Scientists report that a new preclinical drug has the potential to be groundbreaking for brain injury, depression, and cognitive impairment conditions.
James Bibb, Ph.D., a professor in the University of Alabama at Birmingham Department of Surgery, describes the drugs’ mechanism of action as targeting and inhibiting the Cdk5 enzyme. This enzyme is a vital regulator in neuronal brain signaling. A plethora of studies have successfully concluded that it plays a significant role in neuropsychiatric and neurodegenerative conditions like Alzheimer’s disease. In studies conducted on mice, knocking out the enzyme has resulted in greater resilience to stress, neuronal protection from stroke, and even enhanced overall cognition.
Bibb and colleagues set out to research and report findings of their brain-permeable drug, called 25-106. “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,” Bibb explains in a statement.
The researchers studied this by measuring the pharmacokinetic and pharmacodynamic parameters of the drug in the blood plasma and brains of mice, as well as off-target distribution in the kidneys and liver. They used molecular modeling to show that 25-106 appears to function in the same way as well-studied Cdk5 inhibition drug, Seliciclib (roscovitine). It does so by occupying the same hydrophobic binding pocket, which is the site of a protein that contains amino acids which don’t interact with water.
Similar to a multitude of previous studies regarding Cdk-inhibitors, the team reports that the mice experienced reductions in anxiety and improved behavior in the open field maze and tail suspension tests, which are two commonly used tests to determine patterns of anxiety and depressive behavior. To date, there has been no Cdk-5 inhibitor that has successfully been approved to treat any related conditions.
It is the hope of Bibb and researchers that this changes in order to reflect consistent scientific findings that these types of drugs have great neurological potential.
They further explain that they wish to inspire other researchers to open the door to assess the effects of other Cdk-inhibitors with regards to a wide range of mood-related conditions and neurodegenerative diseases. “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,” concludes Bibb.
The study is published in the Frontiers in Pharmacology.