:
2020
Abstract:

Los ganglios de la base son un conjunto de núcleos conectados entre sí que conforman un circuito neuronal encargado de controlar el movimiento voluntario. La substantia nigra pars reticulata (SNr) forma parte de este circuito y además posee un lugar privilegiado dentro de esta red siendo así la estructura que integra toda la información y permite la selección y la ejecución de tareas motoras. En la enfermedad de Parkinson (EP), esta función integradora y de selección de acciones se ve perjudicada, lo que conduce a la aparición de los síntomas motores de la EP. Estudios recientes han identificado varios tipos de neuronas dentro de la SNr, cuyas funciones en el control motor son actualmente desconocidas. El objetivo de mi doctorado consistió en caracterizar estos tipos de neuronas con el objetivo de desarrollar estrategias terapéuticas más selectivas para así restaurar la función motora en modelos de roedores con EP. Para ello combinamos técnicas inmunohistoquímicas y electrofisiológicas en una línea de ratones que nos permitía diferenciar entre dos tipos de neuronas y observar qué subpoblación era más susceptible a la EP y al consiguiente tratamiento con L-DOPA (tratamiento por excelencia en EP). El conocimiento generado por este proyecto de investigación básica permitirá el desarrollo de enfoques terapéuticos para reducir los síntomas motores en los pacientes con EP.

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Estudio de los receptores adrenérgicos ¿2 y la proteína espinofilina en la corteza prefrontal postmortem de sujetos con esquizofrenia

BROCOS MOSQUERA, IRIA

Directors:
CALLADO HERNANDO, LUIS FELIPE;
ERDOZAIN FERNANDEZ, AMAIA MAITE
Mentions:
Cum Laude Distinction
Grade:
Excellent Cum Laude
Year:
2021
Abstract:

La esquizofrenia (SZ) es una enfermedad mental crónica e incapacitante. Su etiología es de carácter multifactorial teniendo un componente genético y otro ambiental que intervienen en su aparición y el curso de la enfermedad. Los primeros síntomas que aparecen son los cognitivos y no tienen tratamiento. La hipótesis principal de esta Tesis Doctoral se basa en que los receptores adrenérgicos ¿2A (¿2A-AR) de la corteza prefrontal (CPF) son hipofuncionantes y pueden estar relacionados con los déficits cognitivos de la patología. Para ello se ha estudiado en la CPF de humanos postmortem (1) la expresión proteica de los ¿2A-AR y ¿2C-AR en el sinaptosoma, la fracción presináptica y postsináptica, (2) la funcionalidad de los ¿2-AR, (3) la expresión génica de los genes ADRA2A y ADRA2C, (4) modificaciones epigenéticas en los promotores de los genes ADRA2A y ADRA2C y (5) evaluar la expresión proteica de espinofilina, como marca de espinas dendríticas, en el sinaptosoma, la fracción presináptica y postsináptica. Todo ello se ha realizado comparando cerebros de sujetos controles y sujetos con esquizofrenia, evaluando la influencia de los fármacos antipsicóticos (AP) en todo ello. Los resultados más destacables de esta Tesis Doctoral son (1) el aumento de la expresión proteica de los ¿2A-AR en la fracción postsináptica en sujetos con SZ y AP, (2) una hipofunción de los ¿2-AR sujetos con SZ y AP, (3) una disminución de la expresión génica del ADRA2A sujetos con SZ y AP y de ADRA2C en SZ, (4) alteración en modificaciones epigenéticas en los dos promotores en SZ y (5) una disminución en la expresión proteica de espinofilina en la fracción postsináptica en sujetos con SZ y AP. Estos resultados sugieren que los AP pueden alterar la funcionalidad y expresión de los ¿2-AR y la expresión de dendritas sinápticas en la CPF de sujetos con SZ.

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Learning and memory improvement mediated by CB1 cannabinoid receptors in animal models of cholinergic dysfunction

MORENO RODRIGUEZ, MARTA

Directors:
RODRIGUEZ PUERTAS, RAFAEL
Mentions:
Cum Laude Distinction
International Thesis
Grade:
Excellent Cum Laude
Year:
2018
Abstract:

