In vivo imaging of A7 nicotinic receptors as a novel method to monitor neuroinflammation after cerebral ischemia

In vivo positron emission tomography (PET) imaging of nicotinic acetylcholine receptors (nAChRs) is a promising tool for the imaging evaluation of neurologic and neurodegenerative diseases. However, the role of alpha 7 nAChRs after brain diseases such as cerebral ischemia and its involvement in inflammatory reaction is still largely unknown. In vivo and ex vivo evaluation of alpha 7 nAChRs expression after transient middle cerebral artery occlusion (MCAO) was carried out using PET imaging with [C-11]NS14492 and immunohistochemistry (IHC). Pharmacological activation of alpha 7 receptors was evaluated with magnetic resonance imaging (MRI), [F-18]DPA-714 PET, IHC, real time polymerase chain reaction (qPCR) and neurofunctional studies. In the ischemic territory, [C-11]NS14492 signal and IHC showed an expression increase of alpha 7 receptors in microglia and astrocytes after cerebral ischemia. The role played by alpha 7 receptors on neuroinflammation was supported by the decrease of [F-18]DPA-714 binding in ischemic rats treated with the alpha 7 agonist PHA 568487 at day alpha 7 after MCAO. Moreover, compared with non-treated MCAO rats, PHA-treated ischemic rats showed a significant reduction of the cerebral infarct volumes and an improvement of the neurologic outcome. PHA treatment significantly reduced the expression of leukocyte infiltration molecules in MCAO rats and in endothelial cells after in vitro ischemia. Despite that, the activation of alpha 7 nAChR had no influence to the blood brain barrier (BBB) permeability measured by MRI. Taken together, these results suggest that the nicotinic alpha 7 nAChRs play a key role in the inflammatory reaction and the leukocyte recruitment following cerebral ischemia in rats.