The use of a senalylindole in the pursuit of happiness

Depression is the most prevalent psychiatric disorder in the world, affecting approximately 300 million people. The pathophysiology of this disorder has not been fully elucidated, possibly because it is highly heterogenic and multifactorial. However, evidences suggest that a dysfunction in monoaminergic and glutamatergic neurotransmission, hyperactivity of the hypothalamus-pituitary-adrenal axis, inflammation, and oxidative stress are associated with behavioral changes observed in patients. Despite the socioeconomic relevance, 40% of depressed patients do not show symptomatic improvement with the drug treatments available today. Thus, considering the multifactorial nature of depression and the need for more efficient treatments, the importance of looking for multi-target molecules with antidepressant effect becomes clear. Initial studies carried out by our research group reported that the compound 3-[(4-chlorophenyl)selenyl]-1-methyl-1H-indole (CMI) has antioxidant effect and protects mice against the depressive-like behavior induced by inflammation. This hybrid molecule combines the pharmacological effects of the selenium atom with the indole group. Thus, the need for more efficient drugs for depression combined with the promising effects of CMI prompted us to dive into the CMI's ability to reverse depression-like behavior in different animal models. In chapter 1 of this thesis, we deepened our knowledge about the potential of CMI to neutralize inflammation-derived oxidants. In chapter 2, we observed that the CMI reversed the depressive-like behavior in mice subjected to acute restraint stress, while also reversed neuroinflammation and oxidative stress. In chapter 3, we faced the ability of CMI to reverse depressive- and anxiogenic-like behavior induced by acute inflammation, through the modulation of the serotonergic system. In chapter 4, we observed that CMI reversed depressive-like behavior and cognitive impairment in mice with breast tumors, through the modulation of nitro-oxidative stress and neuroinflammation. In chapter 5, we advanced the knowledge about the involvement of the BDNF/mTOR pathway in the antidepressantand anxiolytic-like effect of CMI. In chapter 6, we investigated the ability of CMI to improve the depression-like and ansiogenic-like behavior and cognitive impairment in mice that survived sepsis, through modulation of blood parameters, peripheral oxidative stress, neuroinflammation and central nitro-oxidative stress. Together, our results describe the pharmacological potential of CMI and reinforce the relevance of neuroinflammation and nitro-oxidative stress as targets for the treatment of depression. Thus, we aimed to contribute to the development of a new therapeutic adjuvant capable of improving the quality of life of depressed patients and to collaborate with the science communication to help breaking the stigmatization that depression is a purely mental illness.Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPqA depressão é o transtorno psiquiátrico mais prevalente no mundo, afetando aproximadamente 300 milhões de pessoas. A patofisiologia desse transtorno ainda não foi completamente elucidada, possivelmente por ser multifatorial e heterogênea. No entanto, evidências sugerem que a disfunção na neurotransmissão monoaminérgica e glutamatérgica, hiperativação do eixo hipotálamo-ituitáriaadrenal, inflamação e estresse oxidativo estão associados com as alterações comportamentais observadas nos pacientes. Apesar da relevância socioeconômica, 40% dos pacientes depressivos não apresentam melhora sintomatológica com os medicamentos disponíveis. Dessa forma, considerando o caráter multifatorial da depressão e a necessidade de tratamentos mais eficientes, torna-se clara a importância da procura por moléculas multialvo com efeito antidepressivo. Estudos iniciais realizados pelo nosso grupo de pesquisa reportaram que o composto 3-[(4-clorofenil)selenil]-1-metil-1H-indol (CMI) apresentou efeito antioxidante e protegeu camundongos contra o comportamento tipo-depressivo induzido pela inflamação. Essa molécula de caráter híbrido, combina os efeitos farmacológicos do átomo de selênio com o grupo indólico. Assim, a necessidade de fármacos mais eficientes para a depressão aliada ao promissor efeito do CMI nos impulsionou a aprofundar o conhecimento a respeito da capacidade do CMI em reverter o comportamento tipodepressivo em diferentes modelos animais. No capítulo 1 desta tese, descreveu-se o potencial do CMI em neutralizar oxidantes derivados da inflamação. No capítulo 2, explorou-se a capacidade do CMI em reverter o comportamento tipo-depressivo em camundongos submetidos ao estresse agudo de restrição, e sua capacidade de reverter a neuroinflamação e o estresse oxidativo nos córtex pré-frontais e hipocampos dos camundongos. No capítulo 3, investigou-se a capacidade do CMI em reverter o comportamento tipo-depressivo e tipo-ansiogênico induzido pela inflamação aguda, através da modulação do sistema serotoninérgico. No capítulo 4, observou-se que o CMI reverteu o comportamento tipo-depressivo e o déficit cognitivo em camundongos portadores de tumor mamário, através da modulação do estresse nitrooxidativo e da neuroinflamação. No capítulo 5, constatou-se que o efeito tipoantidepressivo e tipo-ansiolítico do CMI depende da ativação da via do BDNF/mTOR. No capítulo 6, descobriu-se que o CMI melhorou o comportamento tipo-depressivo, tipo-ansiogênico e o prejuízo cognitivo em camundongos que sobreviveram a sepse, através da modulação de parâmetros sanguíneos, estresse oxidativo periférico, neuroinflamação e estresse nitro-oxidativo central. Em conjunto, nossos resultados descrevem o potencial farmacológico do CMI e reforçam a relevância da neuroinflamação e do estresse nitro-oxidativo como alvos para o tratamento da depressão. Dessa forma, objetiva-se contribuir com o desenvolvimento de um novo adjuvante terapêutico capaz de melhorar a qualidade de vida de pacientes depressivos e colaborar com a divulgação cientifica e a quebra do estigma de que a depressão é uma doença puramente mental

