Behavioural Brain Research 396 (2021) 112874 Available online 21 August 2020 0166-4328/© 2020 Elsevier B.V. All rights reserved. A pyrazole-containing selenium compound modulates neuroendocrine, oxidative stress, and behavioral responses to acute restraint stress in mice Paloma T. Birmann a , Micaela Domingues a , Angela M. Casaril a , Thiago ˆ A. Smaniotto a , Daniela Hartwig b , Raquel G. Jacob b , Lucielli Savegnago a, * a Technologic Development Center, Biotechnology Unit, Neurobiotechnology Research Group, Federal University of Pelotas, Pelotas, RS, Brazil b Center of Chemical, Pharmaceutical and Food Sciences, Laboratory of Clean Organic Synthesis, Federal University of Pelotas, Pelotas, RS, Brazil A R T I C L E INFO Keywords: Anxiety Nociception Stress Pyrazole Selenium Mice ABSTRACT The contribution of oxidative stress has been described in numerous studies as one of the main pathways involved in the pathophysiology of anxiety and its comorbidities, such as chronic pain. Therefore, in this study, we investigated the anxiolytic-like, antiallodynic, and anti-hyperalgesic effects of 3,5-dimethyl-1-phenyl-4-(phe- nylselanyl)-1H-pyrazole (SePy) in response to acute restraint stress (ARS) in mice through the modulation of oxidative stress and neuroendocrine responses. Mice were restrained for 2 h followed by SePy (1 or 10 mg/kg, intragastrically) treatment. Behavioral, and biochemical tests were performed after further 30 min. The treat- ment with SePy reversed (i) the decreased time spent and the number of entries in the open arms of the elevated plus-maze apparatus, (ii) the decreased time spent in the central zone of the open feld test and the increased number of grooming, (iii) the increased number of marbles buried, (iv) the increased response frequency of Von Frey Hair stimulation, and (v) the decreased latency time to nociceptive response in the hot plate test stress induced by ARS. Biochemically, SePy reversed ARS-induced increased levels of plasma corticosterone, and reversed the ARS-induced alterations in the levels of reactive species, lipid peroxidation, and superoxide dis- mutase and catalase activities in the prefrontal cortices and hippocampi of mice. Moreover, a molecular docking approach suggested that SePy may interact with the active site of the glucocorticoid receptor. Altogether, these results indicate that SePy attenuated anxiolytic-like behavior, hyperalgesia, and mechanical allodynia while modulating oxidative stress and neuroendocrine responses in stressed mice. 1. Introduction The neurochemical and neuroendocrine changes that occur after exposure to short-term stress contribute to several physiological and behavioral changes that can result in neuropsychiatric disorders, such as anxiety [1]. These changes are mediated through the release of the stress hormone cortisol (corticosterone in rodents) by the adrenal gland, which acts as a long-range effector of the hypothalamus-pituitary-adrenal axis (HPA) [2]. The HPA axis is an important neuroendocrine system that is activated in stress responses [3]. The hyperactivation of this axis results in a brief and prolonged increase in cortisol, which promotes changes in the expression of antioxidant genes and modulates cellular respiration, resulting in the excessive production of reactive species (RS) [3]. Therefore, one consequence of acute stress is the presence of oxidative stress in specifc regions of the brain tissue that are susceptible to oxidative damage, such as the prefrontal cortices (PFC) and hippocampi (HC). Thus, acute stress can lead to morphological changes, neuronal dysfunction, and impaired synaptic plasticity, resulting in the develop- ment and persistence of anxiogenic symptoms [3]. Anxiety disorder is one of the leading causes of disability and the general burden of disease worldwide, affecting approximately 260 million people around the world [4]. Accumulating evidence has shown that anxiety disorder is often accompanied by other pathologies as comorbidities. The overlap of anxiety and pain is one of the main comorbidities found in the clinical practice with approximately 45 % of chronic pain patients presenting positive episodes of anxiety disorder [5]. Psychiatric disorders not only contribute to pain intensity but can also increase the risk of disability. Furthermore, people suffering from anxiety tend to experience more severe and long-lasting pain and can be more fearful of pain than someone who experiences pain without anx- iety [6]. The idea that the relationship between anxiety and pain resulted mainly from psychological rather than biological factors was * Corresponding author at: Universidade Federal de Pelotas- UFPel, CEP: 96010-900, Pelotas, RS, Brazil. E-mail address: luciellisavegnago@yahoo.com.br (L. Savegnago). Contents lists available at ScienceDirect Behavioural Brain Research journal homepage: www.elsevier.com/locate/bbr https://doi.org/10.1016/j.bbr.2020.112874 Received 4 June 2020; Received in revised form 13 August 2020; Accepted 17 August 2020