Effect of Macrophage Expressed α7 Nicotinic Acetylcholine Receptor (α7nAChR) on Migration of Macrophages During Inflammation

Sepsis is a life-threatening condition characterized by overwhelming inflammation, resulting in organ system damage, leading to a high mortality rate. Care in the clinical setting is supportive, and there are no approved sepsis-specific treatments. In septic mice, activation of the cholinergic anti-inflammatory pathway decreases cytokine secretion by leukocytes and improves survival. The cholinergic anti-inflammatory pathway is a reflex of the parasympathetic nervous system, converging on the α7 nicotinic acetylcholine (α7nAChR) at the surface of macrophages. Signaling through the receptor blocks NF-kB activation, thus cytokine secretion. Receptor activation has other effects on macrophages, including modulating their migration to target tissues during inflammation. The goal of this study was to describe the contribution of α7nAChR to macrophage migration during sepsis, using both activation with agonist PNU-282987 and α7nAChR-/- mice. We showed that α7nAChR-deficiency impedes migration to inflamed tissues, and that α7nAChR activation promotes macrophage accumulation in tissues, an effect mediated through altered expression of integrin aMb2

Cellular And Molecular Insight Into Autonomic Function And Dysfunction

The autonomic nervous system (ANS) controls several vital functions of the body, especially the autonomic regulation of respiratory and cardiovascular systems. Dysfunction of either can be life-threatening. Some of cellular and molecular mechanisms underlying the respiratory and cardiovascular dysfunction is more critical and general. The demonstration of such general processes not only may help the understanding of etiology and pathophysiology of the diseases, but also suggests potential therapeutic modalities for the diseases. Severe breathing disorders including high apnea rate and breathing irregularity are found in Rett syndrome (RTT). In a novel rat model of RTT, we compared rat physical condition and behaviors with traditional mouse models of RTT. We found that the novel Mecp2−/Y rat model as an alternative RTT model recapitulated numerous RTT-like symptoms. To uncover the neuronal mechanisms underlying the RTT respiratory disorders, we performed in vivo recording from brainstem neurons in ventral respiratory column (VRC). Excessive activity of both inspiratory and expiratory neurons as well as ectopic discharge of phrenic nerve were detected in null rats. Such defects were likely caused by hyperexcitability of respiratory neurons due to inadequate synaptic inhibition necessary for phase switching. Then we took the GABAergic intervention to hyperexcitability of respiratory neurons, and successfully corrected the defects in neuronal firing patterns as well as the RTT breathing phenotypes. Similarly, change of cellular excitability was also observed in diabetic vascular complications. A critical player for the membrane excitability of vascular smooth muscle cells (VSMCs) is the KATP channel that is strongly suppressed by methylglyoxal (MGO) known to be overly produced with persistent hyperglycemia. The elevated level of microRNA (miR)-9a-3p contributed to the down-regulation of vascular KATP channels. miR-9a-3p inhibition using antisense oligonuecleotides corrected the dysfunction of KATP channels. Since VSMC membrane excitability plays an important role in vascular tone regulation, we generated a new strain of transgenic Tagln-ChR mouse model and demonstrate an alterative to manipulate VSMC membrane excitability and vascular tone using optogenetic approaches. Thus several molecular targets in cardiorespiratory system have been demonstrated underlying membrane excitability and the developments of several disease conditions in this thesis study

Device use in chronic pain

Interventional treatments are of vital importance in patients with chronic pain who do not respond to conventional drug therapy. Neuraxial drug delivery systems can be used for intractable cancer-induced pain. These devices, which are frequently used today and have advanced technological equipment, provide effective analgesia to patients. Another technique preferred especially in neuropathic pain is implantable devices that provide neurostimulation. Spinal cord stimulation (SCC) and Dorsal root ganglion stimulation (DRG-S) are the most commonly used. This article describes frequently used devices that provide neurostimulation and nöraxial drug delivery device are mentioned, and their working principles, application techniques, and technological features. Pubmed and Google scholar were used to search the articles, and Google was used for device images and manufacturer information

Role of Neuronal Nitric Oxide Synthase on Cardiovascular Functions in Physiological and Pathophysiological States

