Inhibitors of Cyclin-Dependent Kinases: Potential Drugs for the Treatment of Neurodegenerative Disorders?

Merce      Pallas; Anna   M.   Canudas; Ester      Verdaguer; Clemens      Allgaier; Susana   Garcia   de Arriba; Daniel      Alvira; Francesc   X.   Sureda; Antoni      Camins

doi:10.2174/1568015054022371

Abstract

The pharmacological treatment of neurodegenerative disorders such as Alzheimers disease, Parkinsons disease and amyotrophic lateral sclerosis (ALS) currently represents a major medical challenge. The mechanisms involved in the apoptotic neuronal cell death, associated with such disorders, are still not clear, but recent data suggest that cyclindependent kinases (CDKs) play a prominent role (Liu et al., 2003). Canonical CDKs such as CDK2 and CDK4/CDK6 are enzymes associated with cyclin regulatory subunits that control cell cycle progression. The evidence that neurons in postmortem brain tissue from patients with neurodegenerative diseases express CDKs, supports to the hypothesis that re-entry into the cell cycle could be an apoptotic pathway involved in the neurodegenerative process. Several authors suggest that the transcription factor E2F-1 function as a link between the cell cycle and apoptosis in neurons. Additionally the expression of CDK5 has been demonstrated in postmortem brain tissue from patients with neurodegenerative diseases. CDK5 is an atypical CDK, that does not require association with a cyclin and is not implicated in the cell cycle progression. Instead, it is associated with the neuronal co-activators p35 and p39, and is required for neuronal development, axonal outgrowth, learning and memory. Recent evidence also points to a leading role for CDK5/p25 in apoptosis and neurodegeneration. CDK inhibitors such as flavopiridol and roscovitine are being developed and tested in clinical trials as novel antineoplasic agents. Thus, due to the implication of CDKs in neuronal apoptosis, a new application of these drugs in the treatment of neurodegenerative diseases is suggested.

Keywords: phosphorylation, cytoskeletal alterations, egfr kinase, roscovitine, amp-activated protein kinase (ampk), aloisines, apoptosis inducing factor (aif), caspaseindependent pathway