title: Antinociceptive, anti-inflammatory and gastroprotective effects of a hydroalcoholic extract from the leaves of Eugenia punicifolia (Kunth) DC. in rodents.
abstract: BACKGROUND
  An ethnopharmacological survey indicated that leaves from Eugenia punicifolia (Kunth) DC. (Myrtaceae) are popularly used as a natural therapeutic agent to treat pain and inflammation.
  
  
  OBJECTIVE
  The overall objective of the present study was to evaluate the antinociceptive, anti-inflammatory and gastroprotective activities of a hydroalcoholic extract of leaves from Eugenia punicifolia (HEEP) in rodents.
  
  
  METHODS
  The antinociceptive effects of HEEP were evaluated in mice after oral administration in chemical (formalin and glutamate) and thermal (hot-plate) tests. We evaluated the involvement of the glutamatergic, opioidergic and nitrergic pathways in the antinociception of HEEP and the effect of HEEP on the inhibition of p38α MAPK. The anti-inflammatory effect of HEEP was evaluated in mice and rats using xylene-induced ear edema and carrageenan-induced paw edema, respectively. Furthermore, the gastroprotective effect of HEEP was evaluated in rats with acute gastric lesions induced by ethanol or indomethacin. Finally, we performed a phytochemical analysis of HEEP.
  
  
  RESULTS
  The oral administration of HEEP (125, 250 and 500mg/kg, p.o.) significantly inhibited the neurogenic and inflammatory phases of formalin-induced licking, and HEEP (250mg/kg, p.o.) also significantly inhibited the nociception caused by glutamate. The antinociceptive effects of HEEP were significantly reversed by l-arginine (500mg/kg, i.p.) but not by naloxone (1mg/kg, i.p.) in the formalin test. HEEP did not affect animal motor performance in the rotarod model. In addition, HEEP also increased the paw withdraw latency in the hot-plate test. HEEP significantly inhibited ear edema induced by xylene (64%) and paw edema induced by carrageenan (50%) compared to the control group. Furthermore, HEEP (3-30mg/mL) also inhibited the phosphorylation of p38α MAPK by approximately 90%. In addition, HEEP (125, 250 and 500mg/kg, p.o.) protected the rats against ethanol (88.4-99.8%) and indomethacin (53-72.3%) and increased the mucus levels of the gastric mucosa without producing an antisecretory effect. The phytochemical profile of HEEP obtained using HPLC-PDA showed secondary metabolites already reported for the genus, mostly flavonoids, gallotannins and proanthocyanidins.
  
  
  CONCLUSIONS
  These data show for the first time that HEEP has significant antinociceptive and anti-inflammatory effects, which appear to be related to the inhibition of the glutamatergic system, the synthesis of nitric oxide and the inhibition of the phosphorylation of p38α MAPK. HEEP also has interesting gastroprotective effects related to the maintenance of protective factors, such as mucus production. These results support the use of Eugenia punicifolia in popular medicine and demonstrate that this plant has therapeutic potential for the development of phytomedicines with antinociceptive, anti-inflammatory and gastroprotective properties.
authors.affiliation: Univ. Estadual Paulista-UNESP, Departamento de Fisiologia, Instituto de Biociências, CEP 18618-970, Botucatu, SP, Brazil.
authors.forename: Rosanna T
authors.initials: RT
authors.lastname: Basting
authors.affiliation: Univ. Estadual Paulista-UNESP, Departamento de Fisiologia, Instituto de Biociências, CEP 18618-970, Botucatu, SP, Brazil.
authors.forename: Catarine M
authors.initials: CM
authors.lastname: Nishijima
authors.affiliation: Univ. Estadual Paulista-UNESP, Departamento de Fisiologia, Instituto de Biociências, CEP 18618-970, Botucatu, SP, Brazil.
authors.forename: Juliana A
authors.initials: JA
authors.lastname: Lopes
authors.affiliation: Univ. Estadual Paulista-UNESP, Departamento de Fisiologia, Instituto de Biociências, CEP 18618-970, Botucatu, SP, Brazil.
authors.forename: Raquel C
authors.initials: RC
authors.lastname: Santos
authors.affiliation: Univ. Estadual Paulista-UNESP, Departamento de Fisiologia, Instituto de Biociências, CEP 18618-970, Botucatu, SP, Brazil.
authors.forename: Larissa
authors.initials: L
authors.lastname: Lucena Périco
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Eberhard Karls University of Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Laufer
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Eberhard Karls University of Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Bauer
authors.affiliation: Univ. Estadual Paulista-UNESP, Departamento de Química Orgânica, Instituto de Química, CEP 14800-900, Araraquara, SP, Brazil.
authors.forename: Miriam F
authors.initials: MF
authors.lastname: Costa
authors.affiliation: Univ. Estadual Paulista-UNESP, Departamento de Química Orgânica, Instituto de Química, CEP 14800-900, Araraquara, SP, Brazil.
authors.forename: Lourdes C
authors.initials: LC
authors.lastname: Santos
authors.affiliation: Univ. Estadual Paulista-UNESP, Departamento de Fisiologia, Instituto de Biociências, CEP 18618-970, Botucatu, SP, Brazil.
authors.forename: Lúcia R M
authors.initials: LR
authors.lastname: Rocha
authors.affiliation: Univ. Estadual Paulista-UNESP, Campus Experimental do Litoral Paulista, CEP 11330-900, São Vicente, SP, Brazil.
authors.forename: Wagner
authors.initials: W
authors.lastname: Vilegas
authors.affiliation: Universidade Federal de Santa Catarina, Departamento de Ciências Fisiológicas, CEP 88040-900, Florianópolis, SC, Brazil.
authors.forename: Adair R S
authors.initials: AR
authors.lastname: Santos
authors.affiliation: Univ. Estadual Paulista-UNESP, Departamento de Ciências Biológicas, Faculdade de Ciências e Letras, CEP 19806-900, Assis, SP, Brazil. Electronic address: csantos@assis.unesp.br.
authors.forename: Catarina
authors.initials: C
authors.lastname: Dos Santos
authors.affiliation: Univ. Estadual Paulista-UNESP, Departamento de Fisiologia, Instituto de Biociências, CEP 18618-970, Botucatu, SP, Brazil. Electronic address: hiruma@ibb.unesp.br.
authors.forename: Clélia A
authors.initials: CA
authors.lastname: Hiruma-Lima
mesh_terms: D000700:Analgesics / Q000008:administration & dosage / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000302:isolation & purification / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000188:drug therapy; D000068856:Eugenia / Q000737:chemistry*; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D008519:Medicine, Traditional; D051379:Mice; D010146:Pain / Q000188:drug therapy; D010147:Pain Measurement; D010936:Plant Extracts / Q000008:administration & dosage / Q000494:pharmacology*; D018515:Plant Leaves; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000700:Analgesics; D000893:Anti-Inflammatory Agents; D010936:Plant Extracts; D018698:Glutamic Acid
keywords: Anti-inflammatory; Antinociceptive; Eugenia punicifolia; Gastroprotective; Myrtaceae; p38α MAPK