Following traumatic brain injury, there is an enhanced cell proliferative and neurogenic response in the young adult hippocampus, which may be associated with innate cognitive recovery. However, in the aged brain, an increased level of inflammatory cell responses was observed following injury concomitant to decreased hippocampal neurogenesis and cognitive recovery in the aging population. This suggests that excessive inflammation produced in the injured aging brain has a detrimental effect on neurogenesis and cognitive function. In this study, we examined the effect of anti-inflammatory treatment with minocycline on cell proliferation and generation of new neurons in the dentate gyrus (DG) of the hippocampus in both young and aged rats. Fisher 344 rats aged at 3 months and 20 months were subjected to a moderate lateral fluid percussion injury (LFPI) or cortical impact injury (CCI). Minocycline was administered intraperitoneally starting either at 30 minutes or 4 hours post-injury, thereafter twice daily for 2 days. BrdU was injected at 2 days post-injury to label injury-induced proliferating cells. To examine the effect of minocycline on cell proliferation, generation of new neurons, and inflammatory cell response at the acute stage post-injury, the rats were perfused 3 days post-injury. Brain sections were immunostained for BrdU and early neuronal marker doublecortin (DCX). The results show that short-term anti-inflammatory treatment with minocycline reduces the cell proliferative response, presumably inflammatory cell responses, in young and aged rats following LFPI and CCI injury, and enhances generation of new neurons in the hippocampus in both young and aged rats following LFPI and in aged rats following CCI injury. Therapies that enhance hippocampal neurogenesis may also have potential to improve cognitive recovery following TBI.

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / A esquizofrenia à um transtorno mental grave que afeta cerca de 1 % da populaÃÃo acima da idade de 18 anos e à capaz de comprometer o pensamento, vontade prÃpria, percepÃÃo, afeto e interaÃÃo social. O efeito insuficiente da farmacoterapia atual sobre os sintomas negativos e dÃficits cognitivos reflete nossa mà compreensÃo da etiologia da esquizofrenia. Tem sido hipotetizado que as alteraÃÃes na sinalizaÃÃo nitrÃrgica e o desequilÃbrio oxidativo desempenham um papel na neurobiologia da esquizofrenia. EvidÃncias preliminares sugerem que o tratamento adjuvante com minociclina à eficaz para sintomas negativos e cognitivos desse transtorno. Assim, esse estudo investigou os efeitos da minociclina na prevenÃÃo e reversÃo de comportamentos tipo esquizofrenia induzidos por cetamina em camundongos. No protocolo de reversÃo, diferentes grupos de animais receberam cetamina (20 mg/kg) ou DMSO (veÃculo usado nos grupos controles) por 14 dias e, do 8 ao 14 dia, receberam adicionalmente minociclina (25 ou 50mg/kg), risperidona (0,5mg/kg) ou DMSO 30 minutos depois. No protocolo de prevenÃÃo, os camundongos foram prÃ-tratados com ambas as doses de minociclina, risperidona ou DMSO por 14 dias e, do 8 ao 14 dia, receberam adicionalmente cetamina 30 minutos depois. Todas as drogas foram administradas intraperitonealmente e uma vez ao dia. Comportamentos relacionados aos sintomas positivos (inibiÃÃo prÃ-pulso e atividade locomotora), negativos (interaÃÃo social) e cognitivos (labirinto Y) da esquizofrenia tambÃm foram avaliados. Glutationa (GSH), substÃncias reativas ao Ãcido tiobarbitÃrico (TBARS) e os nÃveis de nitrito foram medidos no cÃrtex prÃ-frontal (CPF), hipocampo (HC) e no corpo estriado (CE). Os resultados dos testes comportamentais mostraram que a cetamina promoveu um dÃficit no filtro sensÃrio-motor, aumento da atividade locomotora, diminuiÃÃo da interaÃÃo social e prejuÃzo na memÃria de trabalho. Praticamente todos esses parÃmetros foram prevenidos e revertidos pela administraÃÃo de minociclina (25 e 50mg/kg) e risperidona. A cetamina tambÃm promoveu alteraÃÃes nos marcadores oxidativos, atravÃs do aumento da peroxidaÃÃo lipÃdica e diminuiÃÃo dos nÃveis do antioxidante GSH, alÃm do aumento dos nÃveis de nitrito no CE. Seguindo a mesma linha dos resultados comportamentais, a minociclina e risperidona foram capazes de prevenir e reverter tais alteraÃÃes. Estes dados fornecem evidÃncias