New preclinical drug could have potential to combat depression, brain injury and cognitive disorders

summary: A preclinical drug that inhibits Cdk5 kinase may have potential to treat depression, brain injury, and disorders associated with cognitive impairment.

source: University of Alabama Birmingham

Dr. James Beebe and colleagues describe a new preclinical drug that could have the potential to combat depression, brain injury and cognitive-impairing diseases. The drug, which is particularly permeable to the brain, inhibits the enzyme Cdk5 kinase.

Cdk5 is an important regulator of signaling in neurons in the brain. Over three decades of study, it has been implicated in neurological, psychiatric, and neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. Elimination of the enzyme in mice makes them resilient to stress, enhances their cognition, protects neurons from stroke and head trauma, and reduces neurodegeneration.

While Cdk5 inhibitors could offer potential therapeutic benefits and new ways to study basic brain function, earlier first- and second-generation Cdk5 compounds are largely blocked at the blood-brain barrier that restricts the movement of solutes from the blood into the CNS extracellular fluid system. To date, the Cdk5 inhibitor has not been approved for the treatment of any neuropsychiatric or degenerative diseases.

Pep and colleagues now report the details of their anti-Cdk5 compound, a brain-permeable compound, 25-106. They also showed that striatal administration of 25-106 altered neurobehaviour in mice, reducing anxiety-like behavior.

said Pep, a professor at the University of Alabama in the Department of Surgery at Birmingham.

“Achieving systemic applicability can be considered a step forward towards testing Cdk5 inhibitors for the treatment of neuropsychiatric and neurodegenerative diseases. This provides a promising landscape for future studies evaluating the brain’s permeable effects of Cdk5 inhibitors to combat stress, anxiety, depression, addiction, cancer, and neurodegeneration.”

The study, “System administration of a Cdk5 inhibitor permeating to the brain alters neurobehaviour,” was 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 the well-established Cdk5 inhibitor roscovitine.

This indicates the outline of the head
Cdk5 is an important regulator of signaling in neurons in the brain. The image is in the public domain

They showed that 25-106 inhibited Cdk5 activity in a dose-dependent manner in ex vivo striatal brain slices, 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 the blood plasma and brains of rats, and the off-target distribution of 25-106 in the liver and kidneys.

Mice given systemic 25–106 showed altered neural behavior in the open field maze test and tail suspension test, and anxiolytic changes that have been previously 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 present in the brain. However, any off-target or toxic effects of systemic inhibition of Cdk2 by 25–106 remain unknown.

About this research news in psychopharmacology and neurology

author: press office
source: University of Alabama Birmingham
Contact: Press Office – University of Alabama Birmingham
picture: The image is in the public domain

original search: open access.
Systemic administration of a Cdk5-mediated inhibitor to the brain alters neurobehaviourWritten by Alan Amfris et al. Frontiers in psychopharmacology

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Systemic administration of a Cdk5-mediated inhibitor to the brain alters neurobehaviour

Cyclin-dependent kinase 5 (Cdk5) is a critical regulator of neuronal signal transmission. Cdk5 activity is implicated in many neuropsychiatric and neurodegenerative conditions such as stress, anxiety, depression, addiction, Alzheimer’s disease and Parkinson’s disease.

Whereas constitutive Cdk5 knockdown is lethal in the perinatal period, conditional knockout mice show resilience in stress induction, enhanced cognition, neuroprotection from stroke and head trauma, and enhanced neurodegeneration. Thus, Cdk5 represents a major target for therapy in a range of neurological and neuropsychiatric conditions.

Whereas intracranial infusion or treatment of acutely dissected brain tissue with Cdk5-inhibiting compounds has allowed the study of kinase function and pro-conditional knockout outcomes, potent systemically deliverable brain-penetrating Cdk5 inhibitors are very limited, and a Cdk5 inhibitor is not approved for the treatment of any Neurological, psychiatric or degenerative diseases to date.

Here, we screened aminopyrazole-based analogs as potential inhibitors of Cdk5 and identified a new analogue, 25-106, as a unique brain-penetrating anti-Cdk5 drug. We characterize the pharmacological and dynamic responses of 25–106 in mice and functionally investigate the effects of Cdk5 inhibition on open field and tail suspension behaviors.

Altogether, 25-106 preclinical Cdk5 inhibitor represents a promising systemically administered Cdk5 inhibitor with great potential as a neuroprotective/neuropsychotherapy.