PKCe plays a very important role in mediating the protection against myocardial ischemia and reperfusion injury induced by ischemic preconditioning (IPC) and pharmacologic preconditioning (PPC). The redistribution of PKCe was assessed by subcellular fractionation and western blotting in the Langendorff-perfused rabbit heart. Either 5min ischemia or 5min administration of adenosine A1 and/or A3 agonists, bradykinin, angiotensin II, and d1-opioid agonists resulted in PKCe redistribution from the cytosol to the mitochondria. This effect of IPC on PKCe redistribution was visible up to at least 30min of reperfusion, while that of PPC was lost by 10min of drug washout, indicative of the transient nature of PKCe redistribution. PKCe redistribution to mitochondria by IPC was also visualized using immunogold electron microscopy. Thus, IPC and PPC caused PKCe redistribution from the cytosol to the mitochondria, which was longer-lasting in IPC than in PPC.

Study evaluates adenosine, which is used as an adjunct to conventional reperfusion therapy (percutaneous coronary intervention, i.e. PCI), role in reducing the infarct size and preserving the left ventricular function in patients with acute myocardial infarction. During the study we examined patients with the left ventricular anterior wall acute myocardial infarction (AMI), when PCI and stenting were used for infarct-related artery (IRA) re-opening. Study evaluates influence of complementary use of adenosine in reducing the myocardial ischemic-reperfusion injury, the manifestation of slow-reflow or no-reflow phenomenon. The results of reperfusion therapy with adjunctive adenosine and without adenosine were analyzed in two homogeneous patient groups. By using new non-invasive imaging methods (single photon emission computer tomography, transthoracic Doppler echocardiography, dobutamine stress echocardiography) it was estimated, that adenosine preserves myocardial contractility and coronary flow reserve during the acute phase of myocardial infarction, reduces the final infarct size, improves the recovery of left ventricular global and segmental contractile function at five months follow-up. Those results are achieved due to adenosine impact on improving blood flow restoration not only in major coronary arteries, but also at microcirculatory level and ensuring of adequate and effective myocardial reperfusion. / Tyrime analizuojama adenozino, kuriuo papildoma įprastinė reperfuzinė terapija (perkutaninė koronarinė intervencija), įtaka mažinant infarkto dydį ir išsaugant kairiojo skilvelio funkciją pacientams, sergantiems ūminiu miokardo infarktu. Tyrimo metu siekta įvertinti PKI ir stentavimo būdu atveriant priekinės nusileidžiančios šakos spindį, kurio okliuzija sąlygojo kairiojo skilvelio priekinės sienelės ūminį miokardo infarktą, papildomai naudojamo adenozino įtaką mažinant miokardo išeminį-reperfuzinį pažeidimą, lėtos ar nutrūkusios tėkmės fenomeno pasireiškimą ir išplitimą. Reperfuzinės terapijos (PKI naudojant adenoziną ir PKI be adenozino) rezultatų ypatumai ir skirtumai palyginti dviejose homogeniškose pagal kontrolinius kintamuosius pacientų grupėse. Pasitelkus naujausius neinvazinius vaizdinimo metodus (miokardo perfuzijos radionuklidinę kompiuterinę tomografiją, transtorakalinę doplerinę echokardiografiją, dobutamino krūvio echokardiografiją) nustatyta, kad adenozinas, gerindamas kraujo tėkmės atstatymą ne tik stambiosiose vainikinėse arterijose, bet ir mikrocirkuliacijos grandyje, užtikrindamas adekvačią bei efektyvią miokardo reperfuziją, išsaugo miokardo kontraktilinį bei koronarinės tėkmės rezervus ūminio miokardo infarkto metu, mažina galutinį infarkto dydį, gerina bendrosios ir segmentinės kairiojo skilvelio kontraktilinės funkcijos atsistatymą praėjus 5 mėn. po reperfuzinio miokardo infarkto gydymo.

