1. Academic Validation
  2. α7-Acetylcholine Receptor Signaling Reduces Neuroinflammation After Subarachnoid Hemorrhage in Mice

α7-Acetylcholine Receptor Signaling Reduces Neuroinflammation After Subarachnoid Hemorrhage in Mice

  • Neurotherapeutics. 2021 Jul;18(3):1891-1904. doi: 10.1007/s13311-021-01052-3.
Ari Dienel 1 Remya A Veettil 1 Kanako Matsumura 1 Jude P J Savarraj 1 H Alex Choi 1 2 Peeyush Kumar T 3 Jaroslaw Aronowski 4 Pramod Dash 5 Spiros L Blackburn 1 Devin W McBride 6
Affiliations

Affiliations

  • 1 The Vivian L Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center At Houston, Houston, TX, USA.
  • 2 Department of Neurology, McGovern Medical School, The University of Texas Health Science Center At Houston, Houston, TX, USA.
  • 3 The University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA.
  • 4 The University of Texas McGovern Medical School, Houston, TX, USA.
  • 5 Department of Neurobiology and Anatomy, McGovern Medical School, The University of Texas Health Science Center At Houston, Houston, TX, USA.
  • 6 The Vivian L Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center At Houston, Houston, TX, USA. devin.w.mcbride@uth.tmc.edu.
Abstract

Aneurysmal subarachnoid hemorrhage (aSAH) causes a robust inflammatory response which leads worse brain injury and poor outcomes. We investigated if stimulation of nicotinic acetylcholine α7 receptors (α7-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 α7-AChR stimulation, SAH was induced in adult mice which were then treated with a α7-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 α7-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 α7-AChR agonism. Analysis of eighty-two patient plasma samples confirmed enhanced systemic inflammation after aSAH. α7-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 α7-AChR agonist's benefits, supporting α7-AChR as a target of the agonist's therapeutic effect. The Cell Culture experiment showed that α7-AChR agonism is directly beneficial to microglia. Our results demonstrate that activation of α7-AChR represents an attractive target for treatment of SAH. Our findings suggest that α7-AChR agonists, and specifically galantamine, might provide therapeutic benefit to aSAH patients.

Keywords

Galantamine; Neuroinflammation; Nicotinic acetylcholine receptor; Subarachnoid hemorrhage.

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