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Time dependent effect of an α7nACHR antagonist (methyllycaconitine citrate) on heart rate and body temperature in conscious rats given saline or LPS (0.1 mg/kg). Data are shown as Mean ± SEM. MLA: methyllycaconitine citrate. a P<0.05 (two-way ANOVA) in comparison with control group, b P<0.01 (two-way ANOVA) compared to LPS-treated group. * P<0.05 (Bonferroni's posttest) in comparison with LPS-treated group.
Source publication
Previous reports have indicated that artificial stimulation of the vagus nerve reduces systemic inflammation in experimental models of sepsis. This phenomenon is a part of a broader cholinergic anti-inflammatory pathway which activates the vagus nerve to modulate inflammation through activation of alpha7 nicotinic acetylcholine receptors (α7nACHR)....
Citations
... endotoxemia and sepsis), reduced heart rate variability and increased cardiac cycle regularity are observed. These effects can be triggered by LPS injection and IL-6 administration indicating a role of inflammation [126]. α7 nAChR is implicated in myocardial fibrosis, including right ventricular (RV) fibrosis, a maladaptive RV hypertrophy associated with poor outcomes in pulmonary hypertension [127]. ...
Genes restricted to humans may contribute to human-specific traits and provide a different context for diseases. CHRFAM7A is a uniquely human fusion gene and a negative regulator of the α7 nicotinic acetylcholine receptor (α7 nAChR). The α7 nAChR has been a promising target for diseases affecting cognition and higher cortical functions, however, the treatment effect observed in animal models failed to translate into human clinical trials. As CHRFAM7A was not accounted for in preclinical drug screens it may have contributed to the translational gap. Understanding the complex genetic architecture of the locus, deciphering the functional impact of CHRFAM7A on α7 nAChR neurobiology and utilizing human-relevant models may offer novel approaches to explore α7 nAChR as a drug target.
... Studies even reveal that several indexes of HRV seem to be related to inflammatory biomarkers in humans [21][22][23][24]. The exploration of HRV has provided a deeper understanding of the cholinergic anti-inflammatory pathway (CAP) [25][26][27][28], a neuroimmune mechanism that inhibits pro-inflammatory cytokine release via the vagus nerve [29]. ...
... Thus, linear methods of HRV may not account for all aspects of cardiac performance, especially the complex interactions between the control mechanisms that regulate heart function, due to assumptions and conditioning needed for linear HRV analysis [49]. In any case, both linear and nonlinear processing algorithms of HRV have provided useful computational tools for diagnosing a wide range of inflammatory conditions and pathologies [26][27][28][29]. According to a review of 2020, the most measurable nonlinear features of HRV are representation features (e.g., Poincaré plot representation, recurrence plot analysis, asymmetry); fractal (e.g., detrended fluctuation analysis, Hurst exponent); entropy or complexity-based features (e.g., Shannon entropy, sample entropy, multiscale entropy) and symbolic dynamics [50]. ...
Preeclampsia is a pregnancy-specific condition which gets detected through hypertension and excessive protein excretion in urine. While preeclampsia used to be regarded as a self-limiting maternal condition which resolved with the delivery of the placenta, it is nowadays considered a complex and multifactorial disease that affects the offspring. Unfortunately, the etiology and pathophysiology of this multifaceted disorder remain elusive. Recent findings have confirmed that an altered maternal autonomic function may play a vital role in developing preeclampsia in conjunction with an imbalanced maternal immune system. Additionally, further evidence supports the crucial role of an exacerbated immune response driven by a non-infectious trigger during preeclampsia. Therefore, as a sterile inflammation, the elucidation of the neuroinflammatory mechanisms of preeclampsia warrants obtaining relevant knowledge suitable for translational clinical applications.
Heart rate variability (HRV) is an affordable and non-invasive method for indirectly assessing the autonomic nervous system and the cholinergic anti-inflammatory pathway (CAP). Notably, the nonlinear analysis of HRV offers novel indexes to explore the neuroimmune interactions in diverse preclinical and clinical settings of inflammation. Given that the dynamics of HRV is nonlinear in health, we hypothesized that a neuroinflammatory condition in preeclampsia might be associated with changes in nonlinear features of maternal and fetal HRV. Thus, the present review aims to present evidence of the potential changes in maternal-fetal HRV associated with neuroinflammatory modifications in preeclamptic women. We considered that there is still a need for assessing the nonlinear features of maternal and fetal HRV as complementary biomarkers of inflammation in this population in future studies, being a potential route for translational clinical applications.
