Therapeutic effect of alpha 7 nicotinic receptor activation after ischemic stroke in rats

Nicotinic acetylcholine alpha 7 receptors (alpha 7 nAChRs) have a well-known modulator effect in neuroinflammation. Yet, the therapeutical effect of alpha 7 nAChRs activation after stroke has been scarcely evaluated to date. The role of alpha 7 nAChRs activation with PHA 568487 on inflammation after brain ischemia was assessed with positron emission tomography (PET) using [F-18]DPA-714 and [F-18]BR-351 radiotracers after transient middle cerebral artery occlusion (MCAO) in rats. The assessment of brain oedema, blood brain barrier (BBB) disruption and neurofunctional progression after treatment was evaluated with T-2 weighted and dynamic contrast-enhanced magnetic resonance imaging (T-2 W and DCE-MRI) and neurological evaluation. The activation of alpha 7 nAChRs resulted in a decrease of ischemic lesion, midline displacement and cell neurodegeneration from days 3 to 7 after ischemia. Besides, the treatment with PHA 568487 improved the neurofunctional outcome. Treated ischemic rats showed a significant [F-18]DPA-714-PET uptake reduction at day 7 together with a decrease of activated microglia/infiltrated macrophages. Likewise, the activation of alpha 7 receptors displayed an increase of [F-18]BR-351-PET signal in ischemic cortical regions, which resulted from the overactivation of MMP-2. Finally, the treatment with PHA 568487 showed a protective effect on BBB disruption and blood brain vessel integrity after cerebral ischemia.