Agonism of the α7-acetylcholine receptor/PI3K/Akt pathway promotes neuronal survival after subarachnoid hemorrhage in mice
| Autor: | Kanako Matsumura, Remya A Veettil, Jaroslaw Aronowski, Devin W. McBride, Pramod K. Dash, Ari Dienel, H. Alex Choi, T Peeyush Kumar, Andrey S. Tsvetkov, Spiros Blackburn |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Male
Agonist animal structures alpha7 Nicotinic Acetylcholine Receptor medicine.drug_class Apoptosis Pharmacology Article Mice Phosphatidylinositol 3-Kinases Developmental Neuroscience Galantamine medicine Animals cardiovascular diseases Receptor Protein kinase B PI3K/AKT/mTOR pathway Neurons business.industry Subarachnoid Hemorrhage nervous system diseases Mice Inbred C57BL Nicotinic acetylcholine receptor Nicotinic agonist Neurology Knockout mouse business Proto-Oncogene Proteins c-akt Signal Transduction medicine.drug |
| Zdroj: | Exp Neurol |
| ISSN: | 0014-4886 |
| DOI: | 10.1016/j.expneurol.2021.113792 |
| Popis: | Subarachnoid hemorrhage (SAH) results in severe neuronal dysfunction and degeneration. Since the nicotinic acetylcholine α(7) receptors (α(7)-AChR) are involved in neuronal function and survival, we investigated if stimulation of α(7)-AChR would promote neuronal survival and improve behavioral outcome following SAH in mice. Male mice subjected to SAH were treated with either galantamine (α(7)-AChR agonist) or vehicle. Neurobehavioral testing was performed 24 hours 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(7)-AChR agonism independent of other cells. Treatment with the α(7)-AChR agonist promoted neuronal survival and improved functional outcomes 24 hours post-SAH. The improved outcomes corresponded with increased PI3K/Akt activity. Antagonism of α(7)-AChR or PI3K effectively reversed galantamine’s beneficial effects. Tissue from α(7)-AChR knockout mice confirmed α(7)-AChR’s role in neuronal survival after SAH. Data from the neuronal cell culture experiment supported a direct effect of α(7)-AChR agonism in promoting cell survival. Our findings indicate that α(7)-AChR is a therapeutic target following SAH which can promote neuronal survival, thereby improving neurobehavioral outcome. Thus, the clinically relevant α(7)-AChR agonist, galantamine, might be a potential candidate for human use to improve outcome after SAH. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect