| 1. |
- Caravaca, April S., et al.
(författare)
-
Vagus Nerve Stimulation Reduces Indomethacin-Induced Small Bowel Inflammation
- 2022
-
Ingår i: Frontiers in Neuroscience. - : Frontiers Media SA. - 1662-4548 .- 1662-453X. ; 15
-
Tidskriftsartikel (refereegranskat)abstract
- Crohns disease is a chronic, idiopathic condition characterized by intestinal inflammation and debilitating gastrointestinal symptomatology. Previous studies of inflammatory bowel disease (IBD), primarily in colitis, have shown reduced inflammation after electrical or pharmacological activation of the vagus nerve, but the scope and kinetics of this effect are incompletely understood. To investigate this, we studied the effect of electrical vagus nerve stimulation (VNS) in a rat model of indomethacin-induced small intestinal inflammation. 1 min of VNS significantly reduced small bowel total inflammatory lesion area [(mean +/- SEM) sham: 124 +/- 14 mm(2), VNS: 62 +/- 14 mm(2), p = 0.002], intestinal peroxidation and chlorination rates, and intestinal and systemic pro-inflammatory cytokine levels as compared with sham-treated animals after 24 h following indomethacin administration. It was not known whether this observed reduction of inflammation after VNS in intestinal inflammation was mediated by direct innervation of the gut or if the signals are relayed through the spleen. To investigate this, we studied the VNS effect on the small bowel lesions of splenectomized rats and splenic nerve stimulation (SNS) in intact rats. We observed that VNS reduced small bowel inflammation also in splenectomized rats but SNS alone failed to significantly reduce small bowel lesion area. Interestingly, VNS significantly reduced small bowel lesion area for 48 h when indomethacin administration was delayed. Thus, 1 min of electrical activation of the vagus nerve reduced indomethacin-induced intestinal lesion area by a spleen-independent mechanism. The surprisingly long-lasting and spleen-independent effect of VNS on the intestinal response to indomethacin challenge has important implications on our understanding of neural control of intestinal inflammation and its potential translation to improved therapies for IBD.
|
|
| 2. |
- Donahue, Mary, et al.
(författare)
-
Wireless optoelectronic devices for vagus nerve stimulation in mice
- 2022
-
Ingår i: Journal of Neural Engineering. - : IOP Publishing. - 1741-2560 .- 1741-2552. ; 19:6, s. 066031-
-
Tidskriftsartikel (refereegranskat)abstract
- Objective. Vagus nerve stimulation (VNS) is a promising approach for the treatment of a wide variety of debilitating conditions, including autoimmune diseases and intractable epilepsy. Much remains to be learned about the molecular mechanisms involved in vagus nerve regulation of organ function. Despite an abundance of well-characterized rodent models of common chronic diseases, currently available technologies are rarely suitable for the required long-term experiments in freely moving animals, particularly experimental mice. Due to challenging anatomical limitations, many relevant experiments require miniaturized, less invasive, and wireless devices for precise stimulation of the vagus nerve and other peripheral nerves of interest. Our objective is to outline possible solutions to this problem by using nongenetic light-based stimulation. Approach. We describe how to design and benchmark new microstimulation devices that are based on transcutaneous photovoltaic stimulation. The approach is to use wired multielectrode cuffs to test different stimulation patterns, and then build photovoltaic stimulators to generate the most optimal patterns. We validate stimulation through heart rate analysis. Main results. A range of different stimulation geometries are explored with large differences in performance. Two types of photovoltaic devices are fabricated to deliver stimulation: photocapacitors and photovoltaic flags. The former is simple and more compact, but has limited efficiency. The photovoltaic flag approach is more elaborate, but highly efficient. Both can be used for wireless actuation of the vagus nerve using light impulses. Significance. These approaches can enable studies in small animals that were previously challenging, such as long-term in vivo studies for mapping functional vagus nerve innervation. This new knowledge may have potential to support clinical translation of VNS for treatment of select inflammatory and neurologic diseases.
|
|
| 3. |
- Kumawat, Ashok Kumar, 1982-, et al.