Correction: Computational and biological evidences on the serotonergic involvement of SeTACN antidepressant-like effect in mice.

[This corrects the article DOI: 10.1371/journal.pone.0187445.]

Computational and biological evidences on the serotonergic involvement of SeTACN antidepressant-like effect in mice

<div><p>A series of phenylselanyl-1<i>H</i>-1,2,3-triazole-4-carbonitriles with different substituents were screened for their binding affinity with serotonin transporter (SERT) and dopamine transporter (DAT) by docking molecular. 5-(4methoxyphenyl)-1-(2-(phenylselanyl)phenyl)-1H-1,2,3-triazole-4-carbonitrile (SeTACN) exhibited the best conformation with SERT even higher than fluoxetine and serotonin, suggesting a competitive inhibition. SeTACN demonstrated additional affinity to other serotonergic receptors involved in antidepressant effects: 5HT_1a, 5HT_2a and 5HT₃. In another set of experiments, SeTACN led to significant reductions in the immobility time of mice submitted to forced swimming test (FST) in the dose range of 0.1- 20mg/kg, suggesting an antidepressant-like effect. The possible mechanism of action was investigated using serotonergic and dopaminergic antagonists. The antidepressant-like effect of SeTACN (0.1mg/kg i.g.) was prevented by the pretreatment with WAY100635 (a selective 5HT_1a antagonist), ketanserin (a 5HT2_a/c antagonist) and ondansetron (a selective 5ht₃ antagonist), PCPA (an inhibitor of serotonin synthesis) but not with SCH23390 (dopaminergic D₁ antagonist) and sulpiride (D₂ antagonist). Sub-effective dose of fluoxetine was able to potentiate the effects of a sub-effective dose of SeTACN in FST. None of the treatments affected locomotor activity in open field test (OFT). These results together, suggest that the SeTACN antidepressant-like effect is mediate, at least in parts, by serotonergic system.</p></div

Scores (kcal/mol) of docking results of phenylselanyl-1<i>H</i>-1,2,3-triazole-4-carbonitriles class of compounds in serotonin transporter (SERT) and dopamine transporter (DAT).

<p>Scores (kcal/mol) of docking results of phenylselanyl-1<i>H</i>-1,2,3-triazole-4-carbonitriles class of compounds in serotonin transporter (SERT) and dopamine transporter (DAT).</p

Experimental paradigms illustrating the drugs and compound administration followed by behavioral tests.