... The CAIP can reduce systemic inflammation of endotoxemia and improve acute heart failure. Agonists such as nicotine or PY, acting on the α7nAChR and α4β2nAChR, can not only reduce LPS-induced hypotension, tachycardia, and cardiac autonomic nerve dysfunction but also dose-dependently reduce the elevation of serum TNF-α and control the overproduction of inflammatory cytokines [198][199][200][201][202][203]. Some studies have also reported that intervention with an M1 agonist (McN-A-343) and an α7nAChR agonist (PNU282987) via the CNS produces the same effect, of which PNU282987 can restore the proliferation and immunity of CD4 + T cells, with increased release of IL-2 and IFN-γ and reduced release of IL-4. ...
The immune system and the nervous system depend on each other for their fine tuning and working, thus cooperating to maintain physiological homeostasis and prevent infections. The cholinergic system regulates the mobilization, differentiation, secretion, and antigen presentation of adaptive and innate immune cells mainly through α7 nicotinic acetylcholine receptors (α7nAChRs). The neuro-immune interactions are established and maintained by the following mechanisms: colocalization of immune and neuronal cells at defined anatomical sites, expression of the non-neuronal cholinergic system by immune cells, and the acetylcholine receptor-mediated activation of intracellular signaling pathways. Based on these immunological mechanisms, the protective effects of cholinergic system in animal models of diseases were summarized in this paper, such as myocardial infarction/ischemia–reperfusion, viral myocarditis, and endotoxin-induced myocardial damage. In addition to maintaining hemodynamic stability and improving the energy metabolism of the heart, both non-neuronal acetylcholine and neuronal acetylcholine in the heart can alleviate myocardial inflammation and remodeling to exert a significant cardioprotective effect. The new findings on the role of cholinergic agonists and vagus nerve stimulation in immune regulation are updated, so as to develop improved approaches to treat inflammatory heart disease.
... At the cellular level, the neurotransmitter acetylcholine (ACh) is released following vagal activation, modulating both electrical and mechanical functions of the heart. ACh binds to the α7 nicotinic acetylcholine receptor (α7nAChR), an ionotropic receptor that presents in the endothelial layer of heart tissues to modulate tonic activity of the heart (Mazloom et al., 2013). α7nAChR also presents widely in immune cells, specifically in the myocardium. ...
Background
Myocardial infarction (MI) reperfusion therapy causes paradoxical cardiac complications. Following restoration of blood flow to infarcted regions, a multitude of inflammatory cells are recruited to the site of injury for tissue repair. Continual progression of cardiac inflammatory responses does, however, lead to adverse cardiac remodeling, inevitably causing heart failure.
Main Body
Increasing evidence of the cardioprotective effects of both invasive and non-invasive vagal nerve stimulation (VNS) suggests that these may be feasible methods to treat myocardial ischemia/reperfusion injury via anti-inflammatory regulation. The mechanisms through which auricular VNS controls inflammation are yet to be explored. In this review, we discuss the potential of autonomic nervous system modulation, particularly via the parasympathetic branch, in ameliorating MI. Novel insights are provided about the activation of the cholinergic anti-inflammatory pathway on cardiac macrophages. Acetylcholine binding to the α7 nicotinic acetylcholine receptor (α7nAChR) expressed on macrophages polarizes the pro-inflammatory into anti-inflammatory subtypes. Activation of the α7nAChR stimulates the signal transducer and activator of transcription 3 (STAT3) signaling pathway. This inhibits the secretion of pro-inflammatory cytokines, limiting ischemic injury in the myocardium and initiating efficient reparative mechanisms. We highlight recent developments in the controversial auricular vagal neuro-circuitry and how they may relate to activation of the cholinergic anti-inflammatory pathway.
Conclusion
Emerging published data suggest that auricular VNS is an inexpensive healthcare modality, mediating the dynamic balance between pro- and anti-inflammatory responses in cardiac macrophages and ameliorating cardiac ischemia/reperfusion injury.
