Intracerebroventricular Administration of Streptozotocin as an Experimental Approach to Depression: Evidence for the Involvement of Proinflammatory Cytokines and Indoleamine-2,3-Dioxygenase.
There is a lack of information about the molecular events underlying the depressive-like effect of an intracerebroventricular injection of streptozotocin (ICV-STZ) in mice. Elevated activity of the tryptophan-degrading enzyme indoleamine-2,3-dioxygenase (IDO) has been proposed to mediate depression in inflammatory disorders. In this study, we report that ICV-STZ activates IDO in the hippocampus of mice and culminates in depressive-like behaviors, measured by an increased duration in immobility time in the forced swimming test and decreased total time of grooming in the splash test. Indirect blockade of IDO activation with the cytokine inhibitor minocycline prevents the development of depressive-like behaviors and attenuates STZ-induced upregulation of proinflammatory cytokines in the hippocampus. Minocycline abrogates the increase in tryptophan and kynurenine levels as well as prevents serotonin dysfunction in the hippocampus of STZ-injected mice. These results suggest that hippocampal IDO activation in STZ-associated depressive-like behavior is mediated by proinflammatory cytokine-dependent mechanisms. Our study not only extends the evidence that IDO has a critical role in mediating inflammation-induced depression but also supports the notion that neuroinflammation and the kynurenine pathway are important targets of novel therapeutic drugs for depression. In addition, our study provides new insights into the neurobiological mechanisms underlying ICV-STZ and indicates that this model could be employed in the preclinical research of depression.
Laboratório de Avaliações Farmacológicas e Toxicológicas Aplicadas às Moléculas Bioativas - LaftamBio Pampa, Universidade Federal do Pampa, Itaqui, RS, CEP 97650-000, Brazil.
Leandro Cattelan
LC
Souza
Laboratório de Avaliações Farmacológicas e Toxicológicas Aplicadas às Moléculas Bioativas - LaftamBio Pampa, Universidade Federal do Pampa, Itaqui, RS, CEP 97650-000, Brazil. cristianoricardojesse@yahoo.com.br.
Cristiano R
CR
Jesse
Laboratório de Avaliações Farmacológicas e Toxicológicas Aplicadas às Moléculas Bioativas - LaftamBio Pampa, Universidade Federal do Pampa, Itaqui, RS, CEP 97650-000, Brazil.
Marcelo Gomes
MG
de Gomes
Laboratório de Avaliações Farmacológicas e Toxicológicas Aplicadas às Moléculas Bioativas - LaftamBio Pampa, Universidade Federal do Pampa, Itaqui, RS, CEP 97650-000, Brazil.
Cristini Escobar
CE
Viana
Laboratório de Avaliações Farmacológicas e Toxicológicas Aplicadas às Moléculas Bioativas - LaftamBio Pampa, Universidade Federal do Pampa, Itaqui, RS, CEP 97650-000, Brazil.
Etiara
E
Mattos
Laboratório de Avaliações Farmacológicas e Toxicológicas Aplicadas às Moléculas Bioativas - LaftamBio Pampa, Universidade Federal do Pampa, Itaqui, RS, CEP 97650-000, Brazil.
Neici Cáceres
NC
Silva
Laboratório de Avaliações Farmacológicas e Toxicológicas Aplicadas às Moléculas Bioativas - LaftamBio Pampa, Universidade Federal do Pampa, Itaqui, RS, CEP 97650-000, Brazil.
Silvana Peterini
SP
Boeira
D000818:Animals; D001786:Blood Glucose; D016207:Cytokines / Q000378:metabolism*; D003863:Depression / Q000139:chemically induced / Q000378:metabolism*; D004195:Disease Models, Animal; D006120:Grooming / Q000187:drug effects; D006624:Hippocampus / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D046353:Immobility Response, Tonic / Q000187:drug effects; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D057967:Infusions, Intraventricular; D007737:Kynurenine / Q000378:metabolism; D008297:Male; D051379:Mice; D008911:Minocycline / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism; D013311:Streptozocin / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D014364:Tryptophan / Q000378:metabolism
D001786:Blood Glucose; D016207:Cytokines; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D012701:Serotonin; D007737:Kynurenine; D006897:Hydroxyindoleacetic Acid; D013311:Streptozocin; D014364:Tryptophan; D008911:Minocycline
Depressive-like behavior; Indoleamine-2,3-dioxygenase; Inflammation; Serotonin; Streptozotocin