Early brain neuroinflammatory and metabolic changes identified by dual tracer microPET imaging in mice with acute liver injury.

Background: Acute liver injury (ALI) that progresses into acute liver failure (ALF) is a life-threatening condition with an increasing incidence and associated costs. Acetaminophen (N-acetyl-p-aminophenol, APAP) overdosing is among the leading causes of ALI and ALF in the Northern Hemisphere. Brain dysfunction defined as is one of the main diagnostic criteria for ALF.

Cholinergic Stimulation Exerts Cardioprotective Effects and Alleviates Renal Inflammatory Responses after Acute Myocardial Infarction in Spontaneous Hypertensive Rats (SHRs).

Background: In this investigation, we explored the effects of pharmacological cholinergic stimulation on cardiac function and renal inflammation following acute myocardial infarction (AMI) in spontaneously hypertensive rats (SHRs).

Methods: Adult male SHRs were randomized into three experimental groups: sham-operated; AMI + Veh (infarcted, treated with vehicle); and AMI + PY (infarcted, treated with the cholinesterase inhibitor, pyridostigmine bromide (PY)-40 mg/kg, once daily for seven days). Rats were euthanized 7 or 30 days post-surgery.

Electrical stimulation of the dorsal motor nucleus of the vagus in male mice can regulate inflammation without affecting the heart rate.

Background: The vagus nerve plays an important role in neuroimmune interactions and in the regulation of inflammation. A major source of efferent vagus nerve fibers that contribute to the regulation of inflammation is the brainstem dorsal motor nucleus of the vagus (DMN), as recently shown using optogenetics. In contrast to optogenetics, electrical neuromodulation has broad therapeutic implications.

Cholinergic signaling via the α7 nicotinic acetylcholine receptor regulates the migration of monocyte-derived macrophages during acute inflammation.

Background: The involvement of the autonomic nervous system in the regulation of inflammation is an emerging concept with significant potential for clinical applications. Recent studies demonstrate that stimulating the vagus nerve activates the cholinergic anti-inflammatory pathway that inhibits pro-inflammatory cytokines and controls inflammation. The α7 nicotinic acetylcholine receptor (α7nAChR) on macrophages plays a key role in mediating cholinergic anti-inflammatory effects through a downstream intracellular mechanism involving inhibition of NF-κB signaling, which results in suppression of pro-inflammatory cytokine production.

Galantamine ameliorates experimental pancreatitis.

Background: Acute pancreatitis is a common and serious inflammatory condition currently lacking disease modifying therapy. The cholinergic anti-inflammatory pathway (CAP) is a potent protective anti-inflammatory response activated by vagus nerve-dependent α7 nicotinic acetylcholine receptor (α7nAChR) signaling using splenic CD4 T cells as an intermediate. Activating the CAP ameliorates experimental acute pancreatitis.

Voltammetry in the spleen assesses real-time immunomodulatory norepinephrine release elicited by autonomic neurostimulation.

Background: The noradrenergic innervation of the spleen is implicated in the autonomic control of inflammation and has been the target of neurostimulation therapies for inflammatory diseases. However, there is no real-time marker of its successful activation, which hinders the development of anti-inflammatory neurostimulation therapies and mechanistic studies in anti-inflammatory neural circuits.

Methods: In mice, we performed fast-scan cyclic voltammetry (FSCV) in the spleen during intravenous injections of norepinephrine (NE), and during stimulation of the vagus, splanchnic, or splenic nerves.

Increased plasma lipopolysaccharide-binding protein and altered inflammatory mediators in overweight women suggest a state of subclinical endotoxemia.

Chronic low-grade inflammation has been recognized as an underlying event linking obesity to cardiovascular disease (CVD). However, inflammatory alterations in individuals who are overweight remain understudied. To provide insight, we determined the levels of key circulating biomarkers of endotoxemia and inflammation, including lipopolysaccharide-binding protein (LBP), CRP, IL-6, leptin, and adiponectin in adult female subjects (n = 20) who were lean or overweight and had high cholesterol and/or high blood pressure - two important conventional risk factors for CVD.

