title: Antidepressant-like effect of nitric oxide synthase inhibitors and sildenafil against lipopolysaccharide-induced depressive-like behavior in mice.
abstract: Inflammation, oxidative and nitrosative stress underlie depression being assessed in rodents by the systemic administration of lipopolysacharide (LPS). There is an increasing body of evidence of an involvement of nitric oxide (NO) pathway in depression, but this issue was not investigated in LPS-induced model. Thus, herein we evaluated the effects of NO-pathway-modulating drugs, named aminoguanidine, l-NAME, sildenafil and l-arginine, on the behavioral (forced swimming test [FST], sucrose preference [SPT] and prepulse inhibition [PPI] of the startle) and neurochemical (glutathione [GSH], lipid peroxidation, IL-1β) alterations in the prefrontal cortex, hippocampus and striatum as well as in BDNF levels in the hippocampus 24h after LPS (0.5mg/kg, i.p.) administration, a time-point related to depressive-like behavior. Twenty-four hours post LPS there was an increase in immobility time in the FST, decrease in sucrose preference and PPI levels accompanied by a decrease in GSH levels and an increase in lipid peroxidation, IL-1β and hippocampal BDNF levels suggestive of a depressive-like state. The pretreatment with the NOS inhibitors, l-NAME and aminoguanidine as well as sildenafil prevented the behavioral and neurochemical alterations induced by LPS, although sildenafil and l-NAME were not able to prevent the increase in hippocampal BDNF levels induced by LPS. The iNOS inhibitor, aminoguanidine, and imipramine prevented all behavioral and neurochemical alterations induced by LPS. l-arginine did not prevent the alterations in immobility time, sucrose preference and GSH induced by LPS. Taken together our results show that the NO-cGMP pathway is important in the modulation of the depressive-like alterations induced by LPS.
authors.affiliation: Neuropharmacology Laboratory, Department of Physiology and Pharmacology, Universidade Federal do Ceará, Fortaleza, CE, Brazil.
authors.forename: V S
authors.initials: VS
authors.lastname: Tomaz
authors.affiliation: Neuropharmacology Laboratory, Department of Physiology and Pharmacology, Universidade Federal do Ceará, Fortaleza, CE, Brazil.
authors.forename: R C
authors.initials: RC
authors.lastname: Cordeiro
authors.affiliation: Neuropharmacology Laboratory, Department of Physiology and Pharmacology, Universidade Federal do Ceará, Fortaleza, CE, Brazil.
authors.forename: A M N
authors.initials: AM
authors.lastname: Costa
authors.affiliation: Neuropharmacology Laboratory, Department of Physiology and Pharmacology, Universidade Federal do Ceará, Fortaleza, CE, Brazil.
authors.forename: D F
authors.initials: DF
authors.lastname: de Lucena
authors.affiliation: Department of Clinical and Toxicological Analysis, School of Pharmacy, Laboratory of Bioprospection and Experiments in Yeast, LABEL, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: H V
authors.initials: HV
authors.lastname: Nobre Júnior
authors.affiliation: Neuropharmacology Laboratory, Department of Physiology and Pharmacology, Universidade Federal do Ceará, Fortaleza, CE, Brazil.
authors.forename: F C F
authors.initials: FC
authors.lastname: de Sousa
authors.affiliation: Neuropharmacology Laboratory, Department of Physiology and Pharmacology, Universidade Federal do Ceará, Fortaleza, CE, Brazil.
authors.forename: S M M
authors.initials: SM
authors.lastname: Vasconcelos
authors.affiliation: Laboratory of Inflammation and Cancer Pharmacology, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: M L
authors.initials: ML
authors.lastname: Vale
authors.affiliation: Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciuma, SC, Brazil; Center for Experimental Models in Psychiatry, Department of Psychiatry and Behavioral Sciences, The University of Texas Medical School at Houston, Houston, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Quevedo
authors.affiliation: Neuropharmacology Laboratory, Department of Physiology and Pharmacology, Universidade Federal do Ceará, Fortaleza, CE, Brazil. Electronic address: daniellesilmacedo@gmail.com.
authors.forename: D
authors.initials: D
authors.lastname: Macêdo
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001120:Arginine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D003866:Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology; D007099:Imipramine / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology*
chemical_list: D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D004791:Enzyme Inhibitors; D006146:Guanidines; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D009569:Nitric Oxide; D001120:Arginine; D000068677:Sildenafil Citrate; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP; D007099:Imipramine; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester
keywords: BDNF; LPS; depressive-like behavior; neuroinflammation; nitric oxide; oxidative stress