Neuroprotective Efficacy of the Peroxisome Proliferator-Activated Receptor-γ Ligand in Chronic Cerebral Hypoperfusion

Hale      Sayan-Ozacmak; V.      Haktan Ozacmak; Figen      Barut; Ewa      Jakubowska-Dogru

Abstract

Chronic cerebral hypoperfusion can cause learning and memory impairment and neuronal damage resembling the effects observed in vascular dementia. PPAR-γ agonists were shown to modulate inflammatory response and neuronal death following cerebral ischemia. The present study was designed to evaluate possible neuroprotective effects of rosiglitazone, a PPAR-γ agonist, in rat model of chronic cerebral hypoperfusion. 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 S100B protein-immunoreactive astrocytes and the OX-42-labeled microglial activation were estimated. Synaptogenesis was also evaluated by the measurement of synaptophysin, the presynaptic vesicular protein, level via western blotting technique. Cerebral hypoperfusion for 30 days induced a significant cognitive impairment along with hyperactivation of both microglial and astroglial cells, and reduction of synaptophysin level. Rosiglitazone treatment (3 and 6 mg/kg) not only suppressed the activation of astrocytes and microglia markedly but also alleviated the impairment of memory and increased the synaptophysin level. In conclusion, 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. Thus, it appears that rosiglitazone may be a promising pharmacological agent in the development of therapeutic approaches for the prevention or treatment of cerebrovascular diseases.

Keywords: Chronic cerebral hypoperfusion, S100, synaptophysin, spatial learning, NEUROPROTECTIVE, PEROXISOME, PROLIFERATOR-ACTIVATED RECEPTOR, CEREBRAL HYPOPERFUSION, pre-synaptic, protein-immunoreactive, astrocytes, microglial, Cerebral