Anti-inflammatory activity of complex compounds tin (IV) chloride (SnCl4) with salicyloyl hydrazones benzaldehyde and 4-bromobenzaldehyde on carrageenan and formalin-induced inflammation

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ANTI-INFLAMMATORY ACTIVITY OF COMPLEX COMPOUNDS TIN (IV) CHLORIDE (SnCl₄) WITH SALICYLOYL HYDRAZONES BENZALDEHYDE AND 4-BROMOBENZALDEHYDE ON CARRAGEENAN AND FORMALIN-INDUCED INFLAMMATION

Резюме/Summary

Anti-inflammatory properties of new complexes of SnCl₄ with benzaldehyde and 4-bromobenzaldehyde salicyloyl hydrazones the were studied in the rats using models on carrageenan and formalin-induced inflammation of paw. Solutions of benzaldehyde, 4-bromobenzaldehyde and salicylic acid were also used to determine their contribution to the anti-inflammatory activity of the complexes. The development of inflammatory process was assessed by changes in the volume and width of the inflamed paw. The use of complexes of SnCl₄ with benzaldehyde and 4- bromobenzaldehyde salicyloyl hydrazones for treatment resulted in normalization of the width and volume of the inflamed paw following 3 days of treatment. Six days after the start of the experiment (carrageenan model), the volume of the affected limb almost reached the control values in animals that received complex compounds I and II, benzaldehyde and salicylic acid. During the experiment it was determined that complex compounds I and II demonstrated the best anti-inflammatory activity in both models of inflammation.

Key words: anti-inflammatory activity, complex compound, benzaldehyde, carrageenan, formalin.

antiinflammatory benzaldehyde bromobenzaldehyde salicyloyl hydrazones

ПРОТИЗАПАЛЬНА АКТИВНІСТЬ НОВИХ КОМПЛЕКСІВ SnCl₄ З САЛІЦІЛОІЛГІДРАЗОНАМИ БЕНЗАЛЬДЕГІДУ І 4- БРОМБЕНЗАЛЬДЕГІДУ НА МОДЕЛЯХ КАРРАГІНАН- І ФОРМАЛІН-ІНДУКОВАНОГО ЗАПАЛЕННЯ

Прокопчук О.Г., Александрова О.І., Кравченко І.А.

Протизапальні властивості нових комплексних сполук SnCl₄ з бензальдегідом і 4-бромбензальдегідом саліцілоілгідразонов вивчали на щурах на моделях каррагінан- і формалін-індукованого набряку лапи. Розчини бензальдегиду, 4-бромбензальдегіду і саліцилової кислоти також використовувалися для визначення вкладу їх функціональних груп у протизапальну активність комплексів. Розвиток запального процесу оцінювали за змінами об'єму і ширини запаленої лапи. Застосування комплексних сполук SnCl₄ бензальдегиду і 4-бромбензальдегіду саліцілоілгідразонів призводило до нормалізації ширини і об'єму запаленої лапи через 3 дні після початку лікування. У тварин, які отримували лікування комплексними сполуками I і II, бензальдегідом і саліцилової кислотою, вже через шість днів після початку експерименту (на моделі каррагінан-індукованого запалення) обсяг ураженої кінцівки практично досяг контрольних значень. В ході експерименту було встановлено, що комплексні сполуки I і II продемонстрували найкращу протизапальну активність на обох моделях запалення.

Ключові слова: протизапальна активність, комплексні сполуки, бензальдегід, каррагінан, формалін.

ПРОТИВОВОСПАЛИТЕЛЬНАЯ АКТИВНОСТЬ НОВЫХ КОМПЛЕКСОВ SnCl₄ С САЛИЦИЛОИЛГИДРАЗОНАМИ БЕНЗАЛЬДЕГИДА И 4-БРОМБЕНЗАЛЬДЕГИДА НА МОДЕЛЯХ КАРРАГИНАН- И ФОРМАЛИН-ИНДУЦИРОВАННОГО ВОСПАЛЕНИЯ

Прокопчук Е.Г., Александрова А.И., Кравченко И.А.

