Therapeutic effect of <b>α</b> 7 nicotinic receptor activation after ischemic stroke in rats
Laura Aguado, Ana Joya, Maider Garbizu, Sandra Plaza‐García, Leyre Iglesias, María Isabel Hernández, María Ardaya, Naroa Mocha, Vanessa Gómez‐Vallejo, Unai Cossío, Makoto Higuchi, Alfredo Rodríguez-Antigüedad, Mari Mar Freijo, Marı́a Domercq, Carlos Matute, Pedro Ramos‐Cabrer, Jordi Llop, Abraham Martín
Abstract
Nicotinic acetylcholine α7 receptors (α7 nAChRs) have a well-known modulator effect in neuroinflammation. Yet, the therapeutical effect of α7 nAChRs activation after stroke has been scarcely evaluated to date. The role of α7 nAChRs activation with PHA 568487 on inflammation after brain ischemia was assessed with positron emission tomography (PET) using [ 18 F]DPA-714 and [ 18 F]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 α7 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 [ 18 F]DPA-714-PET uptake reduction at day 7 together with a decrease of activated microglia/infiltrated macrophages. Likewise, the activation of α7 receptors displayed an increase of [ 18 F]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.