Objective: 

Chronic cerebral hypoperfusion can cause learning and memory impairment and neuronal damage resembling the effects observed in vascular dementia. The present study was designed to evaluate possible neuroprotective effects of rosiglitazone, a PPAR-gamma agonist, in rat model of chronic cerebral hypoperfusion.

Methods: 

Cerebral hypoperfusion was induced by permanent bilateral occlusion of the common carotid arteries. Oral administration of rosiglitazone (1.5, 3, and 6 mg/kg/day) or vehicle was carried out for 5 weeks, starting one week before the surgery. Cognitive performance was assessed using the Morris water maze. The density of the OX-42-labeled microglial activation and hippocampal neuronal death were estimated. Synaptogenesis was also evaluated by the measurement of synaptophysin, the pre-synaptic vesicular protein, and level via western blotting technique.

Results: 

Cerebral hypoperfusion for 30 days induced a significant cognitive impairment along with hyperactivation of microglial and astroglial cells, hippocampal neuronal loss, and reduction of synaptophysin level. The escape latencies for both 3 and 6 mg/kg of rosiglitazone-treated groups were significantly shorter than in the ischemia control group (P<0.05). For the group treated with 3 mg/kg of rosiglitazone, the number of OX-42 positive cells significantly decreased, as compared with two other treatment groups (P<0.05). Compared to the sham-operated group, the amounts of synaptophysin protein in the ischemia, 1.5 mg/kg, and 3 mg/kg rosiglitazone-treated groups, were statistically lower (P<0.05), whereas in the group treated with 6 mg/kg of rosiglitazone, no significant difference was noted.

Conclusions: 

Our results suggest that the chronic administration of rosiglitazone significantly prevents chronic cerebral hypoperfusion-induced brain damage, at least, partly through suppressing glial activation and preserving synaptic plasticity.