This review describes and summarizes the role of neuronal nitric oxide synthase (nNOS) on the central nervous system, particularly on brain regions such as the ventrolateral medulla (VLM) and the periaqueductal gray matter (PAG), and on blood vessels and the heart that are involved in the regulation and control of the cardiovascular system (CVS). Furthermore, we shall also review the functional aspects of nNOS during several physiological, pathophysiological, and clinical conditions such as exercise, pain, cerebral vascular accidents or stroke and hypertension. For example, during stroke, a cascade of molecular, neurochemical, and cellular changes occur that affect the nervous system as elicited by generation of free radicals and nitric oxide (NO) from vulnerable neurons, peroxide formation, superoxides, apoptosis, and the differential activation of three isoforms of nitric oxide synthases (NOSs), and can exert profound effects on the CVS. Neuronal NOS is one of the three isoforms of NOSs, the others being endothelial (eNOS) and inducible (iNOS) enzymes. Neuronal NOS is a critical homeostatic component of the CVS and plays an important role in regulation of different systems and disease process including nociception. The functional and physiological roles of NO and nNOS are described at the beginning of this review. We also elaborate the structure, gene, domain, and regulation of the nNOS protein. Both inhibitory and excitatory role of nNOS on the sympathetic autonomic nervous system (SANS) and parasympathetic autonomic nervous system (PANS) as mediated via different neurotransmitters/signal transduction processes will be explored, particularly its effects on the CVS. Because the VLM plays a crucial function in cardiovascular homeostatic mechanisms, the neuroanatomy and cardiovascular regulation of the VLM will be discussed in conjunction with the actions of nNOS. Thereafter, we shall discuss the up-to-date developments that are related to the interaction between nNOS and cardiovascular diseases such as hypertension and stroke. Finally, we shall focus on the role of nNOS, particularly within the PAG in cardiovascular regulation and neurotransmission during different types of pain stimulus. Overall, this review focuses on our current understanding of the nNOS protein, and provides further insights on how nNOS modulates, regulates, and controls cardiovascular function during both physiological activity such as exercise, and pathophysiological conditions such as stroke and hypertension

The Role of Neuroinflammation in Postoperative Cognitive Dysfunction: Moving From Hypothesis to Treatment

Postoperative cognitive dysfunction (POCD) is a common complication of the surgical experience and is common in the elderly and patients with preexisting neurocognitive disorders. Animal and human studies suggest that neuroinflammation from either surgery or anesthesia is a major contributor to the development of POCD. Moreover, a large and growing body of literature has focused on identifying potential risk factors for the development of POCD, as well as identifying candidate treatments based on the neuroinflammatory hypothesis. However, variability in animal models and clinical cohorts makes it difficult to interpret the results of such studies, and represents a barrier for the development of treatment options for POCD. Here, we present a broad topical review of the literature supporting the role of neuroinflammation in POCD. We provide an overview of the cellular and molecular mechanisms underlying the pathogenesis of POCD from pre-clinical and human studies. We offer a brief discussion of the ongoing debate on the root cause of POCD. We conclude with a list of current and hypothesized treatments for POCD, with a focus on recent and current human randomized clinical trials

Preclinical Animal Modeling in Medicine

The results of preclinical animal research have been successfully implemented in various medical and biological practices. The use of animals in medicine is based on significant anatomical, physiological, and molecular similarities between humans and animals. Particularly, mammals that have vast biological commonalities with humans represent not only a valuable model to explore the mechanisms of varied human diseases, but also to define new diagnostic and treatment strategies. This book covers broad but important aspects of animal modeling for scientific medicine as well as for translational systems and biological sciences. Alternative methods such as cell culture and in vitro experiments that do not require the sacrifice of an animal are encouraged for scientific and medical studies

Mapping and Modulating the Stomach-Brain Neuroaxis

The stomach and the brain interact closely with each other. Their interactions are central to digestive functions and the “gut feeling”. The neural pathways that mediate the stomach-brain interactions include the vagus nerve and the thoracic nerve. Through these nerves, the stomach can relay neural signals to a number of brain regions that span a central gastric network. This gastric network allows the brain to monitor and regulate gastric physiology and allows the stomach to influence emotion and cognition. Impairment of this gastric network may lead to both gastric and neurological disorders, e.g., anxiety, gastroparesis, functional dyspepsia, and obesity. However, the structural constituents and functional roles of the central gastric network remain unclear. In my dissertation research, I leveraged complementary techniques to characterize the central gastric network in rats across a wide range of scales and different gastric states. I used functional magnetic resonance imaging (fMRI) to map blood-oxygen-level-dependent (BOLD) activity synchronized with gastric electrical activity and to map brain activations induced by electrical stimulation applied to the vagus nerve or its afferent terminals on the stomach. I also used neurophysiology to characterize gastric neurons in the brainstem in response to gastric electrical stimulation. My results suggest that gastric neurons in the brainstem are selective to the orientation of gastric electrical stimulation. This electrical stimulation can also evoke neural activity beyond the brainstem and drive fast blood oxygenation level dependent (BOLD) activity in the central gastric network, primarily covering the cingulate cortex, somatosensory cortex, motor cortex, and insular cortex. Stimulating the vagus nerve – the primary neural pathway between the stomach and the brain, can evoke BOLD responses across widespread brain regions partially overlapped with the brain network evoked by gastric electrical stimulation. BOLD activity within the gastric network is also coupled to intrinsic gastric activity. Specifically, gastric slow waves are synchronized with the BOLD activity in the central gastric network. The synchronization manifests itself as the phase-coupling between BOLD activity and gastric slow waves as well as the correlation between BOLD activity and power fluctuations of gastric slow waves. This synchronization is primarily supported by the vagus nerve and varies across the postprandial and fasting states. My dissertation research contributes to the foundation of mapping and characterizing the central and peripheral mechanisms of gastric interoception and sheds new light on where and how to stimulate the peripheral nerves to modulate stomach-brain interactions.PHDBiomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/170007/1/jccao_1.pd

