Short communication “Neuropeptides in the brain defense against distant organ damage” Mike Yoshio Hamasaki, Hermes Vieira Barbeiro, Denise Frediani Barbeiro, Débora Maria Gomes Cunha, Marcia Kiyomi Koike, Marcel Cerqueira César Machado, Fabiano Pinheiro da Silva ⁎ Emergency Medicine Department, University of São Paulo, São Paulo, Brazil abstract article info Article history: Received 16 August 2015 Received in revised form 13 November 2015 Accepted 16 November 2015 Available online xxxx Keywords: Neuropeptides Inflammation Biomarkers Critical care Acute pancreatitis Delirium, or acute confusional state, is a common manifestation in diseases that originate outside the central ner- vous system, affecting 30–40% of elderly hospitalized patients and up to 80% of the critically ill, even though it remains unclear if severe systemic inflammation is able or not to induce cellular disturbances and immune acti- vation in the brain. Neuropeptides are pleotropic molecules heterogeneously distributed throughout the brain and possess a wide spectrum of functions, including regulation of the inflammatory response, so we hypothesized that they would be the major alarm system in the brain before overt microglia activation. In order to investigate this hypothesis, we induced acute pancreatitis in 8–10 week old rats and collected brain tissue, 12 and 24 h following pancreatic injury, to measure neuropeptide and cytokine tissue levels. We found significantly higher levels of β-endorphin, orexin and oxytocin in the brain of rats submitted to pancre- atic injury, when compared to healthy controls. Interestingly, these differences were not associated with in- creased local cytokine levels, putting in evidence that neuropeptide release occurred independently of microglia activation and may be a pivotal alarm system to initiate neurologic reactions to distant inflammatory non-infectious aggression. © 2015 Elsevier B.V. All rights reserved. 1. Introduction Systemic inflammation is a common manifestation of many critical illnesses, such as trauma, hemorrhagic shock, major surgeries and se- vere acute pancreatitis. The systemic manifestations of these clinical ca- tastrophes have a strong effect on the brain, as exemplified by the high incidence of delirium in this population. It has been hypothesized that microglia activation would play a key role in this scenario. Indeed, sev- eral molecules that belong to innate immunity are able to trigger sustained inflammation at the local level and in distant organs, inducing cell disturbances and self-damage (Dambrauskas et al., 2010). The main neuropsychiatric symptoms of systemic inflammation are disorientation, restlessness, delirium, unconsciousness or slowed reac- tion, apathy and depression. The subjacent mechanism remains unclear, but possible explanations include the proteolytic effects induced by molecules released from damaged cells and dysregulation of the tran- scriptional response. In the same direction, pro-inflammatory com- pounds increase the blood brain barrier permeability, cause vasogenic edema, myelinolysis, microglia activation and electrolytic disturbances (Zhang and Tian, 2007), leading to acute cerebral manifestations. The prefrontal cortex is associated with cognitive skills of the highest order. It is an extremely sensitive region of the brain and in cognitive disorders, like delirium, this region is usually affected (Tekin and Cummings, 2002). Neuropeptides are found in many mammalian neurons, where they play key roles as modulators of neuronal activity. Indeed, recent observations suggest that they are important immune effectors, linking the host defense and the nervous systems (Gonzalez-Rey, 2010; van den Pol, 2012; Pinheiro da Silva et al., 2013). Neuropeptides are highly preserved molecules and a powerful signaling mechanism, regulating a myriad of complex functions, that in- clude thermoregulation, feeding behavior, sleep, learning, memory, pain, mood, and inflammation. Indeed, some authors have even de- scribed antimicrobial properties (Augustyniak et al., 2012) for them, so we decided to investigate if sterile systemic inflammation initiated at a distant site by tissue necrosis could affect their production at the prefrontal region of the brain. 2. Material and methods 2.1. Animal model of acute pancreatitis All experiments were performed at the Laboratory of Emergency Medicine (LIM-51), University of São Paulo Faculty of Medicine, Brazil. The protocol was approved by the University of Sao Paulo Faculty of Medicine Animal Research and Ethics Committee (protocol # 156/13). Journal of Neuroimmunology 290 (2016) 33–35 ⁎ Corresponding author at: Faculdade de Medicina da Universidade de São Paulo, Laboratório de Emergências Clínicas (LIM-51), Av. Dr. Arnaldo, 455 Sala 3189, CEP 01246-000 São Paulo, SP, Brazil. E-mail address: pinheirofabiano@hotmail.com (F. Pinheiro da Silva). http://dx.doi.org/10.1016/j.jneuroim.2015.11.014 0165-5728/© 2015 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect Journal of Neuroimmunology journal homepage: www.elsevier.com/locate/jneuroim