Assessment of neuroprotective effects of gamma-hydroxybutyrate and neurosteroids on cellular models of Alzheimer’s disease

This PhD work showed that GHB and neurosteroids efficiently protect neuroblastoma cells against nerve cell death caused by Alzheimer's disease etiological factors including amyloid precursor protein overexpression and oxidative stress. Interestingly, an additive action of GHB and allopregnanolone was identified that may result from the combination of partial stimulation of anti-apoptotic protein expression induced by both compounds. GHB protective effect was blocked by aromatase inhibitors, suggesting that GHB may also induce neuroprotection via the activation of neurosteroidogenesis. Finally, we have used a yeast-based MMP activity assay to check whether GHB and neurosteroids can regulate the activity of human MMP-2 and MMP-9, which both control Aβ peptide degradation. Although we cannot yet conclude from our preliminary results, further improvement of the experimental setup in combination with RT-qPCR and western analyzes in human neuroblastoma cells will help to determine the modulatory action of GHB and neurosteroids on MMP activity and/or expression. Together, our data suggest that GHB and neurosteroids may be used to develop combined neuroprotective strategies against neuronal loss in Alzheimer disease.In der vorliegenden Doktorarbeit konnte gezeigt werden, dass Gamma-Hydroxybutyrat (GHB) und Neurosteroide effektiv in der Lage sind, Neuroblastoma Zellen vor den ätiologischen Faktoren der Alzheimer-Krankheit, darunter insbesondere durch oxidativen Stress und Überexpression von Amyloid-Precursor-Proteinen verursachten Zelltod, zu schützen. Interessanterweise wurde eine additive neuroprotektive Wirkung von GHB und Allopregnanolon gegen den durch oxidativen Stress induzierten Zelltod beobachtet. Diese additive Wirkung ist vermutlich auf eine spezifische Aktivierung von anti-apoptotischen Signalwegen durch GHB und Allopregnanolon zurückzuführen. Die Schutzwirkung von GHB wurde durch Aromatase-Inhibitoren blockiert, was darauf schließen lässt, dass GHB möglicherweise die Neurosteroidogenese aktiviert. Abschließend wurde mit Hilfe eines Hefe-basierten MMP-Aktivitätstests überprüft, ob GHB und/oder Neurosteroide die Aktivität von humanem MMP-2 bzw. MMP-9, welche den Abbau von Aβ-Peptiden kontrollieren, direkt beeinflussen. Auch wenn mit dem verwendeten Testsystem noch kein signifikanter Effekt von GHB und Neurosteroiden beobachtet wurde, sollte eine weitere Optimierung des Testsystems kombiniert mit RT-qPCR und Western-Analysen an humanen Neuroblastoma Zellen dazu beitragen, mögliche regulatorische Effekte von GHB und Neurosteroiden auf die MMP-Aktivitat und -Expression zu bestimmen. Zusammenfassend deuten die vorliegenden Daten darauf hin, dass GHB und Neurosteroide möglicherweise als kombinierte Neuroprotektiva in der Alzheimer-Therapie Anwendung finden könnten

Assessment of neuroprotective effects of gamma-hydroxybutyrate and neurosteroids on cellular models of Alzheimer’s disease