prÃ-clÃnicas para uma melhor avaliaÃÃo da minociclina como um novo agente antipsicÃtico e sugerem que seu mecanismo de aÃÃo inclui efeitos nos sistemas antioxidantes e nitrÃrgicos. / Schizophrenia is a serious mental disorder that affects approximately 1 % of the population over the age of 18 and is able to compromise the thought, will, perception, social interaction and affection. The insufficient effect of current pharmacotherapy on negative symptoms and cognitive deficits reflects our poor understanding of the etiology of schizophrenia. It has been hypothesized that oxidative imbalance and alterations in nitrergic signaling play a role in the neurobiology of schizophrenia. Preliminary evidence suggests that adjunctive minocycline treatment is efficacious for cognitive and negative symptoms of schizophrenia. Thus, this study investigated the effects of minocycline in the prevention and reversal of ketamine-induced schizophrenia-like behaviors in mice. In the reversal protocol, different groups of animals received ketamine (20 mg/kg) or DMSO (vehicle used in controls) for 14 days, and, from the 8th to 14th day, additionally received minocycline (25 or 50mg/kg), risperidone (0.5 mg / kg) or DMSO 30 minutes after. In the prevention protocol, mice were pre-treated with both doses of minocycline, risperidone or DMSO for 14 days, from the 8th to 14th day, additionally received ketamine 30 minutes later. All drugs were administered intraperitoneally and once a day. Behaviors related to positive (locomotor activity and prepulse inhibition of startle), negative (social interaction) and cognitive (Y maze) symptoms of schizophrenia were also assessed. Glutathione (GSH), thiobarbituric acid-reactive substances (TBARS) and nitrite levels were measured in the prefrontal cortex (PFC), hippocampus (HC) and striatum (ST). The result of behavioral tests showed that ketamine promoted a deficit in sensorimotor filter, increased locomotor activity, decreased social interaction and prejudice in working memory. Virtually all of these parameters were prevented and reversed by the administration of minocycline (25 and 50 mg/kg) and risperidone. Ketamine also promoted changes in oxidative markers by increasing lipid peroxidation and antioxidant GSH levels decrease, in addition to increased levels of nitrite in the ST. Following the same line of the behavioral results, minocycline and risperidone were able to prevent and reverse such changes.These data provide a rationale for evaluating minocycline as a novel psychotropic agent and suggest that its mechanism of action includes antioxidant and nitergic systems.

Diese Arbeit beschäftigt sich mit den Auswirkungen der Herz-Lungen-Maschine auf das Gewebe des Hippocampus in einem Ferkelmodell. Die Tiere untereilte man in 5 Gruppen: „Kontrolle“, „Kontrolle mit Minozyklin“, „HLM pulsatil“, „HLM nicht-pulsatil“, sowie „HLM nicht-pulsatil mit Minozyklin“. Es wurde untersucht, ob eine pulsatile Perfusion Schäden in den Zellen des Hippocampus gegenüber eines nicht-pulsatilen Blutflusses während der extrakorporalen Zirkulation abmildern kann. Des Weiteren überprüfte man neuroprotektive Effekte des Tetrazyklin-Derivates Minozyklin während eines kardiochirurgischen Eingriffes mit Herz-Lungen-Maschine. Während der Operation wurde bei allen Ferkeln eine Hypothermie von 28 °C durchgeführt und die HLM-Zeit betrug 90 Minuten. Die Rekonvaleszenzzeit umfasste 120 Minuten. Minozyklin verabreichte man in den entsprechenden Gruppen sowohl zu Beginn des Versuches (4 mg/kg KM) und nach Abkopplung von der Herz-Lungen-Maschine (2 mg/kg KM) intravenös. Hauptbestandteil der Arbeit waren histologische und immunhistochemische Färbemethoden zur Untersuchung des Hippocampus. Mithilfe eines Mikroskops wurden Veränderungen auf zellulärer Ebene im CA1- und CA3-Areal des Cornu ammonis im Hippocampus ausgewertet. Für die Ergebnisse betrachtet man die Pyramidenzellen des Stratum pyramidale. In der Hämatoxylin-Eosin-Färbung wurden Zellen mit den Eigenschaften „Ödem“, „Eosinophilie“ und „Pyknose“ für jedes Versuchstier gezählt. Mit den immunhistochemischen Färbungen sollten Faktoren für den programmierten Zelltod, für Hypoxie (HIF 1-alpha) und für oxidativen Stress (3-Nitrotyrosin) detektiert werden. Als Marker für Apoptose wählte man den Apoptose-induzierenden Faktor (AIF), cleaved