Sustained (S)-roscovitine delivery promotes neuroprotection associated with functional recovery and decrease in brain edema in a randomized blind focal cerebral ischemia study

• Published in: Journal of cerebral blood flow and metabolism Vol. 38; no. 6; pp. 1070 - 1084
• Main Authors: Rousselet, Estelle, Létondor, Anne, Menn, Bénédicte, Courbebaisse, Yann, Quillé, Marie-Lise, Timsit, Serge
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.06.2018
• Subjects: Animals; Brain Edema - drug therapy; Brain Edema - metabolism; Brain Edema - pathology; Brain Edema - physiopathology; Brain Ischemia - drug therapy; Brain Ischemia - metabolism; Brain Ischemia - pathology; Brain Ischemia - physiopathology; Male; Neuroprotective Agents - pharmacokinetics; Neuroprotective Agents - pharmacology; Original; Random Allocation; Rats; Rats, Sprague-Dawley; Recovery of Function - drug effects; Roscovitine - pharmacokinetics; Roscovitine - pharmacology; Brain ischemia; pharmacokinetics; cell cycle; neuroprotection; brain recovery
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1177/0271678X17712163

Stroke is a devastating disorder that significantly contributes to death, disability and healthcare costs. In ischemic stroke, the only current acute therapy is recanalization, but the narrow therapeutic window less than 6 h limits its application. The current challenge is to prevent late cell death, with concomitant therapy targeting the ischemic cascade to widen the therapeutic window. Among potential neuroprotective drugs, cyclin-dependent kinase inhibitors such as (S)-roscovitine are of particular relevance. We previously showed that (S)-roscovitine crossed the blood–brain barrier and was neuroprotective in a dose-dependent manner in two models of middle cerebral artery occlusion (MCAo). According to the Stroke Therapy Academic Industry Roundtable guidelines, the pharmacokinetics of (S)-roscovitine and the optimal mode of delivery and therapeutic dose in rats were investigated. Combination of intravenous (IV) and continuous sub-cutaneous (SC) infusion led to early and sustained delivery of (S)-roscovitine. Furthermore, in a randomized blind study on a transient MCAo rat model, we showed that this mode of delivery reduced both infarct and edema volume and was beneficial to neurological outcome. Within the framework of preclinical studies for stroke therapy development, we here provide data to improve translation of pre-clinical studies into successful clinical human trials.