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.