Caspase 3 und Poly(ADP)Ribose (PAR).:Inhaltsverzeichnis 1 Einführung 1.1 Kinderherzchirurgie 1.2 Herz-Lungen-Maschine 1.3 Pathophysiologie der HLM 1.3.1 Inflammationsreaktion 1.3.2 Ischämie 1.3.3 Reperfusion 1.4 HLM und Folgen für das Gehirn 1.5 Neuroprotektive Strategien 1.5.1 Pulsatile Perfusion 1.5.2 Minozyklin 1.6 Hippocampus 2 Aufgabenstellung 3 Tiere, Material und Methoden 3.1 Versuchstiere 3.2 Versuch Teil 1: Operation 3.2.1 Gruppeneinteilung und Versuchsaufbau 3.2.2 Anästhesie 3.2.3 Operation 3.2.3.1 Vorbereitungszeit 3.2.3.2 Kardioplegie 3.2.3.3 Herz-Lungen-Maschine mit nicht-pulsatilen Blutfluss/ pulsatilen Blutfluss 3.2.3.4 Medikation mit Minozyklin 3.2.4 Intraoperatives Monitoring 3.2.4.1 Vitalparameter 3.2.4.2 Arterielle Blut-Gas-Analyse 3.2.4.3 Elektrolyt-Haushalt 3.2.4.4 Laktat- und Glukose-Haushalt 3.3. Versuch Teil 2: Laboruntersuchungen 3.3.1 Einbetten der Proben und Herstellung der Schnittpräparate 3.3.2 Histologie 3.3.2.1 Hämatoxylin-Eosin-Färbung 3.3.3 Immunhistochemie 3.3.3.1 Allgemeines Prinzip 3.3.3.2 Nachweis: Apoptose-induzierender Faktor 3.3.3.3 Nachweis: Hypoxie-induzierter Faktor 1- alpha 3.3.3.4 Nachweis: cleaved Caspase 3 3.3.3.5 Nachweis: 3-Nitrotyrosin 3.3.3.6 Nachweis: Poly(ADP)Ribose 3.3.4 RP-HPLC – Reversed Phase High Performance Liquid Chromatography 3.4 Blutgasanalyse 3.5 Auswertung am Mikroskop 3.6 Statistik 4 Ergebnisse 4.1 Intraoperatives Monitoring 4.2 Arterielle Blutproben 4.3 Arterielles Blut: Laktat-Haushalt 4.4 Ergebnisse der RP-HPLC 4.5 Ergebnisse der Hämatoxylin-Eosin-Färbung 4.6 Ergebnisse der immunhistochemischen Färbungen 4.6.1 Apoptose-induzierender Faktor 4.6.2 Hypoxie-induzierter Faktor 1-alpha 4.6.3 3-Nitrotyrosin 4.6.4 Cleaved Caspase 3 4.6.5 Poly-(ADP)-Ribose 5 Diskussion 5.1 Tiermodell und Versuchsaufbau 5.2 Blutproben 5.3 Herz-Lungen-Maschine und nicht-pulsatiler Blutfluss versus pulsatiler Blutfluss 5.4 Extrakorporale Zirkulation und die Gabe von Minozyklin 5.5 Beantwortung der Fragestellungen 6 Zusammenfassung 7 Literaturverzeichnis 8 Anhang 8.1 Einführung 8.1.1 Kinderherzchirurgie 8.1.2 Pathophysiologie der HLM 8.2 Tiere, Material und Methoden 8.2.1 Operation 8.2.2 Intraoperatives Monitoring 8.2.3 Laboruntersuchungen 8.3 Ergebnisse 8.3.1 Intraoperatives Monitoring 8.3.2 Arterielles Blut 8.3.3 Arterielles Blut – Laktat-Haushalt 8.3.4 RP-HPLC 8.3.5 Hämatoxylin-Eosin-Färbung 8.3.6 Immunhistochemie 9 Selbständigkeitserklärung 10 Lebenslauf 11 Koautorenschaft 12 Danksagung

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Ischemic stroke occurs as a result of a lack or severe reduction of blood supply to the brain. Presently therapeutic interventions are limited and there is a need to develop new and efficacious stroke treatments. To this end, a great deal of research effort has been devoted to studying the potential molecular mechanisms involved in ischemic neuronal death. Correlative evidence demonstrated a paradoxical activation of the cell cycle machinery in ischemic neurons. The levels and activity of key cell cycle regulators including cyclin D1, Cdk2 and Cdk4 are upregulated following ischemic insults. However, the functional relevance of these various signals following ischemic injury was unclear. Accordingly, the research described in this thesis address the functional relevance of the activation of the cell cycle machinery in ischemic neuronal death. The data indicate that the inhibition of Cdk4 protects neurons from ischemia-induced delayed death, whereas abrogation of Cdk5 activity prevents excitotoxicity-induced damage in vitro and in vivo. Examination of upstream activators of mitotic-Cdks showed that Cdc25A is a critical mediator of delayed ischemic neuronal death. Investigation of the potential molecular mechanism by which cell cycle regulators induced neuronal death revealed perturbations in the levels and activity of key downstream targets of Cdk4. The retinoblastoma protein family members, pRb and p130 are increasingly phosphorylated following ischemic stresses. Importantly, p130 and E2F4 proteins are drastically reduced following ischemic insults. Additionally, E2F1 association with promoters of pro-apoptotic genes are induced while that of E2F4 is reduced. These changes appear to be important determinants in ischemic neuronal death. Cumulatively, the data supports the activation