Tyrime analizuojama adenozino, kuriuo papildoma įprastinė reperfuzinė terapija (perkutaninė koronarinė intervencija), įtaka mažinant infarkto dydį ir išsaugant kairiojo skilvelio funkciją pacientams, sergantiems ūminiu miokardo infarktu. Tyrimo metu siekta įvertinti PKI ir stentavimo būdu atveriant priekinės nusileidžiančios šakos spindį, kurio okliuzija sąlygojo kairiojo skilvelio priekinės sienelės ūminį miokardo infarktą, papildomai naudojamo adenozino įtaką mažinant miokardo išeminį-reperfuzinį pažeidimą, lėtos ar nutrūkusios tėkmės fenomeno pasireiškimą ir išplitimą. Reperfuzinės terapijos (PKI naudojant adenoziną ir PKI be adenozino) rezultatų ypatumai ir skirtumai palyginti dviejose homogeniškose pagal kontrolinius kintamuosius pacientų grupėse. Pasitelkus naujausius neinvazinius vaizdinimo metodus (miokardo perfuzijos radionuklidinę kompiuterinę tomografiją, transtorakalinę doplerinę echokardiografiją, dobutamino krūvio echokardiografiją) nustatyta, kad adenozinas, gerindamas kraujo tėkmės atstatymą ne tik stambiosiose vainikinėse arterijose, bet ir mikrocirkuliacijos grandyje, užtikrindamas adekvačią bei efektyvią miokardo reperfuziją, išsaugo miokardo kontraktilinį bei koronarinės tėkmės rezervus ūminio miokardo infarkto metu, mažina galutinį infarkto dydį, gerina bendrosios ir segmentinės kairiojo skilvelio kontraktilinės funkcijos atsistatymą praėjus 5 mėn. po reperfuzinio miokardo infarkto gydymo. / Study evaluates adenosine, which is used as an adjunct to conventional reperfusion therapy (percutaneous coronary intervention, i.e. PCI), role in reducing the infarct size and preserving the left ventricular function in patients with acute myocardial infarction. During the study we examined patients with the left ventricular anterior wall acute myocardial infarction (AMI), when PCI and stenting were used for infarct-related artery (IRA) re-opening. Study evaluates influence of complementary use of adenosine in reducing the myocardial ischemic-reperfusion injury, the manifestation of slow-reflow or no-reflow phenomenon. The results of reperfusion therapy with adjunctive adenosine and without adenosine were analyzed in two homogeneous patient groups. By using new non-invasive imaging methods (single photon emission computer tomography, transthoracic Doppler echocardiography, dobutamine stress echocardiography) it was estimated, that adenosine preserves myocardial contractility and coronary flow reserve during the acute phase of myocardial infarction, reduces the final infarct size, improves the recovery of left ventricular global and segmental contractile function at five months follow-up. Those results are achieved due to adenosine impact on improving blood flow restoration not only in major coronary arteries, but also at microcirculatory level and ensuring of adequate and effective myocardial reperfusion.

