Browsing by Subject "Acetylcholine"

Now showing 1 - 9 of 9
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    The cholinergic system in the pathophysiology and treatment of Alzheimer's disease
    (Oxford University Press, 2018-07) Hampel, Harald; Mesulam, M.-Marsel; Cuello, A. Claudio; Farlow, Martin R.; Giacobini, Ezio; Grossberg, George T.; Khachaturian, Ara S.; Vergallo, Andrea; Cavedo, Enrica; Snyder, Peter J.; Khachaturian, Zaven S.; Neurology, IU School of Medicine
    Cholinergic synapses are ubiquitous in the human central nervous system. Their high density in the thalamus, striatum, limbic system, and neocortex suggest that cholinergic transmission is likely to be critically important for memory, learning, attention and other higher brain functions. Several lines of research suggest additional roles for cholinergic systems in overall brain homeostasis and plasticity. As such, the brain's cholinergic system occupies a central role in ongoing research related to normal cognition and age-related cognitive decline, including dementias such as Alzheimer's disease. The cholinergic hypothesis of Alzheimer's disease centres on the progressive loss of limbic and neocortical cholinergic innervation. Neurofibrillary degeneration in the basal forebrain is believed to be the primary cause for the dysfunction and death of forebrain cholinergic neurons, giving rise to a widespread presynaptic cholinergic denervation. Cholinesterase inhibitors increase the availability of acetylcholine at synapses in the brain and are one of the few drug therapies that have been proven clinically useful in the treatment of Alzheimer's disease dementia, thus validating the cholinergic system as an important therapeutic target in the disease. This review includes an overview of the role of the cholinergic system in cognition and an updated understanding of how cholinergic deficits in Alzheimer's disease interact with other aspects of disease pathophysiology, including plaques composed of amyloid-β proteins. This review also documents the benefits of cholinergic therapies at various stages of Alzheimer's disease and during long-term follow-up as visualized in novel imaging studies. The weight of the evidence supports the continued value of cholinergic drugs as a standard, cornerstone pharmacological approach in Alzheimer's disease, particularly as we look ahead to future combination therapies that address symptoms as well as disease progression.
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    Inhibition of p21 Activated Kinase (PAK) Reduces Airway Responsiveness In Vivo and In Vitro in Murine and Human Airways
    (Public Library of Science, 2012) Hoover, Wyn C.; Zhang, Wenwu; Xue, Zhidong; Gao, Huanling; Chernoff, Jonathan; Clapp, D. Wade; Gunst, Susan J.; Tepper, Robert S.; Pediatrics, School of Medicine
    The p21-activated protein kinases (Paks) have been implicated in the regulation of smooth muscle contractility, but the physiologic effects of Pak activation on airway reactivity in vivo are unknown. A mouse model with a genetic deletion of Pak1 (Pak1(-/-)) was used to determine the role of Pak in the response of the airways in vivo to challenge with inhaled or intravenous acetylcholine (ACh). Pulmonary resistance was measured in anesthetized mechanically ventilated Pak1(-/-) and wild type mice. Pak1(-/-) mice exhibited lower airway reactivity to ACh compared with wild type mice. Tracheal segments dissected from Pak1(-/-) mice and studied in vitro also exhibited reduced responsiveness to ACh compared with tracheas from wild type mice. Morphometric assessment and pulmonary function analysis revealed no differences in the structure of the airways or lung parenchyma, suggesting that that the reduced airway responsiveness did not result from structural abnormalities in the lungs or airways due to Pak1 deletion. Inhalation of the small molecule synthetic Pak1 inhibitor, IPA3, also significantly reduced in vivo airway responsiveness to ACh and 5-hydroxytryptamine (5-Ht) in wild type mice. IPA3 inhibited the contractility of isolated human bronchial tissues to ACh, confirming that this inhibitor is also effective in human airway smooth muscle tissue. The results demonstrate that Pak is a critical component of the contractile activation process in airway smooth muscle, and suggest that Pak inhibition could provide a novel strategy for reducing airway hyperresponsiveness.
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    Intracoronary acetylcholine for vasospasm provocation in women with ischemia and no obstructive coronary artery disease
    (Elsevier, 2025-03-18) Tjoe, Benita; Pacheco, Christine; Suppogu, Nissi; Samuels, Bruce; Rezaeian, Panteha; Tamarappoo, Balaji; Berman, Daniel S.; Sharif, Behzad; Nelson, Michael; Anderson, R. David; Petersen, John; Pepine, Carl J.; Thomson, Louise E. J.; Merz, C. Noel Bairey; Wei, Janet; Radiology and Imaging Sciences, School of Medicine
    Objectives: To evaluate the utility of higher dose intracoronary acetylcholine (ACh) during invasive coronary function testing (CFT) in women with suspected ischemia and no obstructive coronary artery disease (INOCA) for detection of epicardial vasospasm, relation to quality of life (QoL) and the presence of scar by late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMRI). Background: CFT is an established method for diagnosis of coronary microvascular dysfunction (CMD). The utility of epicardial vasospasm provocation testing with higher dose ACh infusion is not fully understood. Methods: Women with suspected INOCA undergoing invasive CFT were enrolled in the Women's Ischemia Syndrome Evaluation-Pre-Heart Failure with Preserved Ejection Fraction (WISE Pre-HFpEF) study (NCT03876223). Incremental infusions of 0.364, 36.4 μg and 108 μg ACh were used for vasospasm provocation. Vasospasm was defined as ≥75 % artery diameter reduction compared to post-nitroglycerin diameter and related to QoL and LGE on CMRI. Results: Among 73 women (56 ± 11 years), epicardial vasospasm was detected in 17 (23 %). Among women with vasospasm, the vast majority (94 %) had coronary endothelial dysfunction and few (12 %) had other abnormal CFT measures. Those with vasospasm had more nocturnal angina symptoms, calcium channel blocker use, poorer QoL (all p = 0.001) and disease perception (p = 0.02) than those without. LGE scar by CMRI was not associated with vasospasm (p = 0.22). Conclusions: Among women with suspected INOCA, intracoronary Ach spasm testing provoked epicardial vasospasm in one fourth. Women with epicardial vasospasm overwhelmingly had concomitant endothelial dysfunction, worse QoL but not more frequent myocardial scar on CMRI.
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