title: Antidepressant-like and neuroprotective effects of Aloysia gratissima: investigation of involvement of L-arginine-nitric oxide-cyclic guanosine monophosphate pathway.
abstract: BACKGROUND
  Aloysia gratissima (Gill. et Hook) Tronc. (Verbenaceae) is used traditionally for the treatment of headache, bronchitis, and nervous systems disorders including depression.
  
  
  OBJECTIVE
  To investigate the antidepressant-like and neuroprotective effects of Aloysia gratissima aqueous extract (AE) and the involvement of l-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway.
  
  
  METHODS
  The antidepressant-like effect of AE was evaluated through behavioral despair in forced swimming test (FST) and tail suspension test (TST). Swiss albino mice were treated by oral route and after 1h were analyzed the time of immobility in the FST and TST. In addition, the neuroprotective effect of AE against glutamate excitotoxicity was evaluate through cell viability of hippocampal slices, phosphorylation of Akt, and the immunocontent of inducible oxide nitric synthase (iNOS) were investigated by western blotting.
  
  
  RESULTS
  The immobility time in the FST and TST were reduced by AE (100-1000 and 10-300 mg/kg, respectively). The antidepressant-like effect of AE in the TST was prevented by the pretreatment with N-methyl-d-aspartate (NMDA), l-arginine or sildenafil. The subeffective dose of AE produced a synergistic antidepressant-like effect with MK-801 (an antagonist of NMDA receptor), methylene blue, l-NNA (an inhibitor of NO synthase) or ODQ (an inhibitor of soluble guanylate cyclase). In ex vivo experiments, pretreatment with AE prevented the loss of cell viability induced by glutamate, thus affording neuroprotection. Glutamate toxicity caused a decreased Akt phosphorylation and an increased iNOS expression.
  
  
  CONCLUSIONS
  The present study provides convincing evidence of neuroprotection and the involvement of the l-arginine-NO-cGMP pathway in the antidepressant-like effect of AE. Therefore, AE could be of potential interest for the treatment of depressive disorders and neurological conditions associated with glutamate excitotoxicity.
authors.affiliation: Biochemistry Department, Biological Sciences Center, Federal University of Santa Catarina, Florianópolis 88040-900, SC, Brazil.
authors.forename: Ana Lúcia Bertarello
authors.initials: AL
authors.lastname: Zeni
authors.forename: Andréa Dias Elpo
authors.initials: AD
authors.lastname: Zomkowski
authors.forename: Tharine
authors.initials: T
authors.lastname: Dal-Cim
authors.forename: Marcelo
authors.initials: M
authors.lastname: Maraschin
authors.forename: Ana Lúcia S
authors.initials: AL
authors.lastname: Rodrigues
authors.forename: Carla I
authors.initials: CI
authors.lastname: Tasca
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001120:Arginine / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism*; D003863:Depression / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000633:toxicity; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008519:Medicine, Traditional; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D018377:Neurotransmitter Agents / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010766:Phosphorylation; D035261:Plant Components, Aerial; D010936:Plant Extracts / Q000008:administration & dosage / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D010946:Plants, Medicinal; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012997:Solvents / Q000737:chemistry; D013997:Time Factors; D029648:Verbenaceae / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: D000928:Antidepressive Agents; D018696:Neuroprotective Agents; D018377:Neurotransmitter Agents; D010936:Plant Extracts; D012997:Solvents; D014867:Water; D009569:Nitric Oxide; D018698:Glutamic Acid; D001120:Arginine; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D006152:Cyclic GMP