This PhD work showed that GHB and neurosteroids efficiently protect neuroblastoma cells against nerve cell death caused by Alzheimer's disease etiological factors including amyloid precursor protein overexpression and oxidative stress. Interestingly, an additive action of GHB and allopregnanolone was identified that may result from the combination of partial stimulation of anti-apoptotic protein expression induced by both compounds. GHB protective effect was blocked by aromatase inhibitors, suggesting that GHB may also induce neuroprotection via the activation of neurosteroidogenesis. Finally, we have used a yeast-based MMP activity assay to check whether GHB and neurosteroids can regulate the activity of human MMP-2 and MMP-9, which both control Aβ peptide degradation. Although we cannot yet conclude from our preliminary results, further improvement of the experimental setup in combination with RT-qPCR and western analyzes in human neuroblastoma cells will help to determine the modulatory action of GHB and neurosteroids on MMP activity and/or expression. Together, our data suggest that GHB and neurosteroids may be used to develop combined neuroprotective strategies against neuronal loss in Alzheimer disease.In der vorliegenden Doktorarbeit konnte gezeigt werden, dass Gamma-Hydroxybutyrat (GHB) und Neurosteroide effektiv in der Lage sind, Neuroblastoma Zellen vor den ätiologischen Faktoren der Alzheimer-Krankheit, darunter insbesondere durch oxidativen Stress und Überexpression von Amyloid-Precursor-Proteinen verursachten Zelltod, zu schützen. Interessanterweise wurde eine additive neuroprotektive Wirkung von GHB und Allopregnanolon gegen den durch oxidativen Stress induzierten Zelltod beobachtet. Diese additive Wirkung ist vermutlich auf eine spezifische Aktivierung von anti-apoptotischen Signalwegen durch GHB und Allopregnanolon zurückzuführen. Die Schutzwirkung von GHB wurde durch Aromatase-Inhibitoren blockiert, was darauf schließen lässt, dass GHB möglicherweise die Neurosteroidogenese aktiviert. Abschließend wurde mit Hilfe eines Hefe-basierten MMP-Aktivitätstests überprüft, ob GHB und/oder Neurosteroide die Aktivität von humanem MMP-2 bzw. MMP-9, welche den Abbau von Aβ-Peptiden kontrollieren, direkt beeinflussen. Auch wenn mit dem verwendeten Testsystem noch kein signifikanter Effekt von GHB und Neurosteroiden beobachtet wurde, sollte eine weitere Optimierung des Testsystems kombiniert mit RT-qPCR und Western-Analysen an humanen Neuroblastoma Zellen dazu beitragen, mögliche regulatorische Effekte von GHB und Neurosteroiden auf die MMP-Aktivitat und -Expression zu bestimmen. Zusammenfassend deuten die vorliegenden Daten darauf hin, dass GHB und Neurosteroide möglicherweise als kombinierte Neuroprotektiva in der Alzheimer-Therapie Anwendung finden könnten

The role of hemoadsorption in cardiac surgery - a systematic review

BACKGROUND: Extracorporeal blood purification has been widely used in intensive care medicine, nephrology, toxicology, and other fields. During the last decade, with the emergence of new adsorptive blood purification devices, hemoadsorption has been increasingly applied during CPB in cardiac surgery, for patients at different inflammatory risks, or for postoperative complications. Clinical evidence so far has not provided definite answers concerning this adjunctive treatment. The current systematic review aimed to critically assess the role of perioperative hemoadsorption in cardiac surgery, by summarizing the current knowledge in this clinical setting. METHODS: A literature search of PubMed, Cochrane library, and the database provided by CytoSorbents was conducted on June 1st, 2023. The search terms were chosen by applying neutral search keywords to perform a non-biased systematic search, including language variations of terms "cardiac surgery" and "hemoadsorption". The screening and selection process followed scientific principles (PRISMA statement). Abstracts were considered for inclusion if they were written in English and published within the last ten years. Publications were eligible for assessment if reporting on original data from any type of study (excluding case reports) in which a hemoadsorption device was investigated during or after cardiac surgery. Results were summarized according to sub-fields and presented in a tabular view. RESULTS: The search resulted in 29 publications with a total of 1,057 patients who were treated with hemoadsorption and 988 control patients. Articles were grouped and descriptively analyzed due to the remarkable variability in study designs, however, all reported exclusively on CytoSorb$^{®}$ therapy. A total of 62% (18/29) of the included articles reported on safety and no unanticipated adverse events have been observed. The most frequently reported clinical outcome associated with hemoadsorption was reduced vasopressor demand resulting in better hemodynamic stability. CONCLUSIONS: The role of hemoadsorption in cardiac surgery seems to be justified in selected high-risk cases in infective endocarditis, aortic surgery, heart transplantation, and emergency surgery in patients under antithrombotic therapy, as well as in those who develop a dysregulated inflammatory response, vasoplegia, or septic shock postoperatively. Future large randomized controlled trials are needed to better define proper patient selection, dosing, and timing of the therapy