Increased plasma lipopolysaccharide-binding protein and altered inflammatory mediators in overweight women suggest a state of subclinical endotoxemia.

Chronic low-grade inflammation has been recognized as an underlying event linking obesity to cardiovascular disease (CVD). However, inflammatory alterations in individuals who are overweight remain understudied. To provide insight, we determined the levels of key circulating biomarkers of endotoxemia and inflammation, including lipopolysaccharide-binding protein (LBP), CRP, IL-6, leptin, and adiponectin in adult female subjects (n=40) who were lean or overweight and had high cholesterol and/or high blood pressure - two important conventional risk factors for CVD.

Electrical stimulation of the dorsal motor nucleus of the vagus regulates inflammation without affecting the heart rate.

Background: The vagus nerve plays an important role in neuroimmune interactions and in the regulation of inflammation. A major source of efferent vagus nerve fibers that contribute to the regulation of inflammation is the brainstem dorsal motor nucleus of the vagus (DMN) as recently shown using optogenetics. In contrast to optogenetics, electrical neuromodulation has broad therapeutic implications, but the anti-inflammatory efficacy of electrical DMN stimulation (eDMNS) was not previously investigated.

Optogenetic stimulation of the brainstem dorsal motor nucleus ameliorates acute pancreatitis.

Introduction: Inflammation is an inherently self-amplifying process, resulting in progressive tissue damage when unresolved. A brake on this positive feedback system is provided by the nervous system which has evolved to detect inflammatory signals and respond by activating anti-inflammatory processes, including the cholinergic anti-inflammatory pathway mediated by the vagus nerve. Acute pancreatitis, a common and serious condition without effective therapy, develops when acinar cell injury activates intrapancreatic inflammation.

Brief periods of transcutaneous auricular vagus nerve stimulation improve autonomic balance and alter circulating monocytes and endothelial cells in patients with metabolic syndrome: a pilot study.

Background: There is emerging evidence that the nervous system regulates immune and metabolic alterations mediating Metabolic syndrome (MetS) pathogenesis via the vagus nerve. This study evaluated the effects of transcutaneous auricular vagus nerve stimulation (TAVNS) on key cardiovascular and inflammatory components of MetS.

Methods: We conducted an open label, randomized (2:1), two-arm, parallel-group controlled trial in MetS patients.

Transient Receptor Potential Ankyrin-1-expressing vagus nerve fibers mediate IL-1β induced hypothermia and reflex anti-inflammatory responses.

Background: Inflammation, the physiological response to infection and injury, is coordinated by the immune and nervous systems. Interleukin-1β (IL-1β) and other cytokines produced during inflammatory responses activate sensory neurons (nociceptors) to mediate the onset of pain, sickness behavior, and metabolic responses. Although nociceptors expressing Transient Receptor Potential Ankyrin-1 (TRPA1) can initiate inflammation, comparatively little is known about the role of TRPA1 nociceptors in the physiological responses to specific cytokines.

Galantamine attenuates autoinflammation in a mouse model of familial mediterranean fever.

Background: Autoinflammatory diseases, a diverse group of inherited conditions characterized by excessive innate immune activation, have limited therapeutic options. Neuroimmune circuits of the inflammatory reflex control innate immune overactivation and can be stimulated to treat disease using the acetylcholinesterase inhibitor galantamine.

Methods: We tested the efficacy of galantamine in a rodent model of the prototypical autoinflammatory disease familial Mediterranean fever (FMF).

A dual tracer [C]PBR28 and [F]FDG microPET evaluation of neuroinflammation and brain energy metabolism in murine endotoxemia.

Background: Brain metabolic alterations and neuroinflammation have been reported in several peripheral inflammatory conditions and present significant potential for targeting with new diagnostic approaches and treatments. However, non-invasive evaluation of these alterations remains a challenge.

Methods: Here, we studied the utility of a micro positron emission tomography (microPET) dual tracer ([C]PBR28 - for microglial activation and [F]FDG for energy metabolism) approach to assess brain dysfunction, including neuroinflammation in murine endotoxemia.