Противовоспалительные свойства новых комплексных соединений SnCl₄ с бензальдегидом и 4-бромбензальдегидом салицилоилгидразонов изучали на крысах на моделях каррагинан- и формалин-индуцированного отёка лапы. Растворы бензальдегида, 4-бромбензальдегида и салициловой кислоты также использовались для определения вклада их функциональных групп в противовоспалительную активность комплексов. Развитие воспалительного процесса оценивали по изменениям объема и ширины воспаленной лапы. Применение комплексных соединений SnCl₄ бензальдегида и 4-бромбензальдегида салицилоил-гидразонов приводило к нормализации ширины и объема воспаленной лапы спустя 3 дня после начала лечения. У животных, которые получали лечение комплексными соединениями I и II, бензальдегидом и салициловой кислотой, уже через шесть дней после начала эксперимента (на модели каррагинан-индуцированного воспаления) объем пораженной конечности практически достиг контрольных значений. В ходе эксперимента было установлено, что комплексные соединения I и II продемонстрировали наилучшую противовоспалительную активность на обеих моделях воспаления.

Ключевые слова: противовоспалительная активность, комплексные соединения, бензальдегид, каррагинан, формалин.

Complex compounds tin (IV) chloride (SnCl₄) with salicyloyl hydrazones benzal- dehyde and 4-bromobenzaldehyde [1] were previously synthesized at the Department of General Chemistry and Polymers and anti-inflammatory activity of these compounds was determined on models of trypsin, histamine and carrageenan-induced inflammation [2, 3]. Among obtained compounds, it was interesting to study anti-inflammatory activity of benzaldehyde, 4-bromobenzaldehyde and salicylic acid on carrageenan- and formalin induced inflammation in order to determine their role in the anti-inflammatory activity of complex compounds SnCl₄ with Complex compound II Carrageenan-induced inflammation is an acute inflammation that is easily to replicate in the lab and used for studying the new prospective anti-inflammatory medicine, as well as the mechanism of development of the inflammatory process. Oedema, hyperalgesia and erythema develop immediately after inoculation of the of phlogogen injection, the mechanism of inflammation is based on increasing the release of inflammatory mediators (bradykinin, serotonin, histamine), nitric oxide and prostaglandins [4], as well as accompanied by nociceptive changes and the migration of inflammatory cells to the site of phlogogen inoculation. Development mechanism of the anti-inflammatory activity is due to the involvement of cyclooxygenase-2 (COX-2) that is induced by COX isozyme and it develops in the cells and tissues during development of the inflammatory reaction.

Formalin inflammation is the subacute inflammation and along with the local inflammation development and hyperaemia it also manifests itself as a systematic reaction that leads to chronic and localized pain [5], as a result, the inflammatory mediators such as biogenic amines, bradykinins, etc. start to produce. Also, the model of formalin inflammation is used for replication of arthritis in rats that is similar to human arthritis [6,7].

Anti-inflammatory activity of benzaldehyde and 4-bromobenzaldehyde was investigated and demonstrated in previously conducted studies using trypsin and histamine inflammation model [8].

Fig. 1. The volume change of the affected limb with carrageenan-induced inflammation (% of control)

Table 1

Dynamics of changes in the width of the affected limb using carrageenan-induced inflammation model

Materials and methods

Experiments were performed on Wistar male rats with weight around 180220 g that were kept in vivarium conditions on the standard diet with free access to water and nutrition. All studies conformed to the rules of the “European Convention for the Protection of Vertebrate Animals used for Experimental and Other Scientific Purposes” (Strasbourg, 1986) [9] and the principles of the Ukrainian National Congress on Bioethics (Kiev, 2003) [10].

Inflammatory reaction for each type of inflammation was induced by subplan- tar inoculation 0.2 ml of 0.2% aqueous solution of carrageenan (Sigma) and 0.1 ml of 2% formation (Sigma) solution [11,12] into the back surface of the rat's hind limb.

Studies were conducted on 12 groups of animals (6 groups for each type of inflammation), 3 rats each. Animals were treated directly after 24 hours after inflammation development. Control animal group received no treatment. Each tested animal group received treatment peroral: groups 2 and 3 received emulsion solutions of complexes SnCl₄ with salicyloyl hydrazones benzaldehyde and 4-bromobenzaldehyde prospectively; group 4 received emulsion of benzaldehyde in Twin; group 5 received emulsion of 4-bromobenzaldehyde in Twin; group 6 received solution of salicylic acid (40 mg/ kg).

