Summary: A preclinical drug that inhibits the Cdk5 kinase enzyme could have the potential to treat depression, brain damage and disorders associated with cognitive impairment.
Source: University of Alabama at Birmingham
James Bibb, Ph.D., and colleagues have described a new preclinical drug that may have the potential to fight depression, brain damage and diseases that impair cognition. The drug, which is notably permeable to the brain, acts to inhibit the Cdk5 kinase enzyme.
Cdk5 is a crucial regulator of signaling in brain neurons. Over three decades of study, it has been implicated in neuropsychiatric and neurodegenerative conditions, including Alzheimer’s disease and Parkinson’s disease. Eliminating the enzyme in mice makes them resistant to stress, improves their cognition, protects neurons from strokes and head trauma, and reduces neurodegeneration.
While Cdk5 inhibitors could offer potential therapeutic benefits and new ways to study basic brain functions, previous first- and second-generation anti-Cdk5 compounds are largely blocked at the blood-brain barrier that limits the movement of solutes from the blood to the central nervous system. extracellular fluid of the system. To date, no Cdk5 inhibitor has been approved to treat 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 neurological behavior in mice, thereby reducing anxious behavior.
“As perhaps the first robust systemic inhibitor, 25-106 represents an exciting, expandable, and translatable pharmacological tool to study the function of Cdk5 activity in wild-type animals,” said Bibb, a professor at the University of Alabama at Birmingham Department of Surgery. .
“Achieving systemic applicability can be seen as a step forward in testing 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 brain-permeable Cdk5 inhibitor alters neurobehaviour,” is published in the journal Frontiers in pharmacology.
In the paper, the researchers describe the synthesis of the aminopyrazole-based inhibitor and used molecular modeling to show that 25-106 appears to occupy the same hydrophobic binding pocket as roscovitine, a well-established Cdk5 inhibitor. .
They showed that 25-106 inhibited Cdk5 activity in a dose-dependent manner in striated brain 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 liver and kidney.
Mice given systemic 25-106 showed modulated neurobehavior in the open-field maze test and tail suspension test, anxiolytic changes that have previously been linked to Cdk5 knockout mice.
They found that 25-106 is a nonselective inhibitor of 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 Cdk2 inhibition by 25-106 remain unknown.
About this neuropsychopharmacology research news
Original research: Free access.
“Systemic delivery of brain-permeable Cdk5 inhibitor alters neurobehaviour” by Alan Umfress et al. Frontiers in psychopharmacology
Systemic delivery of brain-permeable Cdk5 inhibitor alters neurobehaviour
Cyclin-dependent kinase 5 (Cdk5) is a crucial regulator of neuronal signal transduction. Cdk5 activity is implicated in various neuropsychiatric and neurodegenerative conditions such as stress, anxiety, depression, addiction, Alzheimer’s disease and Parkinson’s disease.
While constitutive Cdk5 knockout is perinatally lethal, conditional knockout mice display resilience to stress induction, enhanced cognition, neuroprotection against stroke and head trauma, and neurodegeneration improved. Thus, Cdk5 represents a prime target for the treatment of a range of neurological and neuropsychiatric conditions.
Although intracranial infusions or treatment of acutely dissected brain tissue with compounds that inhibit Cdk5 have allowed study of kinase function and supported conditional inactivation results, potent systemically released Cdk5 inhibitors by penetration into the brain are extremely limited and no Cdk5 inhibitor has been approved to treat any neuropsychiatric or degenerative diseases to date.
Here, we screened aminopyrazole analogs as potential Cdk5 inhibitors and identified a novel analog, 25-106, as a brain-only 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 suspension behaviors.
Altogether, 25-106 represents a promising preclinical Cdk5 inhibitor that can be administered systemically with significant potential as a neurological/neuropsychiatric therapeutic.
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