Affiliations: Department of Neurology, University of Kuopio, Kuopio,
Finland | Orion Pharma, Turku, Finland
Note: [] Corresponding author: Jukka Jolkkonen, Department of Neurology,
University of Kuopio, PO Box 1627, 70211 Kuopio, Finland. Tel.: +358 17 162519;
Fax: +358 17 162048; E-mail: jukka.jolkkonen@uku.fi
Abstract: Purpose: Rolipram, a specific phosphodiesterase 4 inhibitor (PDE4),
is suggested to facilitate functional recovery following brain injury by
activation of cAMP/CREB pathway. We examined the effect of rolipram on
sensorimotor recovery in rats following transient occlusion of the middle
cerebral artery (MCAO). Methods: Rats were subjected to transient MCAO for 2 h.
Rolipram was administered at a dose of 0.1 or 1 mg/kg (i.p., twice a day, for
13 days) starting administration on postoperative day 2. Sensorimotor outcome
was assessed using limb-placing, beam-walking and cylinder tests at baseline
and 7, 14, and 21 days after MCAO. Results: Rolipram decreased locomotor activity and rearing,
produced atypical head twitches, and possible hyperalgesia immediately after
treatments, which were all considered as acute side effects. The analysis of
hindlimb function utilizing beam-walking tests showed that overall performance
was impaired in MCAO vehicle rats (p < 0.01) and MCAO rats treated with
rolipram, at a dose of 0.1 mg/kg (p < 0.01), compared to sham-operated
rats. Interestingly, MCAO rats treated with rolipram at a dose of 1.0 mg/kg had
significantly fewer slips when traversing an elevated beam than those treated
with a dose of 0.1 mg/kg (p < 0.05) indicating improved sensorimotor
function. More importantly, hindlimb function at the higher rolipram dose was
not different from sham-operated rats after cessation of drug treatment at day
21. There was a significant group effect (p < 0.001) in the cylinder test,
however, this was due to the decreased use of the impaired forelimb in MCAO
rats compared to sham-operated rats at day 7, 14 and 21. In addition, MCAO rats
treated with rolipram seemed to use their impaired forelimbs less compared to
MCAO controls. Limb-placing performance was severely impaired but not different
among MCAO rats. Conclusions: The present data suggest that rolipram provides
some improvement in sensorimotor recovery in MCAO rats possibly by augmenting
cAMP/CREB signalling, but this is masked by its side effects.