Fig. 2. The volume change of the affected limb with formalin-induced inflammation (% of control).

Result evaluation of the experimental study was based on volume changes of limb (using digital plethysmometer 37140 (Ugo Basile, China)) and the width of the affected limb (using an electronic calliper YT-7201 (YATO, Poland)) before and after 24-hours, as well as in the dynamics throughout the experiment. Obtained experimental data were statistically processed by standard methods using the values of the arithmetic mean (M), standard deviation of arithmetic mean (m), Student's f-test and confidence factor. Anti-inflammatory activity of studied compounds was expressed as a percentage inhibition of oedema.

Results and discussions Carrageenan-induced model Represented data [figure 1] indicated that the volume of affected limbs of all tested animals after 24 hours after phl- ogogen inoculation (carrageenan) increased by 60%, but 2 days after the start of the experiment there was a clear trend of decreasing of the inflammatory foci in animals that perorally received complex compounds I and II.

Thus, within one day after the start of the experiment, increased volume of the affected limb for complex II compound was only 13%, for complex compound I - 24%. Then, for complex compound II there was a gradual reduction in volume of the affected limb within five days from the start of the experiment and achieving the volume measures of intact animals. Considering that salicylic acid and benzaldehydes are part of the complex compounds І and ІІ, it was assumed that they might play the main contribution to their anti-inflammatory activity. From the obtained data it is known that salicylic acid, as well as benzaldehyde and 4-bromobenzaldehyde, has an anti-inflammatory effect, which leads to a decrease in the inflammatory process during the first days of the experiment. Six days after the start of the experiment, the volume of the affected limb almost reached the control values in animals that received complex compounds I and II, benzaldehyde and salicylic acid.

It should be noted that dynamic change in the width of the affected limb (Table 1) was similar to the volume changes of the affected limb and demonstrated no statistical differences.

Formalin-induced inflammation.

According to obtained data, [figure 2] demonstrated that both complex compounds absolutely showed an anti-inflammatory effect using the formalin inflammation model.

Thus, three days after formalin inoculation the volume of affected limbs in rats of all tested groups increased by 72% comparing to intact values. Starting from the second day of the treatment with perorally inoculation of the complex compound I, the volume of affected limbs of rats decreased by around 19% and this tendency continued in the following days of the experiment. After 16 days of observation (14^th days of treatment) values of the group that was treated with peroral- l y i nocul ati on of compl ex compound I, almost reached the values of intact group of animals. During the peroral inoculation of the complex compound II the anti-inflammatory effect was also observed. Until 8^th days of observation the decreasing of the volume of affected rat limb was slower than it was in the rat group that were treated with complex compound I and it was 5-9% per day in average. However, all value of the volume of the affected rat limbs reached the control on the 14^th day of treatment. Benzaldehyde and 4-bro- mobenzaldehyde also demonstrated some anti-inflammatory activity throughout the experiment, on the 16^th day of observation (14^th day of treatment) the volume of the affected limbs reached initial values. Salicylic acid demonstrated the best anti-inflammatory activity and on the 7^th day of treatment the values of the affected limbs of rats decreased by around 37%, but the values of volume of affected limbs in rats did not return to the intact level until the end of the experiment in this investigation. During the visual observation of the rat limbs demonstrated no external signs of inflammation, in contrast to the control group of animals, which signs of inflammation were sufficiently pronounced on the 16^th day of observation.

Obtained data from the determination of the width of affected limbs of rats using the formalin-induced model demonstrated that, in general, the dynamic changes of the width of affected limbs matched with dynamic change of the volume, during the usage of all tested compounds, the values did not reach the control values, and 16 days after phlogogen inoculation which, apparently, related with physiology of resorption.

Conclusion

Thus, during the experiment it was determined that complex compounds I and II demonstrated the best anti-inflammatory activity in both models of inflammation. Obviously, the components of complex compounds I and II - salicylic acid and benzaldehydes were involved in the anti-inflammatory activity of these complexes.

References

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