(författare)
-
Inhibition of IL17A Using an Affibody Molecule Attenuates Inflammation in ApoE-Deficient Mice
- 2022
-
Ingår i: Frontiers in Cardiovascular Medicine. - : Frontiers Media S.A.. - 2297-055X. ; 9
-
Tidskriftsartikel (refereegranskat)abstract
- The balance between pro- and anti-inflammatory cytokines released by immune and non-immune cells plays a decisive role in the progression of atherosclerosis. Interleukin (IL)-17A has been shown to accelerate atherosclerosis. In this study, we investigated the effect on pro-inflammatory mediators and atherosclerosis development of an Affibody molecule that targets IL17A. Affibody molecule neutralizing IL17A, or sham were administered in vitro to human aortic smooth muscle cells (HAoSMCs) and murine NIH/3T3 fibroblasts and in vivo to atherosclerosis-prone, hyperlipidaemic ApoE(-/-) mice. Levels of mediators of inflammation and development of atherosclerosis were compared between treatments. Exposure of human smooth muscle cells and murine NIH/3T3 fibroblasts in vitro to alpha IL-17A Affibody molecule markedly reduced IL6 and CXCL1 release in supernatants compared with sham exposure. Treatment of ApoE(-/-) mice with alpha IL-17A Affibody molecule significantly reduced plasma protein levels of CXCL1, CCL2, CCL3, HGF, PDGFB, MAP2K6, QDPR, and splenocyte mRNA levels of Ccxl1, Il6, and Ccl20 compared with sham exposure. There was no significant difference in atherosclerosis burden between the groups. In conclusion, administration of alpha IL17A Affibody molecule reduced levels of pro-inflammatory mediators and attenuated inflammation in ApoE(-/-) mice.
|
|
| 4. |
- Padinhare, Harikesh, et al.
(författare)
-
Ion-tunable antiambipolarity in mixed ion-electron conducting polymers enables biorealistic organic electrochemical neurons
- 2023
-
Ingår i: Nature Materials. - : NATURE PORTFOLIO. - 1476-1122 .- 1476-4660. ; 22, s. 242-248
-
Tidskriftsartikel (refereegranskat)abstract
- Biointegrated neuromorphic hardware holds promise for new protocols to record/regulate signalling in biological systems. Making such artificial neural circuits successful requires minimal device/circuit complexity and ion-based operating mechanisms akin to those found in biology. Artificial spiking neurons, based on silicon-based complementary metal-oxide semiconductors or negative differential resistance device circuits, can emulate several neural features but are complicated to fabricate, not biocompatible and lack ion-/chemical-based modulation features. Here we report a biorealistic conductance-based organic electrochemical neuron (c-OECN) using a mixed ion-electron conducting ladder-type polymer with stable ion-tunable antiambipolarity. The latter is used to emulate the activation/inactivation of sodium channels and delayed activation of potassium channels of biological neurons. These c-OECNs can spike at bioplausible frequencies nearing 100 Hz, emulate most critical biological neural features, demonstrate stochastic spiking and enable neurotransmitter-/amino acid-/ion-based spiking modulation, which is then used to stimulate biological nerves in vivo. These combined features are impossible to achieve using previous technologies.
|
|
| 5. |
- Söderström, Leif, et al.
