Neuropeptides in sepsis: From brain pathology to systemic inflammation

Neuropeptides in sepsis: From brain pathology to systemic inflammation

Peptides 44 (2013) 135–138 Contents lists available at SciVerse ScienceDirect Peptides journal homepage: www.elsevier.com/locate/peptides Review N...

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Peptides 44 (2013) 135–138

Contents lists available at SciVerse ScienceDirect

Peptides journal homepage: www.elsevier.com/locate/peptides

Review

Neuropeptides in sepsis: From brain pathology to systemic inflammation Fabiano Pinheiro da Silva ∗ , Marcel Cerqueira César Machado, Irineu Tadeu Velasco Emergency Medicine Department, University of São Paulo, Brazil

a r t i c l e

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Article history: Received 25 February 2013 Received in revised form 27 March 2013 Accepted 27 March 2013 Available online xxx Keywords: Sepsis Encephalopathy Neuropeptides

a b s t r a c t Septic encephalopathy is frequently diagnosed in critically ill patients and in up to 70% of patients with severe systemic infection [19]. The syndrome is defined by diffuse cerebral dysfunction or structural abnormalities attributed to the effects of systemic infection, rather than a direct central nervous system cause. The clinical characteristics can range from mild delirium to deep coma, but patients are often medically sedated making the diagnosis difficult. Any manifestation, however, is specific and markers of disease are lacking [43]. Sepsis survivors present long term cognitive impairment, including alterations of memory, attention and concentration [10,54]. Here, we propose that neuropeptides may play a key role in septic encephalopathy, leading to a vicious circle characterized by brain disease and systemic inflammation. © 2013 Elsevier Inc. All rights reserved.

Contents 1. 2. 3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Neuropeptides in health and disease: focus on septic shock . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Nervous systems probably evolved in the common ancestor of cnidarians. Attempts to demonstrate fast transmitters in cnidarians, such as cathecolamines and other biogenic amines failed, with the exception of serotonin [56], putting in evidence that neuropeptides are the predominant neurotransmitter, playing a key role in the first nervous systems that emerged in evolution [20]. Neuropeptides exert their action by binding to specific G protein-coupled receptors. Many hundreds of receptors have been identified, but some receptors remain orphans. Activation results in an exchange of GDP for GTP and peptide signaling is then amplified by the induction of multiple intracellular pathways. Neuropeptides are found heterogeneously distributed throughout the brain, and can be expressed on cell bodies, dendrites and axon terminals. Perhaps most neurons in the brain contain some neuropeptide or other neuromodulator in addition to fast-acting amino acid neurotransmitters [57]. Actually, neuropeptides modulate GABA and glutamate synaptic release and activity at post- or

∗ Corresponding author. Tel.: +55 1138879174. E-mail address: [email protected] (F. Pinheiro da Silva). 0196-9781/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.peptides.2013.03.029

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presynaptic sites. Many neurons contain multiple neuropeptides, which possess similar or opposing activities. Neuropeptides possess a wide spectrum of function from neurohormones and neurotransmitters to growth factors and inflammatory mediators [25]. Central and peripheral effects are often quite distinct. An increasing number of heterodimers, moreover, are being described between neuropeptide and more classical receptors [24,27]. The number of cells producing a neuropeptide can be very low and restricted locally, because the synaptic concentration of a neuropeptide is several orders of magnitude lower than a classical neurotransmitter [25]. The actions of many peptides are mediated via multiple receptor subtypes localized in different brain regions. Neuropeptides have been implicated in the control of a variety of cellular processes, including thermoregulation, food and water consumption, sex, sleep, locomotion, learning, memory, responses to stress and pain, suggesting that they may participate in major neuropsychiatric illnesses, including septic encephalopathy (Fig. 1). 2. Neuropeptides in health and disease: focus on septic shock Tachykinins play a critical neuroendocrine regulation of reproduction by acting at the hypothalamic, pituitary and gonadal levels.

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Fig. 1. Pleiotropic effects of neuropeptides in sepsis.

