Novel preclinical drug appears to combat depression and impaired cognition

May 24, 2022
Novel preclinical drug appears to combat depression and impaired cognition

An experimental drug which targets and inhibits a brain signaling enzyme could potentially combat symptoms of depression, brain injury, and diseases that impair cognitive function. Scientists at the University of Alabama at Birmingham (UAB) describe a brain-permeable drug that influences neuropsychiatric behaviour: mice on the drug became more resilient to stress and had enhanced cognition. The drug additionally protected neurons from stroke and head trauma, and lessened neurodegeneration.

UAB scientists developed the drug to inhibit the kinase enzyme Cdk5. Cdk5 is a crucial regulator of signaling in brain neurons and has been implicated in neurodegenerative conditions, including Alzheimer’s disease and Parkinson’s disease.

Previous Cdk5 inhibitors have been unable to cross the blood-brain barrier to enter the central nervous system’s extracellular fluid, hampering their target activity. To date, no Cdk5 inhibitor has been approved to treat any neuropsychiatric or neurodegenerative diseases.

In the UAB study, systemic administration of the drug in mice showed significant inhibition of Cdk5 as well as altered neurobehaviour.

“As perhaps the first robust systemic inhibitor, [Cdk5 drug] represents an exciting and expandable and translatable pharmacological tool to study the function of Cdk5 activity in wild-type animals,” said Dr. James Bibb, a Professor in the UAB School of Medicine, Department of Surgery.

“Achieving systemic applicability may be considered a step forward toward the testing of Cdk5 inhibitors to treat neuropsychiatric and neurodegenerative diseases,” Dr. Bibb added. “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.”

The scientists, however, note that very low levels of Cdk5 are found in the brain and any off-target or toxic effects of Cdk5 inhibition remain unknown.

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