of the cell cycle machinery as a pathogenic signal contributing to ischemic neuronal death. The development of neuroprotectant strategies for stroke has been hampered in part by its complex pathophysiology. Previous research indicated that flavopiridol, a general CDK-inhibitor, is unable to provide sustained neuroprotection beyond one week following cerebral ischemia. The potential benefit of combining flavopiridol with another neuroprotectant, minocycline, was explored. The data indicate that while this approach provided histological protection 10 weeks after insult, the protected neurons are not functional due to progressive dendritic degeneration. This evidence indicates that targeting cell cycle pathways in stroke while important must be combined with other therapeutic modalities to fully treat stroke-induced damage.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / In this work was developed an electroanalytical methodology for determination of the antibiotic minocycline in pharmaceutical formulation and in human milk using differential pulse voltammetry. The voltammograms of the minocycline obtained with carbon paste electrodes showed a well-defined peak at 0.40 V vs. Ag/AgCl, corresponding to the oxidation of minocycline at pH 4.0. The electrodic behavior involved a reversible oxidation process and mass transport controlled by diffusion. The value of the effective area calculated for the carbon paste electrode was 0.3313 cm2, corresponding to a geometric area of 0.0078 cm2. After the optimization of the experimental conditions, such as, pH 4.00; scan speed 30 mV s-1, amplitude 100 mV; analytical curves were obtained in the linear concentration range from 2.0 to 23 μmol L-1 resulting in a detection limit of 0.7 μmol L-1 and the quantification limit of 2.2 μmol L-1. In order to evaluate the robustness of the proposed method the presence of possible interfering was analyzed in the determination of the minocycline, it was observed the interference of the folic acid, ketoconazole and dipyridamole among the possible evaluated interfering. To check the applicability of the developed method were analyzed previously in the optimized conditions, commercial samples of pharmaceutical formulations, one liquid and another in tablet, obtaining a recovery of 100 and 99.3%, respectively; and samples of maternal milk, obtaining a recovery of 96%. In addition to advantages such as high selectivity and sensitivity, the method developed could be used for the analysis of minocycline in pharmaceutical formulation and human milk without any need for prior sample treatment. / Neste trabalho foi desenvolvido uma metodologia eletroanalítica para a determinação do antibiótico minociclina em formulação farmacêutica e em leite materno usando voltametria de pulso diferencial. Os voltamogramas da minociclina obtidos com eletrodos de pasta de carbono apresentaram um pico bem definido em 0,40 V vs. Ag/AgCl, correspondente à oxidação da minociclina em pH 4,0. O comportamento eletródico envolveu um processo de oxidação reversível e um transporte de massa controlado por difusão. O valor da área efetiva calculada para o eletrodo de pasta de carbono foi de 0,3313 cm2, correspondente a uma área geométrica de 0,0078 cm2. Após a otimização das condições experimentais, a saber, pH 4,00; velocidade de varredura 30 mV s-1, amplitude 100 mV, curvas analíticas foram obtidas na faixa linear de concentração de 2,0 a 23 μmol L-1 resultando em um limite de detecção de 0,70 μmol L-1 e um limite de quantificação de 2,2 μmol L-1. A fim de avaliar a robustez do método proposto foi analisada a presença de possíveis interferentes na determinação da minociclina, sendo observado a interferência do ácido fólico, cetoconazol e dipiridamol dentre os possíveis interferentes avaliados. Para verificar a aplicabilidade do método desenvolvido foram analisadas nas condições previamente otimizadas, amostras comerciais de formulações farmacêuticas, uma líquida e outra em comprimido, obtendo uma recuperação de 100 e 99,3%, respectivamente; e amostras de leite materno, obtendo uma recuperação de 96%. Além das vantagens como alta seletividade e sensibilidade, o método desenvolvido pode ser usado para análise de minociclina em formulação farmacêutica e em leite materno sem a necessidade de tratamento prévio da amostra.

