Cdk5 Inhibitor Shows Early Potential in Easing Anxiety, Aiding Neurons

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Researchers have developed a new suppressor of cyclin-dependent kinase 5 (Cdk5) — an enzyme whose activity is associated with neuropsychiatric and neurodegenerative conditions — that can robustly enter the brain and appears to be more potent than previous, similar molecules.

When injected into the bloodstream, the new molecule, named 25-106, was shown to reduce anxiety- and depression-like behaviors in mice, supporting further studies in animal models of conditions that include Parkinson’s disease.

Developing a Cdk5 inhibitor that can be administered directly into the bloodstream and effectively reach the brain “may be considered a step forward toward the testing of Cdk5 inhibitors [suppressors] to treat neuropsychiatric and neurodegenerative diseases,” James Bibb, PhD, the study’s senior author and a professor and vice chair of basic research at the University of Alabama at Birmingham (UAB), said in a press release.

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“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,” Bibb added. 

More research is needed to better understand 25-106’s safety profile and whether derivatives of this molecule may show even greater functional and pharmacological features, the study noted.

Findings were detailed in the study “Systemic Administration of a Brain Permeable Cdk5 Inhibitor Alters Neurobehavior,” published in the journal Frontiers in Pharmacology.

Cdk5 is an enzyme mainly produced by mature nerve cells. Its dysregulated activity has been implicated “in various neuropsychiatric and neurodegenerative conditions such as stress, anxiety, depression, addiction, Alzheimer’s disease, and Parkinson’s disease,” the researchers wrote.

Notably, several Cdk5 suppressors have been shown to reduce stress and anxiety-like behaviors, have neuroprotective effects, and lessen neurodegeneration in animal models, but none “has proven effective in clinical trials,” they added.

This is mainly due to these molecules’ poor specificity — which is associated with its effects on molecules other than Cdk5, called off-targets, and greater toxicity — and limited ability to cross the blood-brain barrier.

This barrier, a highly selective membrane, tightly regulates what substances from the bloodstream can access the central nervous system (CNS; the brain and spinal cord), and crossing it is often a challenge for CNS-targeting therapies.

Bibb and colleagues at UAB and other U.S. institutions developed 25–106, a Cdk5 inhibitor that can be delivered directly into the bloodstream (also known as systemic delivery) and robustly cross the blood-brain barrier.

The molecule was created based on similar compounds known to block Cdk5, and carried chemical modifications that were expected to strengthen its pharmacological properties.

25–106 was shown to suppress Cdk5 activity in a dose-dependent manner in lab-grown mouse brain slices and to rapidly reach the brain when delivered directly into the mice’s bloodstream. In addition, the molecule was still detected in the brain 24 hours after injection.

Its use was also seen to reduce anxiety- and depression-like behaviors in these mice, similar to effects reported in previous studies of mice lacking Cdk5.

These findings indicated that “25–106 modulated several … behaviors that have previously been linked to Cdk5,” the researchers wrote.

Molecular modeling showed that 25–106 likely binds to the same Cdk5 region as the well-established Cdk5 inhibitor roscovitine (also known as seliciclib), but with greater strength.

This may explain 25-106’s apparently superior effects over roscovitine observed in this study, the team noted.

Similar to other Cdk5 inhibitors, 25-106 was found to block another cyclin-dependent kinase, Cdk2. However, very low levels of Cdk2 are found in the brain and other Cdk5 suppressors were shown to be more selective for Cdk5 than Cdk2.

“Any off-target or toxic effects of systemic [whole-body] inhibition of Cdk2 by 25-106 remain unknown,” the researchers wrote.

The molecule “was also well-absorbed by peripheral tissues such as the liver and kidney, which could contribute to off-target effects or toxicity arising from prolonged treatment,” they added.

As such, further studies are needed to comprehensively evaluate 25–106’s safety profile and “the development of derivatives of 25–106 with greater brain permeability and tissue specificity is a reasonable goal,” the researchers wrote.

“Altogether, 25–106 represents a promising preclinical Cdk5 inhibitor that can be systemically administered with significant potential as a neurological/neuropsychiatric therapeutic,” the researchers concluded.

“As perhaps the first robust systemic inhibitor,” 25-106 may also be an effective “tool to study the function of Cdk5 activity in [healthy] animals,” Bibb said.