Les chercheurs ont montré que l’administration systémique du nouveau médicament modifie le comportement neurologique des souris, en réduisant les comportements de type anxieux. Cette découverte ouvre également la voie à de futures études visant à déterminer si le médicament pourrait aider à combattre le stress, l’anxiété, la dépression, la dépendance, le cancer et la neurodégénérescence.
Le médicament préclinique agit en inhibant la kinase Cdk5, présente dans les neurones matures. La Cdk5 est depuis longtemps liée aux troubles neuropsychiatriques et neurodégénératifs, mais les inhibiteurs précédents n’ont pas réussi à traverser la barrière hémato-encéphalique et à pénétrer dans le cerveau.
Un nouveau médicament préclinique rapporté par James Bibb, Ph.D., et ses collègues a le potentiel de combattre la dépression, les lésions cérébrales et les troubles cognitifs. Le médicament, qui a la particularité d’être perméable au cerveau, agit en inhibant l’enzyme kinase Cdk5.
La Cdk5 est un important régulateur de la signalisation dans les neurones du cerveau. Au cours de trois décennies de recherche, elle a été liée à des troubles neuropsychiatriques et dégénératifs tels que Alzheimer’s and Parkinson’s. Knocking out the enzyme in mice makes them more resilient to stress, improves cognition, protects neurons from stroke and brain trauma, and slows neurodegeneration.
While Cdk5 inhibitors may offer potential therapeutic benefits and new ways to study basic brain function, previous first- and second-generation anti-Cdk5 compounds largely get blocked at the blood-brain barrier, which restricts solute movement from the blood to the extracellular fluid of the central nervous system. So far, no Cdk5 inhibitor has been authorized for the treatment of any neuropsychiatric or degenerative condition.
James Bibb, co-author of the study. Bibb holds the Dr. Champ Lyons Endowed Chair in General Surgery at the University of Alabama, Birmingham, and is a senior scientist at the O’Neal Comprehensive Cancer Center.
Bibb and colleagues now report details of their anti-Cdk5, brain-permeable compound, 25-106. They also show that systemic administration of 25-106 alters neurobehavior in mice, reducing anxiety-like behavior.
“As perhaps the first robust systemic inhibitor, 25-106 represents an exciting and expandable and translatable pharmacological tool to study the function of Cdk5 activity in wild-type animals,” said Bibb, a professor in the University of Alabama at Birmingham (UAB) Department of Surgery. “Achieving systemic applicability may be considered a step forward toward the testing of Cdk5 inhibitors to treat neuropsychiatric and neurodegenerative diseases. This provides a promising landscape for future studies to assess the effects of brain-permeable Cdk5 inhibitors to combat stress, anxiety, depression, addiction, cancer, and neurodegeneration.”
The study, “Systemic administration of a brain permeable Cdk5 inhibitor alters neurobehavior,” is published in Frontiers in Pharmacology.
In the paper, researchers describe the synthesis of the aminopyrazole-based inhibitor, and they used molecular modeling to show that 25-106 appears to occupy the same hydrophobic binding pocket as the well-established Cdk5 inhibitor roscovitine.
They showed that 25-106 inhibited Cdk5 activity in a dose-dependent manner in brain striatal slices ex vivo and that it also penetrated the brain after systemic administration in mice to inhibit Cdk5 in vivo. They measured the pharmacokinetic and pharmacodynamic parameters of 25-106 in blood plasma and the brains of mice, and the off-target distribution of 25-106 in the liver and kidneys.
Mice given systemic 25-106 showed modulated neurobehavior in the open field maze test and the tail suspension test, anxiolytic changes that have previously been linked to Cdk5 knockout mice.
They found that 25-106 is a non-selective inhibitor of both Cdk5 and another cyclin-dependent kinase, Cdk2, but note that very low levels of Cdk2 are found in the brain. However, any off-target or toxic effects of systemic inhibition of Cdk2 by 25-106 remain unknown.
According to Bibb, three teams of researchers were involved in this study, including UAB Marnix E. Heersink School of Medicine Department of Surgery neurobiologists Bibb, Alan Umfress, and Ayanabha Chakraborti, as well as Florian Plattner of Neuro-Research Strategies, Houston, Texas. Also involved were UAB Department of Pharmacology and Toxicology researchers Kevin J. Ryan and Edward P. Acosta. The third group was composed of University of Nebraska Medical Center medicinal chemists Sarbjit Singh, Yogesh Sonawane, Jayapal Reddy Mallareddy, and Amarnath Natarajan.
Support came from National Institutes of Health grants MH116896, MH126948, CA127297, and NS061788.
Reference: “Systemic Administration of a Brain Permeable Cdk5 Inhibitor Alters Neurobehavior” by Alan Umfress, Sarbjit Singh, Kevin J. Ryan, Ayanabha Chakraborti, Florian Plattner, Yogesh Sonawane, Jayapal Reddy Mallareddy, Edward P. Acosta, Amarnath Natarajan and James A. Bibb, 12 May 2022, Frontiers in Pharmacology.
DOI: 10.3389/fphar.2022.863762