The selective vulnerability of the basal forebrain cholinergic system (BFCS) is responsible for most of the clinical alterations in learning and memory processes that are characteristic of the Alzheimer¿s disease (AD). The loss of cholinergic neurons and muscarinic receptors (MR) in the nucleus basalis of Meynert has been reported in AD. The endocannabinoid system is a neuromodulator of the BFCS, but there are controversial reports regarding the cannabinoid effects in learning and memory processes. The animal models of cholinergic impairment mimick the main histopathological and behavioral effects observed in patients. The MR antagonism, e.g. using scopolamine (SCOP), is used as a model of amnesia in rodents. The intraparenchymal administration of 192-IgG-saporin (SAP) in the nucleus basalis magnocellularis eliminates cholinergic neurons leading to learning and memory deficits. Then, the present study evaluates the modulation of spatial and working memory with the Barnes Maze following a subchronic treatment with a low dose (0.5 mg/kg) of WIN55,212-2 (WIN) in both the SCOP and SAP models of learning and memory deficit. In the SCOP model, the administration of WIN protects learning and memory impairment during the probe trial, recorded as the time spent in the target quadrant (WIN + SCOP: 78 ± 13 sec vs VEH + SCOP: 45 ± 3 sec; p ¿ 0.001). A similar effect of the treatment was observed in the SAP model (SAP: 50 ± 3 sec vs SAP + WIN: 82 ± 7 sec; p ¿ 0.001). This effect was specifically mediated by CB1 receptors, since it was blocked by the co-administration of the specific CB1 antagonist, SR141716A (0.5 mg/kg) (SAP: 49 ± 3 sec vs SAP + WIN + SR: 48 ± 5 sec). However, higher doses of WIN (3 mg/kg) induced negative effects in learning and memory in control (C) rats, but positive and comparable to the lower dose in the SAP model (C: 89 ± 3 sec, C + WIN-3 mg/kg: 48 ± 3 sec; SAP: 49 ± 3; SAP + WIN-3 mg/kg: 80 ± 12 sec). The CB1 activation by low doses of the cannabinoid agonist WIN are able to block the amnesic effects induced by SCOP and also the learning and memory impairment produced by the BFCS pathway degeneration. CB1 agonists could contribute to improve the clinical symptoms of AD.

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In vivo functional role of the 5-HT2A/mGlu2 receptor heterocomplex in rodents

MOLLINEDO GAJATE, IRENE

Directors:
MEANA MARTINEZ, JOSE JAVIER
Mentions:
Cum Laude Distinction
International Thesis
Grade:
Excellent Cum Laude
Year:
2018
Abstract:

La esquizofrenia es una enfermedad prototípica humana de etiología aún desconocida. La investigación con modelos animales permite estudiar las causas y mecanismos afectados en dicha enfermedad. Así, fármacos como el DOI, actuando como agonista del receptor de serotonina 5-HT2A, induce sintomatología similar a la esquizofrenia de tipo paranoide. Existe un heterocomplejo formado entre los receptores 5-HT2A/mGlu2 en la corteza prefrontal de cerebros humanos y roedores, necesario para desencadenar dicha sintomatología positiva de esquizofrenia. Un número sustancial de artículos habían demostrado la interacción entre ambos receptores, incluyendo estudios celulares, genéticos, biofísicos y bioquímicos in vitro, pero la funcionalidad de este complejo in vivo permanecía aún poco conocida. La presente Tesis Doctoral evalúa la funcionalidad de este heterocomplejo in vivo, mediante el estudio de la liberación de catecolaminas en la corteza frontal de roedor tras la administración del alucinógeno DOI. Asimismo, se ha realizado un estudio de algunos circuitos noradrenérgicos modulados por la administración de este alucinógeno y se ha estudiado brevemente la señalización celular desencadenada por la activación del receptor 5-HT2A.

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Estudio de la expresión de micrornas y su modulacion como potencial diana terapéutica en la retinosis pigmentaria

ANASAGASTI VITERI, ANDER

Directors:
RUIZ EDERRA, JAVIER
Mentions:
Cum Laude Distinction
Grade:
Excellent Cum Laude
Year:
2018
Abstract:

La retinosis pigmentaria (RP) es la principal causa genética de degeneración de la visión en todo el mundo con más de 1.5 millones de afectados, para la que aún no existe un tratamiento estandarizado y eficaz. Esta enfermedad se caracteriza por su gran heterogeneidad clínica y genética, con más de 70 genes relacionados en su desarrollo. Partimos de la hipótesis de que en la RP se ve alterado un conjunto de mecanismos moleculares comunes a distintas formas de la enfermedad, con independencia del gen mutado. Esta idea se apoya en distintos trabajos en los que se ha descrito un patrón común de expresión diferencial tanto de genes, como de microRNAs en distintos modelos animales de RP, causados por mutaciones en genes diferentes. El desarrollo de esta tesis se ha planteado alrededor de dos objetivos principales; por una parte el estudio de la expresión de microRNAs para la identificación de microRNAs diferencialmente expresados que sirvan como potencial diana terapéutica en la RP, y por otra parte la modulación in vivo de un grupo de microRNAs y el análisis del efecto de dicha modulación en un modelo animal de la enfermedad, el ratón rd10.

