Inhibition of CDK5 is protective in necrotic and apoptotic paradigms of neuronal cell death and prevents mitochondrial dysfunction.
Previous studies suggested that pro-apoptotic stimuli may trigger a fatal reactivation of cell cycle elements in postmitotic neurons. Supporting this hypothesis, small molecule inhibitors of cyclin-dependent kinases (CDKs), which are known primarily as cell cycle regulators, are neuroprotective. However, available CDK inhibitors cannot discriminate between the different members of the CDK family and inhibit also CDK5, which is not involved in cell cycle control. Testing a new class of CDK inhibitors, we find that inhibitory activity against CDK5, but not cell cycle-relevant CDKs, confers neuroprotection. Moreover, we demonstrate that cleavage of the CDK5 activator protein p35 to p25 is associated with CDK5 overactivation after focal cerebral ischemia, but not in other models used in this study. We find that blocking CDK5 activity, but not caspase inhibition, protects mitochondrial integrity of lesioned neurons. Thus, in our models, CDK5, rather than cell cycle-relevant CDKs, activates neuronal cell death pathways upstream of mitochondrial dysfunction, and inhibition of CDK5 may promote functional long-term rescue of injured neurons. Moreover, we present the first CDK5-selective small molecule inhibitor, lacking unwanted cytostatic effects due to cross-inhibition of mitotic CDKs.
Weishaupt
Jochen H
JH
Department of Neurology, University Hospital Göttingen, Robert-Koch-Strasse 40, 37075 Göttingen, Germany.
Kussmaul
Lothar
L
Grötsch
Philipp
P
Heckel
Armin
A
Rohde
G
G
Romig
H
H
Bähr
Mathias
M
Gillardon
Frank
F
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002545:Brain Ischemia / Q000188:drug therapy / Q000201:enzymology; D019328:Buthionine Sulfoximine / Q000494:pharmacology / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D009336:Necrosis; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley
D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D019328:Buthionine Sulfoximine; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; C495906:Cdk5 protein, mouse; C495907:Cdk5 protein, rat; D018844:Cyclin-Dependent Kinases