Preclinical drugs work by blocking the kinase Cdk5, which is found in mature neuron cells. Cdk5 has been associated with neuropsychiatric disorders and neurodegenerative diseases for a long time. However, prior inhibitors have not been able to cross the blood-brain border and get into the brain.
James Bibb, Ph.D. and his colleagues have reported a new preclinical drug that could combat depression, brain injury, cognitive disorders, and other mental illnesses. This drug is brain-permeable and works by blocking the enzyme Cdk5.
Cdk5 plays an important role in signaling regulation of brain neurons. It has been implicated in neuropsychiatric disorders and degenerative diseases such as Alzheimer’s disease and Parkinson’s over three decades of research. The enzyme can be removed from mice to make them more resistant to stress, improve cognition, protect neurons against stroke and brain trauma and slow down neurodegeneration.
Cdk5 inhibitors could have therapeutic benefits and offer new ways to study basic brain function. However, first- and second-generation anti Cdk5 compounds get largely blocked at the blood–brain barrier. This prevents solute movement between the blood and the extracellular fluid of central nervous system. No Cdk5 inhibitors have been approved for neuropsychiatric and degenerative conditions.
Bibb and his colleagues have now reported details about their brain-permeable anti-Cdk5 compound, 25-106. They also found that 25-106 systemic administration alters neurobehavior in mice and reduces anxiety-like behavior.
“25-106, perhaps the strongest systemic inhibitor, is an exciting and expandable pharmacological tool to examine the function of Cdk5 activation in wild-type animal models,” stated Bibb, a University of Alabama at Birmingham (UAB), Department of Surgery professor. “Achieving systemic application may be considered a significant step towards the testing of Cdk5 inhibits for neuropsychiatric or neurodegenerative disorders. Future studies will be able to evaluate the brain-permeable Cdk5 inhibitions’ effects on stress, anxiety and depression.
Frontiers in Pharmacology published the study “Systemic administration a brain permeable Cdk5 inhibit alters neurobehavior.”
Researchers describe the synthesis and molecular modeling of an aminopyrazole-based inhibitor. They also show that 25-106 seems to share the same hydrophobic binding area as the well-known Cdk5 inhibitor, roscovitine.
They found that 25-106 inhibited Cdk5 activity ex vivo in brain striatal slices and that it penetrated the brain in systemic administration to mice to inhibit Cdk5 vivo. They also measured the pharmacokinetics and pharmacodynamic parameters for 25-106 in blood plasma, brains and kidneys.
Systemic 25-106 was given to mice, which showed modified neurobehavior in open field maze and tail suspension tests. This is similar to the anxiolytic effects previously linked with Cdk5 knockout mice.
The researchers found that 25-106 is an inhibitor non-selective of Cdk5 as well as Cdk2 (another cyclin-dependentkinase kinase), but that brain levels of Cdk2 remain very low. It is not known if 25-106 can cause toxic or off-target effects on Cdk2 in the system.
According to Bibb there were three research teams involved in this study: UAB Marnix E. Heersink School of Medicine Department of Surgery neurobiologists Bibb and Alan Umfress, Ayanabha Chakraborti and Florian Plattner of Neuro-Research Strategies. Houston, Texas. UAB Department of Pharmacology and Toxicology researchers Kevin J. Ryan and Edward P. Acosta were also involved. The University of Nebraska Medical Center medicinal chemical chemists Jayapal Reddy Mallareddy and Sarbjit Singh were part of the third group.
National Institutes of Health grants MH116896,MH126948 and CA127297 provided support.