La grande disponibilité et les propriétés psychostimulantes de la caféine en font l’un des psychostimulants les plus consommés mondialement. Sa capacité à augmenter la vigilance serait reliée à son action antagoniste des récepteurs adénosinergiques. Le vieillissement s'accompagne de changements dans les mécanismes de régulation de la vigilance, y compris le système adénosinergique, qui pourraient moduler les effets de la caféine. Alors que plusieurs études ont investigué les impacts de la caféine sur la vigilance chez une population jeune, peu ont identifié les effets chez une population plus âgée. Deux protocoles expérimentaux pouvant distinguer les effets différentiels de la caféine selon l’âge ont été élaborés. La première étude a évalué les effets de 200 mg de caféine sur la vigilance, comparée à un placebo, chez une population jeune et d’âge moyen lors d’une privation de sommeil de 25 heures. L’augmentation de la vigilance subjective et de la performance psychomotrice suite à l’administration de caféine est comparable dans les deux groupes d’âge. Or, des modifications de la puissance spectrale de certaines bandes de fréquences de l’EEG d’éveil suite à l’administration de la caféine sont spécifiques au groupe d’âge moyen. Une deuxième étude a évalué les effets de 200 mg de caféine sur la vigilance, comparée à un placebo, chez des sujets jeunes et d’âge moyen consommateurs légers de caféine. La caféine n’a pas augmenté la vigilance subjective des consommateurs légers. Par ailleurs, la caféine a augmenté la performance psychomotrice de façon similaire dans les deux groupes d’âge. De plus, on remarque que la caféine induit des modifications de la puissance spectrale sur certaines bandes de fréquences à l’EEG chez le groupe d’âge moyen uniquement. Ces travaux suggèrent tout d’abord que la caféine tend à augmenter la vigilance, peu importe le niveau basal d’alerte. De plus, malgré l’absence d’effet subjectif de la caféine sur la vigilance, les consommateurs légers de caféine montrent des effets sur les mesures objectives de la vigilance. Bien que la caféine augmente la vigilance chez les deux groupes d’âge, la spécificité de certaines modifications relevées à l’EEG suggère une augmentation de la sensibilité à la caféine selon l’âge. Il est possible qu’il existe des changements du système adénosinergique au cours du vieillissement qui sous-tendent les effets différentiels de la caféine au cours du vieillissement. / The availability and psychoactive properties of caffeine make it one of the most widely consumed behaviourally active substances in the world. The capacity of caffeine to increase vigilance relies on its antagonist action on adenosine receptors. Aging is associated with changes in the mechanisms regulating vigilance, possibly through changes in the adenosinergic system which could in turn affect eh influence of caffeine. While extensive research identified the impacts of caffeine on vigilance in young populations, few studies have investigated the effects in an older population. Two experimental protocols which can highlight the differential effects of caffeine according to age were elaborated. The first study estimated the effects of 200 mg of caffeine on vigilance, compared with a placebo, in young and middle-aged subjects during 25 hours of sleep deprivation. Caffeine increased subjective and psychomotor measures similarly in young and middle-aged subjects. However, modifications of the spectral power in some frequencies bands after caffeine ingestion were specific to the middle-aged group. The second study focused on the effects of 200 mg of caffeine on vigilance, compared with a placebo, in young and middle-aged light caffeine consumers. Caffeine did not increase subjective alertness in light consumers but enhanced psychomotor performance similarly in both age groups. Furthermore, caffeine affected waking EEG spectral power in specific frequencies bands in the middle-aged group only. In conclusion, these results suggest that caffeine enhance vigilance when basal level of alertness is either high or low. Furthermore, light consumers show effects of caffeine on subjective vigilance but not on objective measures. In spite of an increase of alertness in both age groups, some modifications found in the waking EEG of middle-aged subjects suggest a differential effect of caffeine depending on age. It is possible to hypothesize that changes in the adenosinergic system occur during aging and these changes could explain our results.

Adenosine (ADO) is an endogenous neuroprotectant. Under ischemic conditions ADO levels rise in the brain up to 100-fold. ADO in the brain is dependent on the movement across cell membranes by equilibrative nucleoside transporters (ENT) or produced from membrane bound ecto-5’ nucleotidase (eN). We used transgenic neurons with neuronal specific expression of human ENT1 (hENT1) and eN knockout (CD73 KO) astrocytes. The aim of this research was to determine the role of ENT1 and eN in ADO release from ischemic-like conditions in primary cultured neurons, astrocytes or co-cultures. Neurons primarily release intracellular ADO via ENTs; this effect was blocked by transporter inhibitor, dipyridamole (DPR). Astrocytes primarily convert ADO extracellularly from eN; this effect was with eN inhibitor α, β-methylene ADP (AOPCP). Combined neuron and KO astrocytes produced less ADO, extracellular ADO was inhibited by DPR but not AOPCP. Overall these results suggest that eN is prominent in the formation of ADO but other enzymes or pathways contribute to rising ADO levels in ischemic conditions.