Ischemic stroke occurs as a result of a lack or severe reduction of blood supply to the brain. Presently therapeutic interventions are limited and there is a need to develop new and efficacious stroke treatments. To this end, a great deal of research effort has been devoted to studying the potential molecular mechanisms involved in ischemic neuronal death. Correlative evidence demonstrated a paradoxical activation of the cell cycle machinery in ischemic neurons. The levels and activity of key cell cycle regulators including cyclin D1, Cdk2 and Cdk4 are upregulated following ischemic insults. However, the functional relevance of these various signals following ischemic injury was unclear. Accordingly, the research described in this thesis address the functional relevance of the activation of the cell cycle machinery in ischemic neuronal death. The data indicate that the inhibition of Cdk4 protects neurons from ischemia-induced delayed death, whereas abrogation of Cdk5 activity prevents excitotoxicity-induced damage in vitro and in vivo. Examination of upstream activators of mitotic-Cdks showed that Cdc25A is a critical mediator of delayed ischemic neuronal death. Investigation of the potential molecular mechanism by which cell cycle regulators induced neuronal death revealed perturbations in the levels and activity of key downstream targets of Cdk4. The retinoblastoma protein family members, pRb and p130 are increasingly phosphorylated following ischemic stresses. Importantly, p130 and E2F4 proteins are drastically reduced following ischemic insults. Additionally, E2F1 association with promoters of pro-apoptotic genes are induced while that of E2F4 is reduced. These changes appear to be important determinants in ischemic neuronal death. Cumulatively, the data supports the activation of the cell cycle machinery as a pathogenic signal contributing to ischemic neuronal death. The development of neuroprotectant strategies for stroke has been hampered in part by its complex pathophysiology. Previous research indicated that flavopiridol, a general CDK-inhibitor, is unable to provide sustained neuroprotection beyond one week following cerebral ischemia. The potential benefit of combining flavopiridol with another neuroprotectant, minocycline, was explored. The data indicate that while this approach provided histological protection 10 weeks after insult, the protected neurons are not functional due to progressive dendritic degeneration. This evidence indicates that targeting cell cycle pathways in stroke while important must be combined with other therapeutic modalities to fully treat stroke-induced damage.

