The Cholinergic Drug Galantamine Ameliorates Acute Respiratory Distress Syndrome in Mice

Abstract

Acute respiratory distress syndrome (ARDS) is a life‐threatening form of acute lung injury and respiratory failure. The pandemic of SARS‐CoV‐2 has resulted in over 5 million deaths worldwide and many of those deaths have been attributed to complications associated with ARDS. No efficient pharmacological treatments for ARDS are currently available. In addition to lung injury and pulmonary inflammation, patients with ARDS have increased systemic inflammation. Previous insights have highlighted the role of cholinergic signalling in the vagus nerve‐based inflammatory reflex in controlling inflammation (Annu Rev Immunol, 2018, 36:783). Cholinergic anti‐inflammatory signalling can be activated by galantamine ‐ a centrally acting acetylcholinesterase inhibitor that is also clinically approved (for the treatment of Alzheimer’s disease). Here we examined the efficacy of galantamine in attenuating ARDS severity and inflammation in mice. We used a recently developed model of direct acute lung injury and ARDS, in which intratracheal (i.t.) hydrochloric acid (0.1N HCl, 2ml/kg) instillation is combined with LPS (10 mg/kg, i.t.) instillation 24h later in anesthetized mice. Male, 12‐week‐old C57BL/6 mice (n=7‐9), were subjected to this two hit ARDS model and treated 30 mins prior to each insult with galantamine (4 mg/kg, i.p.) or vehicle. Mice were euthanized 6h after LPS instillation and blood and bronchoalveolar lavage (BAL) fluid were collected. Galantamine significantly lowered the levels of BAL myeloperoxidase – an indicator of the accumulation of activated neutrophils in the airspaces of the lung (p = 0.0021) and the BAL total protein ‐ an indicator of alveolar permeability (p = 0.0076), compared with vehicle‐treated mice. BAL pro‐inflammatory cytokine levels were also reduced by galantamine, compared with vehicle‐treated mice – TNF (p = 0.0274), IL‐6 (p = 0.0009), and IL‐1β (p = 0.0380). In addition, treatment with galantamine significantly lowered the levels of serum pro‐inflammatory cytokines ‐ TNF (p = 0.0015), IL‐6 (p = 0.0089), and IL‐1β (p = 0.0149). In conclusion, galantamine reduced the severity of ARDS in mice and alleviated the local and systemic inflammatory responses. These results are of interest for further preclinical and clinical development of galantamine in the treatment of ARDS.

The Effect of Galantamine on Lipopolysaccharide-induced Acute Lung Injury During Neutropenia Recovery in Mice

“…The increase of acetylcholine increases the cholinergic system and vagus nerve activity which leads to the inhibition of the inflammatory response. Galantamine significantly lowered the levels of serum proinflammatory cytokines and alleviated the severity of ARDS in mice (17). Galantamine also ameliorated inflammation caused by hyperoxia in mice (18).…”