... Mazloom et al. estudiaron el receptor nicotínico de acetilcolina alfa siete (α7nACHR) por medio de la VFC en ratas que se les indujo un estado de endotoxemia. Ellos supusieron que dichos receptores pueden modular la disminución de la VFC en ese escenario, puesto que los α7nACHR juegan un papel importante en la activación de la respuesta antiinflamatoria colinérgica vagal (Mazloom et al., 2013). En ese estudio se experimentó con ratas Sprague-Dawley macho y se aplicaron dosis de LPS de 0.1 mg/kg y 1 mg/kg, así como agonistas y antagonistas del α7nACHR. ...
Nuestro conocimiento acerca de las adaptaciones e interacciones
electrofisiológicas, autonómicas e inmunológicas que existen en
el trabajo de parto es aún limitado; sin embargo, la participación
de un mecanismo homeostático como la respuesta colinérgica antiinflamatoria
(RCA) podría disminuir la inflamación en la mujer
durante esta etapa de culminación del embarazo. Dicho mecanismo
podría modular la dinámica eléctrica cardiaca y uterina
para resolver el proceso inflamatorio, debido a que el corazón y el
útero poseen eferencias vagales. Este capítulo ayudará al lector a
entender el proceso de inicio del trabajo de parto (TP) desde una
perspectiva fisiológica integrativa que incorpora las perspectiva
endocrinológica e inmunológica, así como también busca aportar
evidencia de la existencia de asociaciones entre la variabilidad de
la frecuencia cardiaca (VFC), una medición indirecta del sistema
nervioso autónomo (SNA), y el proceso inflamatorio sistémico
que involucra el TP. Finalmente, reflexionamos acerca del potencial
uso de la actividad eléctrica uterina mediante el registro del
electrohisterograma (EHG) para explorar su posible correlación
con la concentración de citocinas liberadas por el músculo (miosinas)
durante el TP.
... (G. Pacheco-López) of the α7 nicotinic acetylcholine receptor (α7nACHR) induced a decrement of the HRF by eliciting an increased inflammation and a febrile response in endotoxemic rats [7]. This response suggests a tonic role of peripheral nicotinic acetylcholine receptors for modulating heart rate dynamics during systemic inflammation. ...
... Lyophilized lipopolysaccharide (LPS) from Escherichia coli, serotype O55:B5 (Sigma-Aldrich, Taufkirchen, Germany), was diluted with sterile saline (NaCl) and administered intraperitoneally (i.p.) at a dose of 0.1 mg/kg in a total volume of 1 ml. We and others have previously shown that this LPS dose induces a rise in peripheral cytokine levels and a moderate fever response [19], as well as changes of HRF parameters [7]. ...
... According with the differences identified between groups, an area under curve (AUC) analysis was then applied at consecutive 2 h periods (+7 to +9h). The AUC analysis was performed posterior to the time reported by Mazloom et al. [7] (i.e. after t = 6 h of the drugs or vehicle injections) and only during dark periods (i.e. before t = 9 h), with the intention of avoiding circadian variations induced by subsequent period of inactivity (light phase) [20]. ...
Objectives:
This study aims to determine the effect of low-intensity focused ultrasound (LIFU) in ischemic heart failure (IHF) and explore the potential neuroimmune mechanism.
Methods:
Sprague-Dawley rats were subjected to ultrasound (US) with specific parameters, and electrocardiograms were recorded to analyze the effect of LIFU and/or vagal denervation on heart rate. Thereafter, myocardial infarction (MI) was induced by left anterior artery ligation, and LIFU was performed three times a day for 25 days after MI. Echocardiography, Masson staining, and ELISA were used to evaluate the effect of LIFU on the structure and function of the heart. Finally, ELISA, flow cytometry, qRT-PCR, and Western blot analysis were performed to determine the effect of LIFU on the inflammation and the expression of the cholinergic anti-inflammatory pathway (CAP)-related mediators.