<p>(A) Antidepressant-like activity of 5-(4methoxyphenyl)-1-(2-(phenylselanyl)phenyl)-1H-1,2,3-triazole-4-carbonitrile (SeTACN). (B) Evaluation of mechanism of action involved in antidepressant-like effect of SeTACN. (C) Synergic effect of the combined treatment with sub-effective doses of clinical antidepressants and SeTACN.</p

Computational and biological evidences on the serotonergic involvement of SeTACN antidepressant-like effect in mice - Fig 6

<p>Effect of pretreatment of mice with (A) SCH233390 (0.05 mg/kg, s.c., a dopaminergic D₁ receptor antagonist) and (B) sulpiride (50 mg/kg, i.p., a dopaminergic D₂ receptor antagonist) on the anti-immobility effect of SeTACN (0.1mg/kg, i.g) in the FST. Data are presented as the mean ± S.E.M. (***) P < 0.001 in comparison to the vehicle treated group.</p

Chemical structure of class phenylselanyl-1<i>H</i>-1,2,3-triazole-4-carbonitriles compounds.

<p>Compound 1: 5-phenyl-1-(2-(phenylselanyl)phenyl)-1H-1,2,3-triazole-4-carbonitrile; Compound 2: 5-(4-fluorophenyl)-1-(2-(phenylselanyl)phenyl)-1H- 1,2,3-triazole-4-carbonitrile; Compound 3: 5-(4-chlorophenyl)-1-(2-(phenylselanyl)phenyl)-1H- 1,2,3-triazole-4-carbonitrile; Compound 4: 5-(4-methoxyphenyl)-1-(2-(phenylselanyl)phenyl)-1H- 1,2,3-triazole-4-carbonitrile and Compound 5: 1-(2-(phenylselanyl)phenyl)-5-(p-tolyl)-1H-1,2,3- triazole-4-carbonitrile.</p

The THYCOVIT (Thyroid Surgery during COVID-19 pandemic in Italy) study: results from a nationwide, multicentric, case-controlled study

none29: The outbreak of the COVID-19 pandemic has led to a disruption of surgical care. The aim of this multi-centric, retrospective study was to evaluate the impact of the pandemic on surgical activity for thyroid disease among the Italian Units of Endocrine Surgery. Three phases of the pandemic were identified based on the epidemiological situation and the public measures adopted from the Italian Government (1st phase: from 9th March to 3rd May 2020; 2nd phase: from 4th May to 14th June; 3rd phase: from 15th June to 31st). The patients operated upon during these phases were compared to those who underwent surgery during the same period of the previous year. Overall, 3892 patients from 28 Italian endocrine surgical units were included in the study, 1478 (38%) operated upon during COVID-19 pandemic, and 2414 (62%) during the corresponding period of 2019. The decrease in the number of operations was by 64.8%, 44.7% and 5.1% during the three phases of COVID-19 pandemic, compared to 2019, respectively. During the first and the second phases, the surgical activity was dedicated mainly to oncological patients. No differences in post-operative complications were noted between the two periods. Oncological activity for thyroid cancer was adequately maintained during the COVID-19 pandemic.noneMedas, Fabio; Ansaldo, Gian Luca; Avenia, Nicola; Basili, Giancarlo; Boniardi, Marco; Bononi, Marco; Bove, Aldo; Carcoforo, Paolo; Casaril, Andrea; Cavallaro, Giuseppe; Chiofalo, Maria Grazia; Conzo, Giovanni; De Pasquale, Loredana; Del Rio, Paolo; Dionigi, Gianlorenzo; Dobrinja, Chiara; Docimo, Giovanni; Graceffa, Giuseppa; Iacobone, Maurizio; Innaro, Nadia; Lombardi, Celestino Pio; Palestini, Nicola; Pedicini, Francesco; Perigli, Giuliano; Pezzolla, Angela; Scerrino, Gregorio; Spiezia, Stefano; Testini, Mario; Calò, Pietro GiorgioMedas, Fabio; Ansaldo, Gian Luca; Avenia, Nicola; Basili, Giancarlo; Boniardi, Marco; Bononi, Marco; Bove, Aldo; Carcoforo, Paolo; Casaril, Andrea; Cavallaro, Giuseppe; Chiofalo, Maria Grazia; Conzo, Giovanni; De Pasquale, Loredana; Del Rio, Paolo; Dionigi, Gianlorenzo; Dobrinja, Chiara; Docimo, Giovanni; Graceffa, Giuseppa; Iacobone, Maurizio; Innaro, Nadia; Lombardi, Celestino Pio; Palestini, Nicola; Pedicini, Francesco; Perigli, Giuliano; Pezzolla, Angela; Scerrino, Gregorio; Spiezia, Stefano; Testini, Mario; Calò, Pietro Giorgi