Ibuprofen New Analogs with Anti‐Inflammatory Activity In Vivo

Abstract

Anti‐inflammatory drugs are among the most prescribed in the world. Ibuprofen is well known as a non‐steroidal anti‐inflammatory drug (NSAID) that has proven anti‐inflammatory effects, but like all NSAID, has adverse effects. Our aim is to evaluate effects of new Ibuprofen analogs (R‐60 and R‐65) on acute inflammation models, which are formalin‐induced paw licking and cell migration to the subcutaneous air pouch with exudate evaluation for mediator's production. Experimental groups (n=6–8, 25–35g) male Swiss webster mice were treated 1 h prior inductions at doses of 0.01, 0.1, 1 or 10 mg/kg. Standard drugs used were Ibuprofen (10 mg/kg, p.o.), acetylsalicylic acid (ASA,200 mg/kg, p.o.) or morphine (2.5 mg/kg, i.p.). The analogues reduced paw licking time in the 1st phase: groups treated with R‐60 0.01 mg/kg licked 41.5 ± 21.6 seconds (sec), 0.1 mg/kg: 33 ± 6.4 sec, 1 mg/kg: 32.1 ± 6.9* sec, 10 mg/kg: 29.7 ± 8.4* sec. In 2nd phase reduced licking: 0.01 mg/kg: 184,4 ± 80,1 sec, 0.1 mg/kg: 198,1 ± 54,2 sec, 1 mg/kg: 207,2 ± 23 sec and 89.4 ± 16.4 *sec when treated with 10 mg/kg. R‐65 reduced licking: 34.9 ± 15* sec at the dose of 0.01 mg/kg in the 1st phase, 0.1 mg/kg: 28 ± 5.7* sec, 1 mg/kg: 25.4 ± 7.5* sec and 10 mg/kg: 17 ± 5.8 * sec. In 2nd phase, 10 mg/kg reduced: 56.1 ± 25.1* sec. Ibuprofen reduced licking time in the 1st phase: 29.3 ± 11.6* sec and second: 97.8 ± 48.4* sec. when compared to vehicle‐treated group: 1st phase 53.8 ± 11.9 sec and 2nd phase 202.9 ± 56.6 sec. Regarding cell migration, treatment reduced leukocyte migration at all doses comparing to the vehicle‐treated group: 73.1±11 × 103 cell/mL. The R‐60 0.01 mg/kg treatment led to a migration of 45.7±13 × 103 cell/mL*; 0.1 mg/kg: 46.8 ± 14.7 × 103 cell/mL*, 1 mg/kg: 42.4 ± 12.3 × 103 cell/mL*, 10 mg/kg: 46.6 ± 13.9 × 103 cell/mL*. When treated with R‐65 0.01 mg/kg 47 ± 15.1 ×103 cell/mL* migrated, 0.01 mg/kg: 42 ± 13.1 × 103 cells/mL*, 1 mg/kg: 45.2 ± 14.8 × 103 cell/mL* and 10 mg/kg: 40.9 ± 6.5 × 103 cell/mL*. Ibuprofen: 40.3 ± 9 ×103 cell/mL*. Nitric oxide production was reduced with 0.01 mg/kg treatment of R‐60: 125.5 ± 90.5 μM, 0.1 mg/kg: 103.6 ± 97.9 μM, 1 mg/kg: 91.8 ± 51.6 μM* and 10 mg/kg: 108.9 ± 34.1 μM. R‐65: 0.01 mg/kg: 163.6 ± 84 μM, 0.1 mg/kg: 129.2 ± 85.4 μM, 1 mg/kg: 70.1 ± 52.5 μM* and 10 mg/kg: 89.2 ± 29.7 μM*. Ibuprofen did not reduce nitrite levels: 141.7 ± 14.6 μM when compared to vehicle group: 193.8 ± 110.4 μM. The analogs reduced IL‐1β production at the highest tested dose (10 mg/kg) when comparing to the vehicle‐treated group (605.4 ± 323.1 ng/mL). R‐60: 255.9 ± 103.1 ng/mL* and R‐65: 237 ± 142.7 ng/mL*. Ibuprofen did not reduce IL‐1β levels at any tested dose. R‐60 and R‐65 analogues demonstrated activity in the peripheral nociception in the formalin‐induced paw licking model, as well as in the reduction of cell migration, nitric oxide and IL‐1β production. This work points its anti‐inflammatory effects, which supports the continuity of the tests and that the compounds may become potential candidates to treat inflammation and pain.Support or Funding InformationThis study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES)/Finance Code 001, CNPq and FAPERJ.Alan Minho (technical support)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.