Results:
LIFU reduced heart rate in rats (control vs LIFU, P < .01), and vagotomy (VT) eliminated this effect of LIFU on heart rate (VT vs LIFU + VT, P > .01). LIFU-ameliorated IHF in terms of cardiac structure and function (MI vs MI + LIFU, P < .01), but VT abrogated the beneficial effect of LIFU (MI + VT vs MI + LIFU + VT, P > .01). After the treatment of LIFU, decreased levels of inflammatory cytokines, increased proportion of anti-inflammatory macrophages, and increased expression of CAP-related mediators (MI vs MI + LIFU, P < .01).
Conclusions:
LIFU ameliorates IHF whereas the CAP plays a promising role. LIFU has the potential to be a novel nonpharmacological and noninvasive therapy for the treatment of coronary artery disease and other cardiovascular diseases.
Chronic liver damage leads to scarring of the liver tissue and ultimately a systemic illness known as cirrhosis. Patients with cirrhosis exhibit multi-organ dysfunction and high mortality. Reduced heart rate variability (HRV) is a hallmark of cirrhosis, reflecting a state of defective cardiovascular control and physiological network disruption. Several lines of evidence have revealed that decreased HRV holds prognostic information and can predict survival of patients independent of the severity of liver disease. Thus, the aim of this review is to shed light on the mechanistic and prognostic implications of HRV analysis in patients with cirrhosis. Notably, several studies have extensively highlighted the critical role systemic inflammation elicits in conferring the reduction in patients' HRV. It appears that IL-6 is likely to play a central mechanistic role, whereby its levels also correlate with manifestations, such as autonomic neuropathy and hence the partial uncoupling of the cardiac pacemaker from autonomic control. Reduced HRV has also been reported to be highly correlated with the severity of hepatic encephalopathy, potentially through systemic inflammation affecting specific brain regions, involved in both cognitive function and autonomic regulation. In general, the prognostic ability of HRV analysis holds immense potential in improving survival rates for patients with cirrhosis, as it may indeed be added to current prognostic indicators, to ultimately increase the accuracy of selecting the recipient most in need of liver transplantation. However, a network physiology approach in the future is critical to delineate the exact mechanistic basis by which decreased HRV confers poor prognosis.
Activation of α-7 nicotinic acetylcholine receptor (α7nAChR) receptor might induce cardiac inflammation, cardiac remodeling, and dysfunction. In this regard, this study aims to clarify the role and mechanism of α7nAChR in the process of cardiac inflammation and damage. Normal male C57BL/6J and NLRP3-knockout mice were used to evaluate the effect of PHA-543613, a selective agonist of α7nAChR, on cardiac inflammation and possible involvement of NLRP3/Caspase-1/IL-18 using western blotting and ELISA. Activation of α7nAChR using PHA-543613 (NE), at the doses of 0.5 mg/kg and 1 mg/kg, induced cardiac inflammation. In addition, both in vivo and in vitro studies showed higher expression of NLRP3 and higher activation of Caspase-1 and IL-18 after treating animals with NE. On the other hand, we did not observe any significant changes in inflammatory cytokines and cardiac inflammation after administration of NE in NLRP3-knockout mice. It could be concluded that blocking the NLRP3/Caspase-1/IL-18 pathway can simultaneously inhibit the inflammatory response mediated by α7nAChR and it would a novel target for inhibiting cardiac inflammation and remodeling.
Cardiac dysfunction is one of the main predictors of poor prognosis in septic patients. Although it has been investigated for more than 30 years, the mechanisms for sepsis-induced cardiac dysfunction are not completely understood, and no specific, effective treatment exists. Traditionally, sepsis-induced cardiac dysfunction was defined as a reversible decrease in ejection fraction of both ventricles with ventricular dilation and depressed response to fluid resuscitation and catecholamines. Many studies have demonstrated that autonomic nervous system imbalance, characterized by sympathetic overactivation and vagal suppression, contributes to the pathogenesis of sepsis-induced cardiac dysfunction. Thus, this kind of cardiac dysfunction can perhaps be best described as a sepsis-induced cardiac autonomic dysfunction as well as an intrinsic systolic and diastolic dysfunction of the whole heart, which is characterized by tachycardia, strongly decreased heart rate variability, and depressed intrinsic systolic and diastolic function of both ventricles. This review will summarize our current knowledge of sepsis-induced cardiac dysfunction, with a special focus on the role of autonomic dysfunction.
