Article
Chemistry, Medicinal
Michael Moir, Samuel Lane, Andrew P. Montgomery, David Hibbs, Mark Connor, Michael Kassiou
Summary: The development of selective CB2 receptor agonists is a promising therapeutic approach for inflammatory diseases. Through structure-activity relationship studies, a potent and selective pyrazolo-[2,3-e]-[1,2,4]-triazine agonist has been discovered, with key structural features of the linkage group being important for its activity.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Brianna Chen, Dylan McCuaig-Walton, Sean Tan, Andrew P. Montgomery, Bryan W. Day, Michael Kassiou, Lenka Munoz, Ariadna Recasens
Summary: The study demonstrates the important role of DYRK1A kinase in regulating the differentiation commitment of glioblastoma stem cells. Inhibiting DYRK1A insulates GSCs from differentiation-inducing signals, promoting differentiation and limiting stemness acquisition through deactivation of CDK5. This novel DYRK1A-CDK5-SOX2 pathway sheds further light on the mechanisms underlying the maintenance of glioblastoma stem cells.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Pharmacology & Pharmacy
Alexander Jackson, Eryn L. Werry, James O'Brien-Brown, Paolo Schiavini, Shane Wilkinson, Erick C. N. Wong, Andre D. J. McKenzie, Alexandra Maximova, Michael Kassiou
Summary: Antagonists of the P2X7 receptor have therapeutic potential for diseases involving neuroinflammation. A recently developed structural hybrid compound showed insights into the interaction of antagonists with the P2X7R. LL-37 was found to enhance the ability of ATP to induce dye uptake.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Andre D. J. Mckenzie, Taylor R. Garrett, Eryn L. Werry, Michael Kassiou
Summary: This review summarizes the current understanding of amyotrophic lateral sclerosis (ALS), the role of purinergic P2X(7) receptor (P2X(7)R) in ALS, the current landscape of P2X(7)R antagonists, and their potential in preclinical ALS models.
ACS CHEMICAL NEUROSCIENCE
(2022)
Review
Clinical Neurology
Jared S. Katzeff, Fiona Bright, Katherine Phan, Jillian J. Kril, Lars M. Ittner, Michael Kassiou, John R. Hodges, Olivier Piguet, Matthew C. Kiernan, Glenda M. Halliday, Woojin Scott Kim
Summary: This study explores and evaluates potential biomarkers for distinguishing frontotemporal dementia and amyotrophic lateral sclerosis, aiming to improve diagnosis and treatment for patients. The two diseases share common genetic and molecular features, with a lack of sensitive and specific biomarkers for diagnostic and disease surveillance purposes.
Article
Chemistry, Analytical
Richard Aarnio, Obada M. Alzghool, Saara Wahlroos, James 'Brien-Brown, Michael Kassiou, Olof Solin, Juha O. Rinne, Sarita Forsback, Merja Haaparanta-Solin
Summary: This study developed a new method to analyze the protein-free fractions of PET tracers and their radiometabolites. The results showed that radiometabolites had a higher protein-free fraction in plasma, which may explain their efficient entry into brain tissue. This detailed understanding is important for translational studies to explain the behavior of tracers in humans.
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
(2022)
Article
Radiology, Nuclear Medicine & Medical Imaging
Annukka Kallinen, Michael Kassiou
Summary: This review outlines the development of small molecule radiotracers for positron emission tomography (PET) imaging of proteinopathies, focusing on the radioligands that have progressed to clinical studies. The introduction provides a brief summary of proteinopathy targets used for PET imaging, including A beta, tau, and alpha-synuclein. The main section discusses clinically relevant A beta and tau radioligand classes and their properties, as well as lead compounds and radioligand candidates studied for a-synuclein imaging in the early discovery and preclinical development phase. Finally, the specific challenges and future directions in proteinopathy radioligand development are summarized.
NUCLEAR MEDICINE AND BIOLOGY
(2022)
Article
Multidisciplinary Sciences
Prita R. Asih, Anne Poljak, Michael Kassiou, Yazi D. Ke, Lars M. Ittner
Summary: The translocator protein (TSPO) plays a role in mitochondrial cholesterol transport, brain inflammation, and other mitochondrial functions. A common A147T polymorphism in TSPO reduces ligand binding and is associated with increased risk of neuropsychiatric disorders. This study found that the A147T polymorphism has fewer binding partners compared to the wild-type TSPO, suggesting a loss of function in mitochondrial protein networks.