Obesity: Current and Potential Pharmacotherapeutics and Targets

Obesity is a global epidemic that contributes to a number of health complications including cardiovascular disease, type 2 diabetes, cancer and neuropsychiatric disorders. Pharmacotherapeutic strategies to treat obesity are urgently needed. Research over the past two decades has increased substantially our knowledge of central and peripheral mechanisms underlying homeostatic energy balance. Homeostatic mechanisms involve multiple components including neuronal circuits, some originating in hypothalamus and brain stem, as well as peripherally-derived satiety, hunger and adiposity signals that modulate neural activity and regulate eating behavior. Dysregulation of one or more of these homeostatic components results in obesity. Coincident with obesity, reward mechanisms that regulate hedonic aspects of food intake override the homeostatic regulation of eating. In addition to functional interactions between homeostatic and reward systems in the regulation of food intake, homeostatic signals have the ability to alter vulnerability to drug abuse. Regarding the treatment of obesity, pharmacological monotherapies primarily focus on a single protein target. FDA-approved monotherapy options include phentermine (Adipex-P®), orlistat (Xenical®), lorcaserin (Belviq®) and liraglutide (Saxenda®). However, monotherapies have limited efficacy, in part due to the recruitment of alternate and counter-regulatory pathways. Consequently, a multi-target approach may provide greater benefit. Recently, two combination products have been approved by the FDA to treat obesity, including phentermine/topiramate (Qsymia®) and naltrexone/bupropion (Contrave®). The current review provides an overview of homeostatic and reward mechanisms that regulate energy balance, potential therapeutic targets for obesity and current treatment options, including some candidate therapeutics in clinical development. Finally, challenges in anti-obesity drug development are discussed

Oleoylethanolamide in the gut-brain axis

Oleoylethanolamide (OEA), a PPAR-α agonist, is a mediator of satiety. After peripheral administration, OEA induces Fos expression and activation in areas of the CNS involved in the control of feeding behavior and energy homeostasis, such as the nucleus of the solitary tract (NST) and in the area postrema (AP) in the brainstem, the hypothalamic paraventricular (PVN), supraoptic (SON) and ventral tuberomammillary (vTMN) nuclei. Moreover, it is known to increase the noradrenergic trasmission in the NST and AP, by increasing the expression of the dopamine-β-hydroxylase (DBH). Visceral ascending fibers were hypothesized to mediate such effects, but recent findings demonstrate that abdominal vagal afferents are not necessary for the anorectic effect of OEA. In fact, OEA is able to decrease food intake both in rats that underwent a subdiaphragmatic vagal deafferentation (SDA), a surgical procedure that eliminates all abdominal vagal afferents but spares about 50% of the vagal efferents, and in SHAM controls. Thus, the aim of the present work was to better elucidate the role of abdominal vagal afferents in mediating OEA's effects on the CNS. To meet this aim, we subjected rats to SDA surgery, using SHAM rats as control. By using immunohistochemistry, Fos and DBH expression patterns were investigated in the NST, in the AP, and in the hypothalamus after OEA administration (10 mg kg -1). Consistently with the behavioral results, OEA increases Fos expression in the NST and in the AP. Moreover, in these nuclei, SDA did not cause any alteration of DBH expression. In the hypothalamus, in line with the behavioral results, OEA is able to increase Fos expression in the PVN and the vTMN, even though in the latter does not reach statistical significance. Overall, our findings indicate that vagal afferents are not strictly necessary for the satiety effect of OEA at both behavioral and neurochemical levels