Those that have been more extensively studied are substance P, neurokinin A (NKA) and neurokinin B (NKB) [29], which act on three different types of G protein-coupled receptors named NK1, NK2 and NK3. Substance P is an 11 amino acid neuropeptide, which activates cells to produce cytokines, reactive oxygen species, other inflammatory mediators and induce pain. Additionally, substance P promotes lymphocytes proliferation, immunoglobulin production and chemotaxis [1]. Substance P and the NK1 receptor are widely distributed in the brain and are specifically found in regions that regulate emotion. Substance P has been associated with the regulation of mood disorders, anxiety, stress, reinforcement, neurogenesis, respiratory rhythm, neurotoxicity, nausea, pain and nociception. Substance P and other sensory neuropeptides can be released from the peripheral terminals of sensory nerve fibers in the skin, muscle and joints. It is proposed that this release is involved in neurogenic inflammation, which is a local inflammatory response to certain types of infection or injury. Substance P also has effects as a potent vasodilator. Substance P-induced vasodilatation is dependent on nitric oxide release. In recent years, the role of substance P in the regulation of inflammatory conditions in LPS and CLP-induced sepsis, as well

as in human sepsis, has been suggested [4,5,35,65]. Treatment with SR140333, a neurokinin-1 receptor antagonist, for example, reduced myeloperoxidase activity, leukocyte infiltration, lung levels of MCP-1 and MIP-2, as well as IL-6, IL-1␤, ICAM-1 and E- and P-selectins in septic rats [22]. Sleep disorders in the Intensive Care seem to lead to the development of delirium and increased mortality [7,14]. Sleep disturbances impair the immune system [39], regenerative processes, memory and cognitive functions [26,48,58]. Although the peripheral response plays a pivotal role, the brain controls overall metabolic tone and is crucial when the peripheral systems cannot compensate [34]. In the arcuate nucleus, for example, neurons that produce pro-opiomelanocortin and those that contain Agouti-related protein (AgRP) and neuropeptide Y abound. Pro-opiomelanocortin is processed to produce ␣-melanocyte stimulating factor (␣-MSH), an agonist for melanocortin-3 (MC3R) and melanocortin-4 (MC4R) receptors, which promote activity, energy expenditure and suppress food intake. AgRP is an inverse agonist for MC3R and MC4R and neuropeptide Y induces negative signaling, suppressing energy use and promoting food intake [59,63]. MC3R and MC4R are expressed in the hypothalamus. Whether the metabolic effects of melanocortins are mediated

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mainly through neuroendocrine pathways, the autonomic nervous system or both remains to be determined [34]. ␣-MSH inhibits multiple forms of inflammation and ameliorates sepsis-induced acute kidney injury and overall inflammation in experimental models [9,12]. Interestingly, experiments in rats showed that the effects of ␣-MSH are more prominent in the oldest group than in middle-aged and young groups [41]. Septic encephalopathy may be facilitated or even manifest as disturbances in the circadian rhythm or alterations in other vegetative functions, such as feeding behavior [31] and energy homeostasis [28,36]. Numerous factors can link the action of neuropeptides to the pathophysiology of septic shock, including local generation of pro-inflammatory mediators, impaired microcirculation, imbalance of neurotransmitters and impact on peripheral organ failure. Changes in cerebral blood flow, release of inflammatory molecules and metabolic alterations contribute to neuronal dysfunction and cell death [49]. Orexin A and B were identified in 1998. Orexin A is a 33-amino acid peptide and its primary structure is completely conserved among several mammalian species. Orexin B is a 28-amino acid peptide that is 46% identical to orexin A [55]. Orexin receptor-1 (OX1R) and orexin receptor-2 (OX2R) show 64% amino acid identity. OX1R has greater affinity for orexin A, while OX2R has similar affinity for both orexin A and B. Orexin deficiency causes narcolepsy in humans, dogs and rodents [47]. In addition, orexin is a critical regulator of feeding behavior, energy homeostasis and reward systems. Orexin is produced at the perifornical area and the lateral and posterior hypothalamic area. These cells diffuse to the entire neuroaxis, excluding the cerebellum [13]. Many orexin neurons express vesicular glutamate transporters. In contrast, orexin neurons are not GABAergic [45]. Orexin neurons also receive innervation from neuropeptide Y, agouti-related peptide and ␣-MSH fibers. Oxytocin is a nine amino acid neurohypophyseal hormone synthesized in the paraventricular and supraoptic nuclei of the hypothalamus. Besides its role in lactation and labor, oxytocin also contributes to feeding, body temperature, cardiovascular regulation and other vegetative functions [53]. Oxytocin secretion during sepsis may represent a neuroendocrine response contributing to the overall host response to infection by decreasing the proinflammatory response [37,38]. Oxytocin and arginine vasopressin are closely related peptides synthesized primarily in magnocellular neurons of the hypothalamus, which project their axon terminals into the posterior pituitary, as well as other brain areas and the spinal cord [21]. Several studies show that oxytocin modulates nociception in the CNS [30,62]. Oxytocin, moreover, plays an important role in social recognition [16] and has anxiolytic effects [60]. Vasopressin has been reported to modulate a variety of behaviors, including anxiety, aggression and social attachment. Oxytocin has been found to dampen the stress and inflammatory response in humans, with important implications to the pathophysiology of septic shock [23,32]. Neuropeptides extensively cross talk. ␣-MSH and opioids, for example, decrease oxytocin release, while corticotropin-released factor, secretin and vasoactive intestinal polypeptide increase oxytocin secretion. An integrative approach comparing the involvement of several neuropeptides in sepsis, however, is complex. Cortisol is up regulated, while many other neuropeptides are down regulated during septic shock, suggesting that neuropeptides are involved in pleotropic functions which cannot be interpreted as a whole. Neurotensin is a 13 amino acid peptide, whose production is localized in the central nervous system and in N cells of the gastrointestinal tract. Neurotensin binds to NTS1 and NTS2 receptors. NTS1 is found in many CNS regions, in the small and large intestine and liver. NTS2 is expressed more diffusely in the CNS, but not in the

