The non-peptide kinin receptor antagonists FR 173657 and SSR 240612: Preclinical evidence for the treatment of skin inflammation

Peptide and non-peptide kinin receptor antagonists were evaluated in cutaneous inflammation models in mice. Topical and i.p. application of kinin B(1) and B(2) receptor antagonists caused a significant inhibition of the capsaicin-induced cutaneous neurogenic inflammatory response. The calculated mean ID(50) for Hoe140 and SSR240612 were 23.83 (9.14-62.14) nmol/kg and 0.23 (0.15-0.36) mg/ear, respectively. The I(max) observed for Hoe140, SSR240612, R-715, FR173657, and FR plus SSR were 61+/-5%, 56+/-3%, 65+/-10%, 48+/-8%, and 52+/-4%, respectively. Supporting these results, double B(1) and B(2) kinin receptors knockout mice showed a significant inhibition of capsaicin-induced ear oedema (42+/-7%). However, mice with a single deletion of either B(1) or B(2) receptors exhibited no change in their capsaicin responses. In contrast, all of the examined kinin receptor antagonists were unable to inhibit the oedema induced by TPA and the results from knockout mice confirmed the lack of kinin receptor signaling in this model. These findings show that kinin receptors are present in the skin and that both kinin receptors seem to be important in the neurogenic inflammatory response. Moreover, non-peptide antagonists were very effective in reducing skin inflammation when topically applied, thereby suggesting that they could be useful tools in the treatment of some skin inflammatory diseases

B(1) and B(2) kinin receptor participation in hyperproliferative and inflammatory skin processes in mice

BACKGROUND: Kinins are released during dermal injury and inflammation and seem to contribute to the pathogenesis of cutaneous diseases. OBJECTIVE: Participation of kinins in skin inflammatory process was evaluated using knockout mice and non-peptide kinin receptor antagonists. METHODS: Chronic skin inflammation was induced by multiple applications of TPA in mice ear. RESULTS: The B(2) knockout mice (B(2)(-/-)) showed a significant increase of ear weight (23±10%) and epidermal cellular hyperproliferation and acanthosis formation upon histological analysis when compared with wildtype mice. Also, evaluation of PCNA levels by Western blot and immunohistochemistry confirmed the increase in the epidermis hyperproliferation in the ear skin of B(2)(-/-) mice. In contrast, no modification in these parameters was detected in B(1) knockout mice (B(1)(-/-)). However, mice lacking both kinin receptors (B(1)B(2)(-/-)) presented a considerable reduction of epidermis thickness and in PCNA levels. Following the establishment of skin inflammation (5th day of TPA application) treatment with the non-peptide antagonists SSR 240612 (B(1) receptor antagonist), FR 173657 (B(2) receptor antagonist), or SSR 240612 plus FR 173657 topically applied, caused a significant inhibition of ear weight (20+/-5%, 34+/-4% and 32+/-6%, respectively). In the histological analysis, the antagonists produced a reduction in epidermal hyperplasia and acanthosis formation; but the treatment with a combination of the two antagonists did not increase efficacy. CONCLUSION: Kinin receptors seem to be involved in the control of the keratinocyte hyperproliferative process, and non-peptide kinin receptor antagonists may be useful tools in the treatment of hyperproliferative skin disorders

Tratamentos pré-germinativos em sementes de araçá-boi (Eugenia stipitata)

O araçá-boi (Eugenia stipitata) é uma fruteira nativa com grande potencial agroindustrial. Suas sementes são intolerantes ao dessecamento e apresentam dormência, o que dificulta sua propagação. O objetivo do trabalho foi analisar as características de germinação das sementes de araçá-boi submetidas a diferentes tratamentos pré-germinativos: retirada parcial do tegumento, lixiviação e fracionamento. A germinação das sementes intactas e com retirada parcial do tegumento foi realizada em dois ambientes: casa de vegetação e viveiro telado com sombrite de 50%. Para a lixiviação, as sementes foram colocadas em balde e submetidas à lixiviação, em água corrente, por até 90 dias, com intervalos de 10 dias. O fracionamento das sementes foi realizado de acordo com a posição da zona meristemática de protrusão da raiz e parte aérea (fracionamento transversal e longitudinal). A retirada parcial do tegumento das sementes de araçá-boi diminui o tempo médio de germinação de 91 para 48 dias, com 100% de emergência. As sementes de araçá-boi mantidas submersas em água corrente por até 50 dias mantêm a viabilidade e o vigor. As frações de sementes que apresentam a protuberância meristemática formam plântulas normais, com as mesmas características de germinação das sementes intactas, porém os diferentes tipos de fracionamento não aceleraram nem uniformizaram a germinação das sementes