New Delhi: Researchers from the University of Alabama at Birmingham have described a novel preclinical drug that could have the potential to cure depression, and can battle brain injury and neurodegenerative diseases also. The study describing the findings, and titled "Systematic administration of a brain permeable Cdk5 Inhibitor Alters Neurobehaviour", was recently published in the journal Frontiers in Pharmacology. 


According to the study, the drug is brain-permeable, and acts to inhibit the kinase enzyme Cdk5, which is a crucial regulator of signalling in brain neurons. Kinase is an enzyme which adds chemicals called phosphates to other molecules such as sugars or proteins. These enzymes regulate the biological activity of proteins by adding phosphate groups to amino acids and use ATP, the energy currency of the cell, as the source of phosphate. This changes an inactive protein to an active one.


What Is Cdk5 Enzyme?


The Cdk5 enzyme has been implicated in neuropsychiatric and neurodegenerative conditions, including Alzheimer's disease and Parkinson's disease, in over three decades of study. When the enzyme is knocked out in mice, they are observed to become resilient to stress. Also, their cognition is enhanced, neurons protected from stroke and head trauma, and neurodegeneration reduced.


What Happens When Cdk5 Inhibitors Are Administered?


Though inhibitors of Cdk5 can offer potential therapeutic benefits and new ways to study basic brain function, previous first- and second-generation anti-Cdk5 compounds largely get blocked at the blood brain barrier that restricts movement of solutes from the blood to the central nervous system's extracellular fluid, the study said. No Cdk5 inhibitor has been approved to treat any neuropsychiatric or degenerative disease, to date.


How Does The New Drug Function?


The researchers have reported details of their anti-Cdk5, brain-permeable compound, 25-106, in the new study, and have shown that systemic administration of the drug alters neurobehaviour in mice, and reduces anxiety-like behaviour.


In a statement released by University of Alabama at Birmingham, James Bibbs, one of the authors on the paper, said 25-106, as perhaps the first robust systemic inhibitor, represents an exciting and expandable and translatable pharmaceutical tool to study the function of Cdk5 activity in wild-type animals. He added that achieving systemic applicability may be considered a step forward toward the testing of Cdk5 Inhibitors to treat neuropsychiatric and neurodegenerative diseases. He further said 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.


New Drug Occupies Same Binding Pocket As Well-Established Cdk5 Inhibitor


The researchers have described the synthesis of the aminopyrazole-based inhibitor, and used molecular modelling to show that 25-106 appears to occupy the same hydrophobic binding pocket as the well-established Cdk5 inhibitor roscovitine. 


The scientists also showed that 25-106 inhibited Cdk5 activity in a dose-dependent manner in brain striatal slices ex vivo, the study said. The drug was found to penetrate the brain after systemic administration into mice to inhibit Cdk5 in vivo. The researchers also measured the off-target distribution of 25-106 in the liver and kidneys. 


The mice who were administered with 25-106 were observed to show modulated neurobehaviour in the open field maze test and the tail suspension test.