(författare)
-
Increased carotid artery lesion inflammation upon treatment with the CD137 agonistic antibody 2A
- 2017
-
Ingår i: Circulation Journal. - 1346-9843. ; 81:12, s. 1945-1952
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Increased inflammatory activity destabilizes the atherosclerotic lesion and may lead to atherothrombosis and symptomatic cardiovascular disease. Co-stimulatory molecules, such as CD137, are key regulators of inflammation, and CD137 activity regulates inflammation in experimental atherosclerosis. Here, we hypothesized that CD137 activation promotes carotid artery inflammation and atherothrombosis. Methods and Results: In a model of inducible atherothrombosis with surgical ligation of the right carotid artery and a subsequent placement of a polyethene cuff, elevated levels of CD137 and CD137 ligand mRNA in atherothrombotic vs. non-atherothrombotic murine carotid lesions was observed. Mice treated with the CD137 agonistic antibody 2A showed signs of increased inflammation in the aorta and a higher proportion of CD8+ T cells in spleen and blood. In carotid lesions of 2A-treated mice, significantly higher counts of CD8+ and major histocompatibility (MHC)-class II molecule I-Ab+ cells were observed. Treatment with the CD137 agonistic antibody 2A did not significantly affect the atherothrombosis frequency in 16-week-old mice in this model. Conclusions: Levels of CD137 and CD137 ligand mRNA were higher in advanced atherosclerotic disease compared to control vessels, and treatment with the CD137 agonistic antibody 2A, in a murine model for inducible atherothrombosis promoted vascular inflammation, but had no significant effect on atherothrombosis frequency at this early disease stage.
|
|
| 6. |
- Caravaca, April S
(författare)
-
Neural control of inflammation
- 2021
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Pioneering research on neural control of inflammation has paved the way for new and exciting developments in the growing field of bioelectronic medicine. In the past couple of decades, pre-clinical research on the role of the vagus nerve in inflammation and immunity has brought electrical stimulation of select nerves into clinical trials for the treatment of chronic inflammatory diseases. Bioelectronic medicine continues to evolve and address challenges in optimizing interfaces and stimulation configurations for activation of specific neural circuits, and deciphering nerve signals that regulate inflammation and immunity with the goal of targeting specific nerve fibers for treatment of excessive inflammation. Ongoing basic, preclinical research strives to provide the insight necessary to develop therapeutic vagus nerve stimulation to mitigate inflammation in disease. Inflammation is normally a protective process that defends from microbial invasion and promotes healing, provided that it is adequately resolved in a timely manner. Dysregulation of resolving mechanisms can result in chronic inflammation and thus, a better understanding of the mechanisms that regulate inflammation is important for improving diagnosis, prevention, and treatment of chronic diseases. Discoveries over three decades show that the central and peripheral nervous systems along with the immune system work together to regulate inflammation. The vagus nerve bridges communication between the central and peripheral nervous systems and other tissues, regulates homeostasis, and serves an immunoregulatory function. Work delineating vagus nerve-mediated regulation of inflammation in experimental models of disease has led to important breakthroughs toward enabling treatment methods using electronic interfaces and devices that activate homeostatic reflexes that regulate the immune system. Considering the speed of action potentials and the anatomical specificity of neurons, activation of nerves that regulate immune cell function and activity, potentially provides an anatomically and temporally precise method to deliver therapeutic interventions in excessive inflammation. Clinical trials aimed at investigating neural control of chronic inflammatory responses in conditions such as inflammatory bowel disease and rheumatoid arthritis have been launched and data is encouraging, however, not yet fully conclusive. Together, these studies show the potential that neural control of inflammation works as a strategy to control excessive inflammation. Accordingly, additional studies with improved design in terms of randomization and controls are needed to evaluate targeted neural stimulation for regulation of the molecular and cellular mechanisms that underlie regulation of inflammation and its resolution. The work in this thesis sets forth to understand neural control mechanisms of inflammation by establishing methods and technology to study mechanisms of neural regulation of excessive inflammation in experimental models. In Study I, we found that a minute-long electrical vagus nerve stimulation impacts the cytokine response to inflammatory stimuli for two days. Study II establishes an effective method for vagus nerve stimulation for studies of experimental inflammation. Study III provides evidence that the vagus nerve accelerates the active resolution phase of inflammation through a cholinergic mechanism that requires release of pro-resolving mediators. Because available methods for vagus nerve stimulation are not suitable for longterm experiments in mice, the understanding of mechanisms of vagus nerve regulation of inflammation in chronic diseases is yet incomplete. In Study IV, we developed technology that attempts to address this methodological shortcoming and enable studies of vagus nerve stimulation in genetic mouse models of chronic inflammatory diseases.
|
|
