α-Acetylcholine Receptor Signaling Reduces Neuroinflammation After Subarachnoid Hemorrhage in Mice.

Aneurysmal subarachnoid hemorrhage (aSAH) causes a robust inflammatory response which leads worse brain injury and poor outcomes. We investigated if stimulation of nicotinic acetylcholine α receptors (α-AChR) (receptors shown to have anti-inflammatory effects) would reduce inflammation and improve outcomes. To investigate the level of peripheral inflammation after aSAH, inflammatory markers were measured in plasma samples collected in a cohort of aSAH patients. To study the effect of α-AChR stimulation, SAH was induced in adult mice which were then treated with a α-AChR agonist, galantamine, or vehicle. A battery of motor and cognitive tests were performed 24 h after subarachnoid hemorrhage. Mice were euthanized and tissue collected for analysis of markers of inflammation or activation of α-AChR-mediated transduction cascades. A separate cohort of mice was allowed to survive for 28 days to assess long-term neurological deficits and histological outcome. Microglia cell culture subjected to hemoglobin toxicity was used to assess the effects of α-AChR agonism. Analysis of eighty-two patient plasma samples confirmed enhanced systemic inflammation after aSAH. α-AChR agonism reduced neuroinflammation at 24 h after SAH in male and female mice, which was associated with improved outcomes. This coincided with JAK2/STAT3 and IRAK-M activity modulations and a robust improvement in neurological/cognitive status that was effectively reversed by interfering with various components of these signaling pathways. Pharmacologic inhibition partially reversed the α-AChR agonist's benefits, supporting α-AChR as a target of the agonist's therapeutic effect. The cell culture experiment showed that α-AChR agonism is directly beneficial to microglia. Our results demonstrate that activation of α-AChR represents an attractive target for treatment of SAH. Our findings suggest that α-AChR agonists, and specifically galantamine, might provide therapeutic benefit to aSAH patients.