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gastrointestinal tract [33]. Neurotensin receptors are found in high concentration in dopamine pathways, such as the nucleus accumbens and in the substancia nigra, modulating dopamine signaling through indirect antagonism of D2 receptors. Neurotensin knockout mice have been used as a model of schizophrenia. Neurotensin can also modulate other neurotransmitter systems, including GABAergic, serotoninergic and cholinergic neurons. It is known to decrease gastric motility and increase insulin levels. In the colon, neurotensin generally stimulates motility. Neurotensin produces a proliferative effect on the mucosa of the normal gastrointestinal tract. High-affinity neurotensin receptors are expressed by mast cells and lymphocytes and induce histamine release and chemotaxis, respectively [2,17]. Neurotensin plasma concentrations are increased in mice after cecal ligation and puncture (CLP) and mice treated with a pharmacological antagonist of neurotensin, or neurotensin-deficient mice, show reduced mortality during CLP [42]. Melatonin is a neuropeptide synthesized by the pineal gland and in small amounts by many other organs, such as the gastrointestinal tract, thymus, bone marrow and lymphocytes. It plays important functions in sleep regulation and mood [44], acts as a free radical scavenger and also has a role in combating infections [52]. Its secretion is synchronized to the dark/light cycle. Once formed, melatonin is immediately secreted by the pineal gland. Melatonin binds to MT1, MT2 and nuclear receptors, such as RZR/ROR receptors [3]. Melatonin has been demonstrated a potent antioxidant, but also displays oxidant activity, which is important for its microbicidal actions. Melatonin increases anti-inflammatory cytokines, such as IL-10, down regulates iNOS, inhibits bacterial growth, reduces proinflammatory cytokines, inhibits myeloperoxidase and lipid peroxidation and suppresses superoxide anions [15]. Protective effects in septic shock have been demonstrated in both animal models [8,61] and humans [6,18]. Melatonin implications in sepsis can be explored in the context of circadian rhythm, sleep disorders and delirium, common features in septic patients. The mechanism of the sleep-promoting effects of melatonin is unknown, but include hypothermia, stimulation of GABA receptors and a direct action on the CNS [46]. Indeed, mechanically ventilated patients have significant sleep disturbances [11], which have important effects on morbidity [14]. Melatonin has been claimed as a potential treatment for septic patients. Melatonin administered to rats prior and after LPS administration reduced lipid peroxidation [50], chemotaxis [40] and erythrocyte deformability [64] compared to placebo. In humans, the melatonin group had statistically lower levels of lipid peroxidation, white cells counts and C-protein levels [18]. Interestingly, melatonin receptors are expressed by immune cells, such as lymphocytes, CD4, CD8 and B cells [51]. 3. Conclusion Neuropeptides play a key role in the pathophysiology of sepsis. We have described that several neuropeptides are down regulated during septic shock. Cortisol, however, is up regulated. Our results emphasize that neuropeptides display a multitude of systemic effects, including direct bacterial killing. Future studies should be directed to answer four questions: Do they play a pro-inflammatory or anti-inflammatory role in humans? Are they produced mostly in the brain or the systemic effects reflect peripheral systems production? How do they induce septic encephalopathy? How can the system involving several neuropeptides be integrated? Acknowledgement FPS is supported by FAPESP, Sao Paulo Research Foundation (Grant # 2009/17731-2).

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