CDK5 as a Target to Reduce Cell Death Following Ischemic Stroke
A great deal of effort goes towards methods of reducing the damage caused by ischemic stroke, the cell death in the brain that occurs in response to even a temporary loss of blood supply. Altering cellular reactions to this ischemia can greatly reduce this cell death response, and a number of different approaches to this goal have been demonstrated in mice over the years. Progress towards the clinic is, as ever, slow and uncertain, however. Ultimately what should be developed are not ways to make a stroke less traumatic, or to improve the presently all too limited degree to which recovery can take place, but rather the means to prevent stroke from occurring at all - therapies that aid in maintenance and periodic repair of the vascular system, preventing it from degenerating into a state in which stroke is possible.
Ischemic stroke is a devastating and major cause of morbidity and mortality worldwide. However, due to the narrow time window of thrombolytic therapy, new pharmacological therapeutic approaches are still necessary. Cyclin-dependent kinase 5 (CDK5) is a proline-directed serine/threonine kinase that interacts with NR2B and phosphorylates NR2B to promote ischemic neuronal death. Targeting aberrant CDK5 is neuroprotective for the neuronal loss, tauopathy, and microglial hyperreactivity induced by stroke.
Previously, a membrane-permeant targeting peptide-based method that rapidly and reversibly knocks down endogenous proteins through chaperone-mediated autophagy (CMA) had been validated. In this study, we synthesized a membrane-permeable peptide (Tat-CDK5-CTM) that specifically disrupts the binding of CDK5 and NR2B and then leads to the degradation of CDK5 by a lysosome-mediated pathway.
We found that the administration of Tat-CDK5-CTM not only retards calcium overload and neuronal death in oxygen and glucose deprivation (OGD)-treated neurons but also reduced the infarction area and neuronal loss and improved the neurological functions in MCAO (middle cerebral artery occlusion) mice. The peptide-directed lysosomal degradation of CDK5 is a promising therapeutic intervention for stroke.
This is a case where both approaches are needed. By repairing the blood vessels you can prevent spontaneous strokes caused by aging damage, but you can never prevent loss of blood flow caused by things such as head injuries, or anything that causes the heart to stop beating for more than a few minutes. Accidents are always going to be a part of life, and as a consequence it's always going to be important to find ways to make the brain more resilient.