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Summary: A preclinical drug that inhibits the kinase enzyme Cdk5 could have the potential to treat depression, brain injury and disorders related to cognitive impairment.
Source: University of Alabama, Birmingham
James Bibb, Ph.D., and colleagues have described a novel preclinical drug that may have the potential to combat depression, brain injury and diseases that affect cognition. The drug, which is particularly permeable to the brain, inhibits the kinase enzyme Cdk5.
Cdk5 is a key regulator of signaling in brain neurons. For over three decades, it has been associated with neuropsychiatric and neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. Turning off the enzyme in mice makes them more resilient to stress, improves their cognition, protects neurons from stroke and head injury, and reduces neurodegeneration.
While inhibitors of Cdk5 could offer potential therapeutic benefits and new avenues to study basic brain functions, previous first- and second-generation anti-Cdk5 compounds are largely blocked at the blood-brain barrier, which controls the movement of solutes from the blood to the central nervous system restricts extracellular fluid of the system. To date, no Cdk5 inhibitor has been approved for the treatment of neuropsychiatric or degenerative diseases.
Bibb and colleagues now report details of their brain-permeable anti-Cdk5 compound 25-106. They also show that systemic administration of 25-106 alters neurobehaviour in mice and reduces anxiety-like behavior.
“As perhaps the first robust systemic inhibitor, 25-106 represents an exciting and extensible and translatable pharmacological tool to study the function of Cdk5 activity in wild-type animals,” said Bibb, a University of Alabama professor in the Birmingham Department of Surgery.
“The achievement of systemic applicability can be seen as a step forward in testing Cdk5 inhibitors for the treatment of neuropsychiatric and neurodegenerative diseases. This provides a promising landscape for future studies evaluating the effects of brain-targeting Cdk5 inhibitors in combating stress, anxiety, depression, addiction, cancer and neurodegeneration.”
The study “Systemic administration of a brain-permeable Cdk5 inhibitor alters neurobehaviour” is published in the journal Frontiers in pharmacology.
In the publication, the 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 established Cdk5 inhibitor roscovitine.
They showed that 25-106 inhibited Cdk5 activity in a dose-dependent manner in brain striatal slices ex vivo and also entered the brain after systemic administration in mice to inhibit Cdk5 in vivo.
They measured the pharmacokinetic and pharmacodynamic parameters of 25-106 in the blood plasma and brain of mice, as well as the off-target distribution of 25-106 in the liver and kidneys.
Mice given 25-106 systemically showed modulated neurological behaviors in the Open Field Maze Test and the Tail Suspension Test, anxiolytic changes previously associated with 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.
About this news from neuropsychopharmacology research
Author: press office
Source: University of Alabama, Birmingham
Contact: Press Office – University of Alabama Birmingham
Picture: The image is in the public domain
Original research: Open access.
“Systemic administration of a brain-permeable Cdk5 inhibitor alters neurobehaviour” by Alan Umfress et al. Frontiers in psychopharmacology
abstract
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Systemic administration of a brain-permeable Cdk5 inhibitor alters neurobehaviour
Cyclin-dependent kinase 5 (Cdk5) is a key regulator of neuronal signal transduction. Cdk5 activity is implicated in various neuropsychiatric and neurodegenerative diseases such as stress, anxiety, depression, addiction, Alzheimer’s disease and Parkinson’s disease.
While constitutive Cdk5 knockout is perinatally lethal, conditional knockout mice show resilience to stress induction, improved cognition, neuroprotection from stroke and head trauma, and improved neurodegeneration. Therefore, Cdk5 represents a primary target for the treatment of a spectrum of neurological and neuropsychiatric disorders.
While intracranial infusions or treatment of acutely dissected brain tissue with compounds that inhibit Cdk5 have allowed investigation of kinase function and confirmed conditional knockout findings, systemically deliverable Cdk5 inhibitors with strong brain penetration are extremely limited, and no Cdk5 inhibitor has been identified as a treatment approved neuropsychiatric or degenerative diseases until today.
Here, we screened aminopyrazole-based analogues as potential Cdk5 inhibitors and identified a novel analogue, 25–106, as a unique brain-penetrating anti-Cdk5 drug. We characterize the pharmacokinetic and dynamic responses of 25–106 in mice and functionally validate the effects of Cdk5 inhibition on open-field and tail behavior.
Overall, 25–106 represents a promising preclinical Cdk5 inhibitor that can be administered systemically and has significant potential as a neurological/neuropsychiatric therapeutic.
