Agonism of the α-acetylcholine receptor/PI3K/Akt pathway promotes neuronal survival after subarachnoid hemorrhage in mice.

Subarachnoid hemorrhage (SAH) results in severe neuronal dysfunction and degeneration. Since the nicotinic acetylcholine α receptors (α-AChR) are involved in neuronal function and survival, we investigated if stimulation of α-AChR would promote neuronal survival and improve behavioral outcome following SAH in mice. Male mice subjected to SAH were treated with either galantamine (α-AChR agonist) or vehicle. Neurobehavioral testing was performed 24 h after SAH, and mice were euthanized for analysis of neuronal cell death or a cell survival (PI3K/Akt) signaling pathway. Neuron cell cultures were subjected to hemoglobin toxicity to assess the direct effects of α-AChR agonism independent of other cells. Treatment with the α-AChR agonist promoted neuronal survival and improved functional outcomes 24 h post-SAH. The improved outcomes corresponded with increased PI3K/Akt activity. Antagonism of α-AChR or PI3K effectively reversed galantamine's beneficial effects. Tissue from α-AChR knockout mice confirmed α-AChR's role in neuronal survival after SAH. Data from the neuronal cell culture experiment supported a direct effect of α-AChR agonism in promoting cell survival. Our findings indicate that α-AChR is a therapeutic target following SAH which can promote neuronal survival, thereby improving neurobehavioral outcome. Thus, the clinically relevant α-AChR agonist, galantamine, might be a potential candidate for human use to improve outcome after SAH.