Cerebral edema is one of the deadliest complications of
ischemic stroke for which there is currently no
pharmaceutical treatment. Aquaporin-4 (AQP4), a
water-channel polarized at the astrocyte endfoot, is known to be highly implicated in
cerebral edema. We previously showed in randomized studies that (S)-
roscovitine, a
cyclin-dependent kinase inhibitor, reduced
cerebral edema 48 h after induction of focal transient
ischemia, but its mechanisms of action were unclear. In our recent blind randomized study, we confirmed that (S)-
roscovitine was able to reduce
cerebral edema by 65% at 24 h post-
stroke (t test, p = .006). Immunofluorescence analysis of AQP4 distribution in astrocytes revealed that (S)-
roscovitine decreased the non-perivascular pool of AQP4 by 53% and drastically increased AQP4 clusters in astrocyte perivascular end-feet (671%, t test p = .005) compared to vehicle. Non-perivascular and clustered AQP4 compartments were negatively correlated (R = -0.78; p < .0001), suggesting a communicating vessels effect between the two compartments. α1-syntrophin, AQP4 anchoring
protein, was colocalized with AQP4 in astrocyte endfeet, and this colocalization was maintained in ischemic area as observed on confocal microscopy. Moreover, (S)-
roscovitine increased AQP4/α1-
syntrophin interaction (40%, MW p = .0083) as quantified by proximity
ligation assay. The quantified interaction was negatively correlated with
brain edema in both treated and placebo groups (R = -.57; p = .0074). We showed for the first time, that a
kinase inhibitor modulated AQP4/α1-
syntrophin interaction, and was implicated in the reduction of
cerebral edema. These findings suggest that (S)-
roscovitine may hold promise as a potential treatment for
cerebral edema in
ischemic stroke and as modulator of AQP4 function in other neurological diseases.