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Constitutive activity and drug functional selectivity of 5-HT2A receptors in post-mortem brain of subjects with schizophrenia/5-HT2A hartzailearen aktibitate konstitutiboa eta farmakoen hautakortasun funtzionala: eskizofrenikoen post-mortem garunean egindako lana

MUNETA ARRATE, ITZIAR

Directors:
HORRILLO FURUNDARENA, IGOR;
MEANA MARTINEZ, JOSE JAVIER
Mentions:
Cum Laude Distinction
International Thesis
Grade:
Excellent Cum Laude
Year:
2022
Abstract:

La esquizofrenia es una enfermedad mental crónica e incapacitante de etiología aún desconocida. El receptor 2A de serotonina (5-HT2AR) es a la vez diana de compuestos alucinógenos y de antipsicóticos atípicos. Los estudios de funcionalidad del receptor en tejido cerebral humano post-mortem de sujetos con esquizofrenia sugieren una hiperactividad del 5-HT2AR. En este contexto se ha demostrado la existencia de una mayor activación de la proteína G¿i1 por el agonista del 5-HT2AR (±)DOI en cerebro humano post-mortem de sujetos con esquizofrenia, sin alteraciones en la vía canónica, es decir la hiperactividad muestra selectividad funcional. La presente tesis doctoral evalúa el hecho de si esta mayor activación se debe a una alteración en la actividad constitutiva del 5-HT2AR sobre la vía alucinógena dependiente de la vía G¿i1, que está aún por demostrar, y para hacerlo es necesario el uso de agonistas inversos. Entre ellos, pimavanerina y altaserina se comportaron como agonistas inversos de la vía G¿i1 pero comoantagonistas neutros sobre la vía canónica G¿q11. En cambio, volinanserina actúa como agonista inverso también sobre la vía G¿q11. Por ello, pimavanserina y volinanserina se utilizaron como herramientas farmacológicas para estudiar la existencia de una mayor actividad constitutiva en cerebro humano post-mortem de sujetos con esquizofrenia. Estos estudios confirmaron la existencia de una mayor actividad constitutiva del 5-HT2AR en sujetos con esquizofrenia frente a sujetos control, mediada selectivamente por la vía pro-alucinógena G¿i1, mientras que no se observan cambios en la vía canónica G¿q/11 del 5-HT2AR. Además, fármacos antipsicóticos atípicos como clozapina y risperidona presentaron un perfil selectivo como agonistas inversos de la vía G¿i1 del 5-HT2AR. Estos hallazgos apoyan la hipótesis de que nuevos fármacos que actúen selectivamente como agonistas inversos del 5-HT2AR sobre la vía pro-alucinógena, podrán presentar una mayor eficacia.

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RODILLA OJEDA, IRATI

Directors:
MENDIGUREN ORDORICA, AITZIBER;
PINEDA ORTIZ, JOSEBA GOTZON

Optimizing pharmacotherapy in the elderly using modelling and simulation methods. Application to Bilastine

LO RE , VALENTINA

Directors:
RODRIGUEZ CALVO,MONICA;
SUAREZ GONZALEZ, MARIA ELENA
Mentions:
Cum Laude Distinction
Industrial Thesis
Grade:
Excellent Cum Laude
Year:
2021
Abstract:

This research project was designed to acquire a deeper knowledge on how physiological changes during aging may affect the pharmacokinetics (PK) and pharmacodynamics (PD). Elderly adults are a vulnerable population due to the physiological changes associated with age and the additional problems of polypharmacy and comorbidity diseases. Therefore, a better understanding of the clinical pharmacology of old age is important in the development of pharmacometric strategies that could support dose selection in this special population. In order to establish if the use of predictive PK/PD models that include changes in the ADME processes as a function of age, already applied to pediatrics, will also be also predictive in the geriatric population, the antihistamine drug bilastine was employed as a probe drug. On the one hand due to the wide knowledge of the research team on this drug, and on the other hand as a PK/PD data package was available in geriatric patients to inform the model building and to validate the predictions. As a first step in this research project, a database was created using data from the public domain used to develop the equations that relate ADME processes with physiological metrics as a function of aging. These equations were then used to develop the Senescence model. The mechanistic approach proposed in this research project integrated the available drug PK knowledge in adults as well as the impact of the physiological changes in elderly affecting the PK and/or PD of bilastine followed by the application of modelling and simulation techniques. The underlying mechanisms affecting the PK of bilastine were elucidated by combining a compartmental model structure together with principles of physiology related to distribution and elimination processes in order to determine the impact of key physiological parameters that were predictive of PK behavior of bilastine in adults and also in the geriatric population. Moreover, considering that the proposed predictive model was built on a physiological basis, it was used to predict PK in elderly patients with renal impairment with the aim of exploring the impact of this pathophysiological condition on bilastine PK. Overall, in both scenarios, the model¿s predictive performance was satisfactory evaluated using available geriatric PK data indicating that the main assumptions concerning the agedependent processes determining the pharmacokinetics of bilastine, are overall well described.

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