Peptides 44 (2013) 135–138 Contents lists available at SciVerse ScienceDirect Peptides j ourna l h o mepa ge: 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 i n f o Article history: Received 25 February 2013 Received in revised form 27 March 2013 Accepted 27 March 2013 Available online 10 April 2013 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. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135 2. Neuropeptides in health and disease: focus on septic shock . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135 3. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137 Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138 1. Introduction Nervous systems probably evolved in the common ancestor of cnidarians. Attempts to demonstrate fast transmitters in cnidar- ians, 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 through- out 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 mod- ulate GABA and glutamate synaptic release and activity at post- or * Corresponding author. Tel.: +55 1138879174. E-mail address: pinheirofabiano@hotmail.com (F. Pinheiro da Silva). 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, more- over, 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 con- centration 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 repro- duction by acting at the hypothalamic, pituitary and gonadal levels. 0196-9781/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.peptides.2013.03.029