Indiana University-Purdue University Indianapolis (IUPUI) / Introduction: Regenerative endodontic therapy in immature teeth with necrotic pulps triggers continued root development thereby improving the prognosis of these teeth. Several agents are under consideration for the disinfection and conditioning phases of this therapy. Triple antibiotic paste (TAP, i.e. equal parts of ciprofloxacin, metronidazole, minocycline) is used for canal disinfection and 17% EDTA solution is used for dentin conditioning. However, TAP and EDTA cause demineralization and their effect on surface loss and surface roughness of radicular dentin during regenerative procedures has not been quantified. Surface loss may be correlated with reduced tooth strength and surface roughness may be correlated with stem cell attachment. Objectives: The aim of this in vitro study was to quantitatively investigate the surface loss and surface roughness on human radicular dentin after treatment with two concentrations of TAP followed by EDTA. Materials and Methods: Human radicular dentin specimens were prepared from extracted human anterior teeth and randomized into six experimental groups. Group 1: saline control; Group 2: 17% EDTA; Group 3: TAP 1 mg/mL; Group 4: TAP 1 mg/mL and 17% EDTA; Group 5: TAP 1,000 mg/mL; Group 6: TAP 1,000 mg/mL and 17% EDTA for 5 minutes. After TAP is applied to Groups 3-6, all groups were incubated for 4 weeks. Then, groups 2, 4, and 6 were treated with EDTA for 5 minutes. Dentin surface loss (μm) and surface roughness (Ra, μm) were quantified after various treatments using non-contact and contact profilometry, respectively. Data were analyzed by one-way analysis of variance (α = 0.05) Hypothesis: It was hypothesized that there would be a significant difference in surface loss or surface roughness between at least two treatment groups. Results: All treatment groups showed significantly higher surface loss compared to untreated control. Dentin treated with 1g/mL TAP caused significant increase in surface loss and surface roughness compared to dentin treated with 1 mg/mL TAP. However, only 1g/mL TAP treated dentin showed significantly higher surface roughness compared to untreated control. The use of EDTA after both concentrations of TAP did not have significant additive effect on surface loss and surface roughness of dentin. Conclusion: The use of 1 mg/mL TAP can minimize surface loss and surface roughness of radicular dentin compared to higher concentrations. The use of EDTA after TAP may not cause additional surface loss and surface roughness of dentin.

No description available.

La gravité du traumatisme crânien (TC) dépend de la sévérité immédiate des lésions primaires mais également de leur aggravation dans les heures et les jours qui suivent le TC, avec l'apparition de lésions secondaires. La neuro-inflammation constitue l'une des cascades physiopathologiques post-TC dont le contrôle a été décrit comme une stratégie neuroprotectrice potentielle. Elle compromet le taux de la forme soluble α du précurseur du peptide ß amyloÏde, sAPPα, un neuroprotecteur endogène issu de l'action des enzymes α-sécrétases (ADAMs). Dans ce contexte, mon travail de thèse a eu pour but d'étudier l'intérêt thérapeutique des composés pharmacologiques modulant le taux de sAPPα post-TC sur les conséquences biochimiques, histopathologiques et fonctionnelles, à court et à long terme, dans un modèle de TC par percussion mécanique chez la souris. Parmi les différents composés, la minocycline, une tetracycline de 2e génération aux effets anti-inflammatoires, et l'étazolate, une pyrazolopyridine récemment décrite comme activateur des α-sécrétases, ont été sélectionnés. Le traitement anti-inflammatoire par la minocycline permet de restaurer le taux de la sAPPα, et cet effet dans la phase précoce est accompagné d'une réduction des conséquences histopathologiques (atrophie callosale et striatale, lésion des bulbes olfactifs et ventriculomégalie) à 3 mois post-TC. Sur le plan fonctionnel, le test d'aversion olfactive a été pour la première fois mis au point sur un modèle expérimental de TC et a permis de révéler un déficit olfactif persistant dans notre modèle. De plus, un déficit cognitif persistant a été également mis en évidence par le test NORT " Novel Object Recognition Test ". Le même traitement par la minocycline a permis de corriger ces déficits olfactif et cognitif à court et à long terme (3 mois) post-TC. Les résultats obtenus sur l'étazolate (étude de fenêtre thérapeutique, étude d'effet-dose) ont montré, pour la première fois dans un modèle de lésion cérébrale, son potentiel anti-inflammatoire et anti-œdémateux, associé à la restauration du taux de la sAPPα, avec une fenêtre thérapeutique d'au moins de 2h. Le même traitement réduit les conséquences histopathologiques (activation microgliale, ventriculomégalie, lésion des bulbes olfactives) et fonctionnelles (hyperactivité locomotrice, déficit cognitif), à court à long terme (3 mois) post-TC. En conclusion, l'ensemble de ce travail a permis d'établir les bénéfices d'une stratégie pharmacologique s'opposant à la fois à la neuro-inflammation et à la chute du taux de la sAPPα dans la phase précoce de TC avec une amélioration histologique et fonctionnelle à long terme, soulignant son intérêt thérapeutique. Il est important de souligner que la minocycline est déjà entrée en essai clinique pour le traitement de TC, et que malgré le peu de données précliniques, l'étazolate (EHT-0202) est tout récemment entré en phase II pour le traitement de la maladie d'Alzheimer.