TY - JOUR
T1 - 3-[(4-chlorophenyl)selanyl]-1-methyl-1H-indole ameliorates long-lasting depression- and anxiogenic-like behaviors and cognitive impairment in post-septic mice
T2 - Involvement of neuroimmune and oxidative hallmarks
AU - Casaril, Angela Maria
AU - Domingues, Micaela
AU - Lourenço, Darling de Andrade
AU - Vieira, Beatriz
AU - Begnini, Karine
AU - Corcini, Carine Dahl
AU - França, Raqueli Teresinha
AU - Varela Junior, Antônio Sergio
AU - Seixas, Fabiana Kӧmmling
AU - Collares, Tiago
AU - Lenardão, Eder João
AU - Savegnago, Lucielli
N1 - Funding Information:
This study was supported by grants from CNPq , CAPES (Financial code 001 ), FINEP , and FAPERGS ( PRONEM 16/2551-0000240 -1, PqG 17/2551-00011046-9 , and DOCFIX 18/2551-0000511-8 ). CNPq is also acknowledged for the fellowship to LS, EJL, FS and TC. We are also grateful to the animal care technicians from the Federal University of Pelotas.
Funding Information:
This study was supported by grants from CNPq, CAPES (Financial code 001), FINEP, and FAPERGS (PRONEM 16/2551-0000240-1, PqG 17/2551-00011046-9, and DOCFIX 18/2551-0000511-8). CNPq is also acknowledged for the fellowship to LS, EJL, FS and TC. We are also grateful to the animal care technicians from the Federal University of Pelotas.
Publisher Copyright:
© 2020
PY - 2020/11/1
Y1 - 2020/11/1
N2 - Only in the last decade the long-term consequences of sepsis started to be studied and even less attention has been given to the treatment of psychological symptoms of sepsis survivors. It is estimated that 60% of sepsis survivors have psychological disturbances, including depression, anxiety, and cognitive impairment. Although the causative factors remain largely poorly understood, blood-brain barrier (BBB) disturbances, neuroinflammation, and oxidative stress have been investigated. Therefore, we sought to explore if the immunomodulatory and antioxidant selenocompound 3-[(4-chlorophenyl)selanyl]-1-methyl-1H-indole (CMI) would be able to ameliorate long-term behavioral and biochemical alterations in sepsis survivors male Swiss mice. CMI treatment (1 mg/kg, given orally for seven consecutive days) attenuated depression- and anxiogenic-like behaviors and cognitive impairment present one month after the induction of sepsis (lipopolysaccharide, 5 mg/kg intraperitoneally). Meantime, CMI treatment modulated the number of neutrophils and levels of reactive species in neutrophils, lymphocytes, and monocytes. In addition, peripheral markers of liver and kidneys dysfunction (AST, ALT, urea, and creatinine) were reduced after CMI treatment in post-septic mice. Notably, CMI treatment to non-septic mice did not alter AST, ALT, urea, and creatinine levels, indicating the absence of acute hepatotoxicity and nephrotoxicity following CMI treatment. Noteworthy, CMI ameliorated BBB dysfunction induced by sepsis, modulating the expression of inflammation-associated genes (NFκB, IL-1β, TNF-α, IDO, COX-2, iNOS, and BDNF) and markers of oxidative stress (reactive species, nitric oxide, and lipid peroxidation levels) in the prefrontal cortices and hippocampi of mice. In conclusion, we unraveled crucial molecular pathways that are impaired in post-septic mice and we present CMI as a promising therapeutic candidate aimed to manage the long-lasting behavioral alterations of sepsis survivors to improve their quality of life.
AB - Only in the last decade the long-term consequences of sepsis started to be studied and even less attention has been given to the treatment of psychological symptoms of sepsis survivors. It is estimated that 60% of sepsis survivors have psychological disturbances, including depression, anxiety, and cognitive impairment. Although the causative factors remain largely poorly understood, blood-brain barrier (BBB) disturbances, neuroinflammation, and oxidative stress have been investigated. Therefore, we sought to explore if the immunomodulatory and antioxidant selenocompound 3-[(4-chlorophenyl)selanyl]-1-methyl-1H-indole (CMI) would be able to ameliorate long-term behavioral and biochemical alterations in sepsis survivors male Swiss mice. CMI treatment (1 mg/kg, given orally for seven consecutive days) attenuated depression- and anxiogenic-like behaviors and cognitive impairment present one month after the induction of sepsis (lipopolysaccharide, 5 mg/kg intraperitoneally). Meantime, CMI treatment modulated the number of neutrophils and levels of reactive species in neutrophils, lymphocytes, and monocytes. In addition, peripheral markers of liver and kidneys dysfunction (AST, ALT, urea, and creatinine) were reduced after CMI treatment in post-septic mice. Notably, CMI treatment to non-septic mice did not alter AST, ALT, urea, and creatinine levels, indicating the absence of acute hepatotoxicity and nephrotoxicity following CMI treatment. Noteworthy, CMI ameliorated BBB dysfunction induced by sepsis, modulating the expression of inflammation-associated genes (NFκB, IL-1β, TNF-α, IDO, COX-2, iNOS, and BDNF) and markers of oxidative stress (reactive species, nitric oxide, and lipid peroxidation levels) in the prefrontal cortices and hippocampi of mice. In conclusion, we unraveled crucial molecular pathways that are impaired in post-septic mice and we present CMI as a promising therapeutic candidate aimed to manage the long-lasting behavioral alterations of sepsis survivors to improve their quality of life.
KW - Behavior
KW - Lipopolysaccharide
KW - Neuroinflammation
KW - Organoselenium
KW - Oxidative stress
KW - Sepsis
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UR - http://www.scopus.com/inward/citedby.url?scp=85092416171&partnerID=8YFLogxK
U2 - 10.1016/j.cbi.2020.109278
DO - 10.1016/j.cbi.2020.109278
M3 - Article
C2 - 33038329
AN - SCOPUS:85092416171
SN - 0009-2797
VL - 331
JO - Chemico-Biological Interactions
JF - Chemico-Biological Interactions
M1 - 109278
ER -