Bioelectronic medicine: Preclinical insights and clinical advances.

The nervous system maintains homeostasis and health. Homeostatic disruptions underlying the pathobiology of many diseases can be controlled by bioelectronic devices targeting CNS and peripheral neural circuits. New insights into the regulatory functions of the nervous system and technological developments in bioelectronics drive progress in the emerging field of bioelectronic medicine.

Famotidine activates the vagus nerve inflammatory reflex to attenuate cytokine storm.

Background: Severe COVID-19 is characterized by pro-inflammatory cytokine release syndrome (cytokine storm) which causes high morbidity and mortality. Recent observational and clinical studies suggest famotidine, a histamine 2 receptor (H2R) antagonist widely used to treat gastroesophageal reflux disease, attenuates the clinical course of COVID-19. Because evidence is lacking for a direct antiviral activity of famotidine, a proposed mechanism of action is blocking the effects of histamine released by mast cells.

Famotidine activates the vagus nerve inflammatory reflex to attenuate cytokine storm.

Severe COVID-19 is characterized by pro-inflammatory cytokine release syndrome (cytokine storm) which causes high morbidity and mortality. Recent observational and clinical studies suggest famotidine, a histamine 2 receptor (H2R) antagonist widely used to treat gastroesophageal reflux disease , attenuates the clinical course of COVID-19. Because evidence is lacking for a direct antiviral activity of famotidine, a proposed mechanism of action is blocking the effects of histamine released by mast cells.

Exploring the vagus nerve and the inflammatory reflex for therapeutic benefit in chronic spinal cord injury.

Purpose Of Review: To describe features and implications of chronic systemic inflammation in individuals with spinal cord injury (SCI) and to summarize the growing therapeutic possibilities to explore the vagus nerve-mediated inflammatory reflex in this context.

Recent Findings: The discovery of the inflammatory reflex provides a rationale to explore neuromodulation modalities, that is, electrical vagus nerve stimulation and pharmacological cholinergic modalities to regulate inflammation after SCI.

Summary: Inflammation in individuals with SCI may negatively impact functional recovery and medical consequences after SCI.

A fully implantable wireless bidirectional neuromodulation system for mice.

Novel research in the field of bioelectronic medicine requires neuromodulation systems that pair high-performance neurostimulation and bio-signal acquisition hardware with advanced signal processing and control algorithms. Although mice are the most commonly used animal in medical research, the size, weight, and power requirements of such bioelectronic systems either preclude use in mice or impose significant constraints on experimental design. Here, a fully-implantable recording and stimulation neuromodulation system suitable for use in mice is presented, measuring 2.

Peripheral nerve stimulation and immunity: the expanding opportunities for providing mechanistic insight and therapeutic intervention.

Pre-clinical research advances our understanding of the vagus nerve-mediated regulation of immunity and clinical trials successfully utilize electrical vagus nerve stimulation in the treatment of patients with inflammatory disorders. This symbiotic relationship between pre-clinical and clinical research exploring the vagus nerve-based 'inflammatory reflex' has substantially contributed to establishing the field of bioelectronic medicine. Recent studies identify a crosstalk between the vagus nerve and other neural circuitries in controlling inflammation and delineate new neural immunoregulatory pathways.

HMGB1 released from nociceptors mediates inflammation.

Inflammation, the body's primary defensive response system to injury and infection, is triggered by molecular signatures of microbes and tissue injury. These molecules also stimulate specialized sensory neurons, termed nociceptors. Activation of nociceptors mediates inflammation through antidromic release of neuropeptides into infected or injured tissue, producing neurogenic inflammation.

The Fourth Bioelectronic Medicine Summit "Technology Targeting Molecular Mechanisms": current progress, challenges, and charting the future.

There is a broad and growing interest in Bioelectronic Medicine, a dynamic field that continues to generate new approaches in disease treatment. The fourth bioelectronic medicine summit "Technology targeting molecular mechanisms" took place on September 23 and 24, 2020. This virtual meeting was hosted by the Feinstein Institutes for Medical Research, Northwell Health.