Papel do sistema colinérgico na lesão cerebral e recuperação funcional após Isquemia

Abstract

Stroke is one of the leading causes of mortality in Brazil and in the world. It is one of the most common causes of functional disability and neurologic deficits in adults. There is evidence that the cholinergic system has neuroprotective effects in different types of brain lesions. Striatal cholinergic interneurons have been shown to be more resistant to ischemic insult when compared to other cells. However, the specific contribution of striatal acetylcholine in ischemic lesions is poorly understood. The 7 nicotinic receptor is another important cholinergic target when investigating ischemia. Studies have shown that this receptor can interact with STI1 (Stress Inducible Protein 1) and PrPC (prion protein) to promote neuroprotective effects. The purpose of this work was to investigate the role of the cholinergic system in cerebral lesions and functional recovery after stroke. Striatal conditional knockout VAChT (vesicular acetylcholine transporter) mice and STI1 genetically modified mice were used to evaluate cerebral lesion induced by left middle cerebral artery occlusion. Evaluation of functional outcomes was made trough adhesive removal, open field and catwalk tests. VAChTD2Cre-flox/flox mice showed larger infarct volumes, lower survival rates and worse functional outcomes after lesion. Further investigation of inflammatory markers, BDNF and apoptosis did not show any difference between genotypes after stroke, however, the levels of phosphorylated GSK3 (Tyr 279,219) was significantly increased in VAChTD2Cre-flox/flox when compared to ischemic controls. Mutant mice haploinsufficient for STI1 (STI1-/+) showed larger infarct areas, larger mortality rates and worse functional outcomes after stroke. However, STI1 transgenic mice, overexpressing this protein 4 fold, adults or aged, did not present improved recovery. Our results indicate that striatal acetylcholine has an important role in limiting the injury and facilitating functional recovery of mice, possibly through the inhibition of GSK3 phosphorylation. Additionally, partial depletion of STI1 increased the vulnerability to ischemic insult, however excess of this protein does not provide protection under the conditions studied.