Abstract
BackgroundBrain ischemia activates the parasympathetic cholinergic pathway in animal models of human disease. However, it remains unknown whether activation of the cholinergic pathway impacts immune defenses and disease outcomes in patients with ischemic stroke. This study investigated a possible association between peripheral cholinergic activity, post-stroke infection, and mortality.MethodsIn this study, we enrolled 458 patients with acute ischemic stroke (< 24 h after onset), 320 patients with ischemic stroke on day 10, and 216 healthy subjects. Peripheral cholinergic activity, reflected by intracellular acetylcholine (ACh) content in human peripheral blood mononuclear cells (PBMCs), was determined by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Expression of acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) was measured by quantitative real-time PCR and western blot. Regression analyses were used to assess associations between peripheral cholinergic function and clinical outcomes.ResultsWithin 24 h after the onset of acute ischemic stroke, there was a rapid increase in peripheral cholinergic activity that correlated with brain infarction volume (r = 0.67, P < 0.01). Specifically, lymphocyte-derived ACh levels were significantly higher in stroke patients with pneumonia (0.21 ± 0.02 ng/106 PBMC versus 0.15 ± 0.01 ng/106 PBMC, P = 0.03). Of note, lymphocytic AChE catalytic activity was significantly lower in these patients. One-year mortality was significantly greater in patients with higher intracellular ACh levels within the first 24 h after acute stroke.ConclusionsLymphocytes produced increased amounts of ACh in patients with acute stroke, and pneumonia was a likely result. The association between this enhanced cholinergic activity and increased risk of pneumonia/mortality suggests that increased cholinergic activity may contribute to fatal post-stroke infection.
Highlights
Brain ischemia activates the parasympathetic cholinergic pathway in animal models of human disease
Pneumonia was the only post-stroke infection noted, and was defined by the following two positive criteria during in-hospital stay: (1) presence of clinical and laboratory or radiological signs of pneumonia and infiltration confirmed by chest X-ray; and (2) plasma high sensitivity C-reactive protein of more than 5 mg/L
Re-determination of peripheral blood mononuclear cells (PBMCs)-derived ACh was performed in 320 patients in the recovery phase of stroke (10 days after stroke). 210 of 320 patients had been followed-up till 30 days after acute stroke
Summary
Brain ischemia activates the parasympathetic cholinergic pathway in animal models of human disease. It remains unknown whether activation of the cholinergic pathway impacts immune defenses and disease outcomes in patients with ischemic stroke. This study investigated a possible association between peripheral cholinergic activity, post-stroke infection, and mortality. Brain ischemia activates neurogenic pathways that lead to the inhibition of immune function by input from the sympathetic nervous system [1, 2]. Overactivation of the sympathetic nervous system and release of norepinephrine are important mediators of stroke-induced immune suppression, which predisposes patients to infection [3, 4]. The cholinergic pathway may Acetylcholine (ACh) is a key neurotransmitter that mediates cholinergic input. Previous studies indicated that AChproducing lymphocytes suppress tissue macrophages and
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