Pimaradienoic acid inhibits inflammatory pain: inhibition of NF-κB activation and cytokine production and activation of the NO-cyclic GMP-protein kinase G-ATP-sensitive potassium channel signaling pathway.
Pimaradienoic acid (1) is a pimarane diterpene (ent-pimara-8(14),15-dien-19-oic acid) extracted at high amounts from various plants including Vigueira arenaria Baker. Compound 1 inhibited carrageenan-induced paw edema and acetic acid-induced abdominal writhing, which are its only known anti-inflammatory activities. Therefore, it is important to further investigate the analgesic effects of 1. Oral administration of 1 (1, 3, and 10 mg/kg) inhibited the acetic acid-induced writhing. This was also observed at 10 mg/kg via sc and ip routes. Both phases of the formalin- and complete Freund's adjuvant (CFA)-induced paw flinch and time spent licking the paw were inhibited by 1. Compound 1 inhibited carrageenan-, CFA-, and PGE2-induced mechanical hyperalgesia. Treatment with 1 inhibited carrageenan-induced production of TNF-α, IL-1β, IL-33, and IL-10 and nuclear factor κB activation. Pharmacological inhibitors also demonstrated that the analgesic effects of 1 depend on activation of the NO-cyclic GMP-protein kinase G-ATP-sensitive potassium channel signaling pathway. Compound 1 did not alter plasma levels of AST, ALT, or myeloperoxidase activity in the stomach. These results demonstrate that 1 causes analgesic effects associated with the inhibition of NF-κB activation, reduction of cytokine production, and activation of the NO-cyclic GMP-protein kinase G-ATP-sensitive potassium channel signaling pathway.
Departamento de Ciências Farmacêuticas - Centro de Ciências de Saúde, Universidade Estadual de Londrina , 86039440, Londrina, Brazil.
Maria I
MI
Possebon
Sandra S
SS
Mizokami
Thacyana T
TT
Carvalho
Ana C
AC
Zarpelon
Miriam S N
MS
Hohmann
Larissa
L
Staurengo-Ferrari
Camila R
CR
Ferraz
Thiago H
TH
Hayashida
Anderson R
AR
de Souza
Sergio R
SR
Ambrosio
Nilton S
NS
Arakawa
Rubia
R
Casagrande
Waldiceu A
WA
Verri
D019342:Acetic Acid / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002351:Carrageenan / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology*; D004487:Edema / Q000139:chemically induced; D005620:Freund's Adjuvant / Q000494:pharmacology; D006930:Hyperalgesia / Q000188:drug therapy; D016753:Interleukin-10 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D054086:KATP Channels / Q000187:drug effects; D015394:Molecular Structure; D010146:Pain / Q000188:drug therapy; D015221:Potassium Channels / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000700:Analgesics; D000893:Anti-Inflammatory Agents; D004224:Diterpenes; D053583:Interleukin-1beta; D054086:KATP Channels; D015221:Potassium Channels; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; C008911:pimaric acid; D002351:Carrageenan; D005620:Freund's Adjuvant; D006152:Cyclic GMP; D019342:Acetic Acid