Adenosine (ADO) is an endogenous neuroprotectant. Under ischemic conditions ADO levels rise in the brain up to 100-fold. ADO in the brain is dependent on the movement across cell membranes by equilibrative nucleoside transporters (ENT) or produced from membrane bound ecto-5’ nucleotidase (eN). We used transgenic neurons with neuronal specific expression of human ENT1 (hENT1) and eN knockout (CD73 KO) astrocytes. The aim of this research was to determine the role of ENT1 and eN in ADO release from ischemic-like conditions in primary cultured neurons, astrocytes or co-cultures. Neurons primarily release intracellular ADO via ENTs; this effect was blocked by transporter inhibitor, dipyridamole (DPR). Astrocytes primarily convert ADO extracellularly from eN; this effect was with eN inhibitor α, β-methylene ADP (AOPCP). Combined neuron and KO astrocytes produced less ADO, extracellular ADO was inhibited by DPR but not AOPCP. Overall these results suggest that eN is prominent in the formation of ADO but other enzymes or pathways contribute to rising ADO levels in ischemic conditions.

Adenosine is an essential purine nucleoside of particular importance within heart and brain. The widespread and diverse actions of adenosine, driven by activation of cell surface receptors, include regulation of sleep/arousal and neuroprotective properties. The mechanisms involved in regulating adenosine concentrations remain poorly understood but are critical to signaling pathways as they determine the availability of adenosine at corresponding receptors within the extracellular space. The equilibrative nucleoside transporter (ENT) family, bi-directional, Na+-independent nucleoside transporters, are key components in both the release and uptake of adenosine. This study has been conducted to investigate ENT3, a novel member of the ENT family. Our work has demonstrated ENT3 to be expressed throughout brain, located in cortex, cerebellum, striatum and hippocampus, at similar levels. Neurons and astrocytes, but not microglia, showed intracellular ENT3 localisation. This was confirmed by differential centrifugation, of cortex and cerebellum, which suggests ENT3 to be found within the cytoplasm.

Animal models are crucial to improve the knowledge of the mechanisms underlying the different pathological processes. These models are also excellent tools to facilitate the research of new targets for the treatment of different diseases and to evaluate the benefit/risk ratio of the potential new treatments. We have focussed this research work in the study of a new potential targets for pain, cognitive and eating disorders using new animal models developed in our laboratory. We first investigated the effects of the interaction between cannabinoids and nicotine on cognitive processes and metabolism using different behavioural models and new experimental devices. In a second part of this work, we investigated new therapeutic targets for neuropathic pain and for this purpose we developed a new behavioural model to improve the study of the therapeutic potential and possible side-effects of novel compounds. / Los modelos animales son cruciales para mejorar el conocimiento sobre los mecanismos que constituyen la base de los diversos procesos patológicos. Estos modelos representan también excelentes herramientas para facilitar la investigación de nuevas dianas para el tratamiento de estas enfermedades y para evaluar el cociente beneficio/riesgo de los nuevos tratamientos potenciales. Este trabajo de investigación se encuentra centrado en el estudio de nuevos dianas terapéuticas para el dolor, los procesos cognitivos y los desórdenes alimentarios utilizando nuevos modelos animales desarrollados en nuestro laboratorio. En primer lugar, hemos investigado los efectos de la interacción entre los cannabinoinoides y la nicotina a nivel los procesos cognitivos y del metabolismo usando diversos modelos comportamentales y nuevos dispositivos experimentales. En una segunda parte de este trabajo, hemos estudiado nuevas dianas terapéuticas para el dolor neuropático y hemos desarrollado para este propósito un nuevo modelo comportamental que permite evaluar el potencial terapéutico y los posibles efectos secundarios de nuevos compuestos.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 5 uppsatser.

Thèse (M.Ress.Renouv.)-- Université du Québec à Chicoutimi, 2002. / Document électronique également accessible en format PDF. CaQCU