Article
Chemistry, Medicinal
Ben B. Ma, Andrew P. Montgomery, Biling Chen, Michael Kassiou, Jonathan J. Danon
Summary: The P2Y(12) receptor plays a key role in platelet aggregation and blood clotting, and its expression and roles in the central nervous system are of interest. Previous studies have shown that P2Y(12) can be used as a reliable biomarker for anti-inflammatory and neuroprotective microglial phenotypes. However, a challenge in studying this receptor in vivo is the lack of selective high-affinity small molecule ligands that can pass the blood-brain barrier and accumulate in the CNS.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Endocrinology & Metabolism
Joachim Brumberg, Richard Aarnio, Anton Forsberg, Paivi Marjamaki, Vera Kerstens, Mohammad M. Moein, Sangram Nag, Saara Wahlroos, Michael Kassiou, Albert D. Windhorst, Christer Halldin, Merja Haaparanta-Solin, Patrik Fazio, Vesa Oikonen, Juha O. Rinne, Andrea Varrone
Summary: This study evaluated the concentrations of the parent compound and metabolites of [C-11]SMW139 in the plasma of mice and humans using radioHPLC. Three major metabolite peaks were observed in the plasma of all subjects, and two metabolite peaks were also found in mouse brain homogenates. Compartment modeling with correction for brain-penetrant metabolites improved the accuracy of quantifying [C-11]SMW139 binding to P2X(7)R in the human brain.
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
(2023)
Review
Pharmacology & Pharmacy
Elijah Genetzakis, Jayson Gilchrist, Michael Kassiou, Gemma A. Figtree
Summary: The P2X(7)R receptor plays a crucial role in inflammation and is associated with various pathological conditions. Despite initial promise, P2X(7)R antagonists failed to show therapeutic benefits in clinical trials for rheumatoid arthritis and Crohn's disease. Recent evidence suggests a potential connection between P2X(7)R and cardiovascular diseases, making it a therapeutic target for atherosclerosis. However, there are barriers to successful clinical translation of P2X(7)R antagonists.
PHARMACOLOGY & THERAPEUTICS
(2022)
Article
Biochemistry & Molecular Biology
Sarah R. Ball, Julius S. P. Adamson, Michael A. Sullivan, Manuela R. Zimmermann, Victor Lo, Maximo Sanz-Hernandez, Xiaofan Jiang, Ann H. Kwan, Andre D. J. McKenzie, Eryn L. Werry, Tuomas P. J. Knowles, Michael Kassiou, Georg Meisl, Matthew H. Todd, Peter J. Rutledge, Margaret Sunde
Summary: Alzheimer's disease poses a growing burden on society and the economy, making effective therapies urgently needed. Researchers have developed small molecules that can limit the conversion of amyloid monomers into toxic oligomers and fibrils, potentially offering a way to modulate the disease outcome. By sequestering the amyloid monomers, these compounds prevent the formation of cytotoxic aggregates and disrupt the autocatalytic process that generates toxic oligomers. The modular design of these inhibitors allows for future exploration and investigation of the different species involved in amyloid assembly.
ACS CHEMICAL NEUROSCIENCE
(2022)
Article
Immunology
Paula Beltran-Lobo, Martina M. Hughes, Claire Troakes, Cara L. Croft, Huzefa Rupawala, Daniel Jutzi, Marc-David Ruepp, Maria Jimenez-Sanchez, Michael S. Perkinton, Michael Kassiou, Todd E. Golde, Diane P. Hanger, Alexei Verkhratsky, Beatriz G. Perez-Nievas, Wendy Noble
Summary: P2X7R protein levels increase in AD brain, correlating with advancing Braak stage and synapse loss. P2X7R is expressed in microglia and astrocytes and is involved in the modulation of inflammation and cytokine production. Inhibition of P2X7R reduces insoluble tau levels, indicating a non-cell autonomous role of glial P2X7R in pathological tau aggregation.
BRAIN BEHAVIOR AND IMMUNITY
(2023)
Article
Medicine, General & Internal
Leah H. Rubin, Yong Du, Shannon Eileen Sweeney, Riley O'Toole, Cykyra L. Thomas, Adeline G. Zandi, Laura K. Shinehouse, Mary Katherine Brosnan, Hwanhee Nam, Michael E. Burke, Samantha C. Bureau, Jessica J. Kilgore, Mark Yoon, Ana R. Soule, Wojciech G. Lesniak, Il Minn, Steven P. Rowe, Daniel P. Holt, Andrew W. Hall, William B. Mathews, Gwenn S. Smith, Christopher J. Nowinski, Michael Kassiou, Robert F. Dannals, Martin G. Pomper, Jennifer M. Coughlin
Summary: This study aimed to test for higher TSPO levels that mark brain injury and repair in a relatively large, unique cohort of former NFL players compared with former elite, noncollision sport athletes. The study found that the regional TSPO levels were higher in former NFL players compared with former elite, noncollision sport athletes.
Correction
Medicine, Research & Experimental
Francois-Xavier Lepelletier, Matthias Vandesquille, Marie-Claude Asselin, Christian Prenant, Andrew C. Robinson, David M. A. Mann, Michael Green, Elizabeth Barnett, Samuel Banister, Marco Mottinelli, Christophe Mesangeau, Christopher R. McCurdy, Inga B. Fricke, Andreas H. Jacobs, Michael Kassiou, Herve Boutin