Delayed treatment with systemic (S)-roscovitine provides neuroprotection and inhibits in vivo CDK5 activity increase in animal stroke models.
BACKGROUND
Although quite challenging, neuroprotective therapies in ischemic stroke remain an interesting strategy to counter mechanisms of ischemic injury and reduce brain tissue damage. Among potential neuroprotective drug, cyclin-dependent kinases (CDK) inhibitors represent interesting therapeutic candidates. Increasing evidence indisputably links cell cycle CDKs and CDK5 to the pathogenesis of stroke. Although recent studies have demonstrated promising neuroprotective efficacies of pharmacological CDK inhibitors in related animal models, none of them were however clinically relevant to human treatment.


RESULTS
In the present study, we report that systemic delivery of (S)-roscovitine, a well known inhibitor of mitotic CDKs and CDK5, was neuroprotective in a dose-dependent manner in two models of focal ischemia, as recommended by STAIR guidelines. We show that (S)-roscovitine was able to cross the blood brain barrier. (S)-roscovitine significant in vivo positive effect remained when the compound was systemically administered 2 hrs after the insult. Moreover, we validate one of (S)-roscovitine in vivo target after ischemia. Cerebral increase of CDK5/p25 activity was observed 3 hrs after the insult and prevented by systemic (S)-roscovitine administration. Our results show therefore that roscovitine protects in vivo neurons possibly through CDK5 dependent mechanisms.


CONCLUSIONS
Altogether, our data bring new evidences for the further development of pharmacological CDK inhibitors in stroke therapy.
Menn
Bénédicte
B
Neurokin S.A., Institut de Neurobiologie de la Méditerranée, Marseille, France.
Bach
Stéphane
S
Blevins
Teri L
TL
Campbell
Mark
M
Meijer
Laurent
L
Timsit
Serge
S
D000818:Animals; D002545:Brain Ischemia / Q000150:complications; D016923:Cell Death / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D004333:Drug Administration Routes; D006801:Humans; D007267:Injections; D008297:Male; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use; D011687:Purines / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D000077546:Roscovitine; D020521:Stroke / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D013997:Time Factors
D018696:Neuroprotective Agents; D011687:Purines; D000077546:Roscovitine; D051360:Cyclin-Dependent Kinase 5