Manipulation of the inflammatory reflex as a therapeutic strategy

Kelly, Mark; Breathnach, Caitríona; Tracey, Kevin J.; Donnelly, Seamas C.

doi:10.1016/j.xcrm.2022.100696

Cited by 52 publications

(50 citation statements)

References 144 publications

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“… Non-invasive brain stimulation (NIBS) techniques for the treatment of individual pathomechanisms of Long-COVID-related fatigue (LCOF). Transcutaneous auricular vagus nerve stimulation (taVNS) has been shown to have anti-inflammatory effects through its efferent projections, the so-called cholinergic anti-inflammatory pathway ( 1 81 ), and could have a stabilizing effect on the dysregulated immune-system after an acute COVID-19 infection that could lead to LCOF. First positive effects support this hypothesis and show a reduction of mental fatigue in people with LCOF after repetitive taVNS sessions ( 2 16 ).…”

Section: Non-invasive Brain Stimulation As a Therapeutic Option For F...mentioning

confidence: 99%

“…In taVNS, the auricular branch of the vagus nerve is stimulated that bilaterally innervates the human ear, resulting in a specific modulation of various brain structures connected with the vagus nerve ( 16 , 120 ). The vagus nerve is able to modulate inflammatory responses through its efferent projections, the so-called cholinergic anti-inflammatory pathway (CAP; 81 , 121 ), and activation of the CAP attenuates neuroinflammation ( 122 , 123 ). Accordingly, electrical stimulation of the vagus nerve has been shown to be effective in reducing inflammatory responses in rheumatoid arthritis ( 124 , 125 ) and inflammatory bowel disease (IBD; 126 ).…”

Section: Non-invasive Brain Stimulation As a Therapeutic Option For F...mentioning

confidence: 99%

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The therapeutic potential of non-invasive brain stimulation for the treatment of Long-COVID-related cognitive fatigue

et al. 2023

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Following an acute COVID-19 infection, a large number of patients experience persisting symptoms for more than four weeks, a condition now classified as Long-COVID syndrome. Interestingly, the likelihood and severity of Long-COVID symptoms do not appear to be related to the severity of the acute COVID-19 infection. Fatigue is amongst the most common and debilitating symptoms of Long-COVID. Other symptomes include dyspnoea, chest pain, olfactory disturbances, and brain fog. Fatigue is also frequently reported in many other neurological diseases, affecting a broad range of everyday activities. However, despite its clinical significance, limited progress has been made in understanding its causes and developing effective treatment options. Non-invasive brain stimulation (NIBS) methods offer the unique opportunity to modulate fatigue-related maladaptive neuronal activity. Recent data show promising results of NIBS applications over frontoparietal regions to reduce fatigue symptoms. In this current paper, we review recent data on Long-COVID and Long-COVID-related fatigue (LCOF), with a special focus on cognitive fatigue. We further present widely used NIBS methods, such as transcranial direct current stimulation, transcranial alternating current stimulation, and transcutaneous vagus nerve stimulation and propose their use as possible therapeutic strategies to alleviate individual pathomechanisms of LCOF. Since NIBS methods are safe and well-tolerated, they have the potential to enhance the quality of life in a broad group of patients.

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Section: Non-invasive Brain Stimulation As a Therapeutic Option For F...mentioning

confidence: 99%

Section: Non-invasive Brain Stimulation As a Therapeutic Option For F...mentioning

confidence: 99%

The therapeutic potential of non-invasive brain stimulation for the treatment of Long-COVID-related cognitive fatigue

et al. 2023

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“… Direct sympathetic modulation of leukocytes in the spleen has become a topic of intense interest in recent years due to the discovery of the cholinergic anti-inflammatory pathway (CAP), which provides a novel approach for activating anti-inflammatory mechanisms in the spleen (Falvey et al, 2022 , Hoover, 2017 , Kelly et al, 2022 , Pavlov and Tracey, 2022 ). This system is unique in having two unexpected cholinergic elements: 1) preganglionic vagal cholinergic input to sympathetic neurons in the celiac/superior mesenteric ganglia and 2) cholinergic T cells, which have a crucial role in non-neuronal release of acetylcholine (ACh) in the spleen.…”

Section: Introductionmentioning

confidence: 99%

Sympathetic innervation of human and porcine spleens: implications for between species variation in function

et al. 2022

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Background The vagus nerve affects innate immune responses by activating spleen-projecting sympathetic neurons, which modulate leukocyte function. Recent basic and clinical research investigating vagus nerve stimulation to engage the cholinergic anti-inflammatory pathway (CAP) has shown promising therapeutic results for a variety of inflammatory diseases. Abundant sympathetic innervation occurs in rodent spleens, and use of these species has dominated mechanistic research investigating the CAP. However, previous neuroanatomical studies of human spleen found a more restricted pattern of innervation compared to rodents. Therefore, our primary goal was to establish the full extent of sympathetic innervation of human spleens using donor tissue with the shortest procurement to fixation time. Parallel studies of porcine spleen, a large animal model, were performed as a positive control and for comparison. Methods Human and porcine spleen tissue were fixed immediately after harvest and prepared for immunohistochemistry. Human heart and porcine spleen were stained in conjunction as positive controls. Several immunohistochemical protocols were compared for best results. Tissue was stained for tyrosine hydroxylase (TH), a noradrenergic marker, using VIP purple chromogen. Consecutive tissue slices were stained for neuropeptide Y (NPY), which often co-localizes with TH, or double-labelled for TH and CD3, a T cell marker. High-magnification images and full scans of the tissue were obtained and analyzed for qualitative differences between species. Results TH had dominant perivascular localization in human spleen, with negligible innervation of parenchyma, but such nerves were abundant throughout ventricular myocardium. In marked contrast, noradrenergic innervation was abundant in all regions of porcine spleen, with red pulp having more nerves than white pulp. NPY stain results were consistent with this pattern. In human spleen, noradrenergic nerves only ran close to T cells at the boundary of the periarterial lymphatic sheath and arteries. In porcine spleen, noradrenergic nerves were closely associated with T cells in both white and red pulp as well as other leukocytes in red pulp. Conclusion Sympathetic innervation of the spleen varies between species in both distribution and abundance, with humans and pigs being at opposite extremes. This has important implications for sympathetic regulation of neuroimmune interactions in the spleen of different species and focused targeting of the CAP in humans.

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“…Finally, maintaining endothelial integrity via metabolic protection reduces fluid losses in the interstitium through capillary leakage. It is possible that the reduction in interleukin 6 at the end of the experiment in the Elamipretide group is the result of inflammation downregulation, which could be mediated by activation of cholinergic anti-inflammatory reflex pathways [60][61][62] or a direct effect of Elamipretide on interleukin 6 expression. Other studies of REBOA in pigs have demonstrated an elevation in serum interleukin 6 concentration [63][64][65] , which correlated with injury severity in trauma patients 66 .…”

Section: Discussionmentioning

confidence: 99%

Elamipretide mitigates ischemia-reperfusion injury in a swine model of hemorrhagic shock

Patel

Johnson

Vapniarsky

et al. 2023

Sci Rep

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Abstractischemia-reperfusion injury (IRI) after hemorrhage is potentiated by aortic occlusion or resuscitative endovascular balloon occlusion of the aorta (REBOA). Given the central role of mitochondrial injury in shock, we hypothesized that Elamipretide, a peptide that protects mitochondria, would mitigate IRI after hemorrhagic shock and REBOA. Twelve pigs were subjected to hemorrhagic shock and 45 min of REBOA. After 25 min of REBOA, animals received either saline or Elamipretide. Animals were transfused with autologous blood during balloon deflation, and pigs were resuscitated with isotonic crystalloids and norepinephrine for 4.25 h. Elamipretide-treated animals required less crystalloids than the controls (62.5 [50–90] and 25 [5–30] mL/kg, respectively), but similar amounts of norepinephrine (24.7 [8.6–39.3] and 9.7 [2.1–12.5] mcg/kg, respectively). Treatment animals had a significant reduction in serum creatinine (control: 2.7 [2.6–2.8]; Elamipretide: 2.4 [2.4–2.5] mg/dL; p = 0.04), troponin (control: 3.20 [2.14–5.47] ng/mL, Elamipretide: 0.22 [0.1–1.91] ng/mL; p = 0.03), and interleukin-6 concentrations at the end of the study. There were no differences in final plasma lactate concentration. Elamipretide reduced fluid requirements and protected the kidney and heart after profound IRI. Further understanding the subcellular consequences of REBOA and mitochondrial rescue will open new therapeutic avenues for patients suffering from IRI after hemorrhage.

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Manipulation of the inflammatory reflex as a therapeutic strategy

Cited by 52 publications

References 144 publications

The therapeutic potential of non-invasive brain stimulation for the treatment of Long-COVID-related cognitive fatigue

The therapeutic potential of non-invasive brain stimulation for the treatment of Long-COVID-related cognitive fatigue

Sympathetic innervation of human and porcine spleens: implications for between species variation in function

Elamipretide mitigates ischemia-reperfusion injury in a swine model of hemorrhagic shock

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