Investigation of Antidepressant Effect of Riparin III: Behavioral and Neurochemical Alterations and Evaluation of Oxidative Stress

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgicoA depressÃo à uma doenÃa recorrente e incapacitante cujo tratamento està relacionado com modulaÃÃes nos sistemas monoaminÃrgicos em diversas Ãreas cerebrais. A riparina III (ripIII), isolada do fruto verde de Aniba riparia, apresentou, em estudos prÃvios, efeito antidepressivo. Dessa forma, objetivando investigar o potencial antidepressivo da ripIII, foram realizados testes comportamentais como o nado forÃado (TNF), suspensÃo da cauda (TSC), hipotermia induzida por apomorfina e campo aberto. Para avaliar o envolvimento das monoaminas, os animais foram prÃ-tratados com antagonistas especÃficos para receptores 5-HT1A, 5-HT2A/2C e 5-HT3 de serotonina (5-HT), D1 e D2 de dopamina (DA) e a1 e a2 de noradrenalina (NA) no TNF. AlÃm disso, os animais prÃ-tratados com ripIII e submetidos ou nÃo ao TNF tiveram as Ãreas cerebrais hipocampo, corpo estriado e cÃrtex prÃ-frontal retiradas para detecÃÃo dos nÃveis de monoaminas ou para realizaÃÃo dos experimentos de estresse oxidativo, investigando a atividade enzimÃtica da catalase e superÃxido dismutase, quantificando os nÃveis de glutationa reduzida (GSH) e nitrito/nitrato, alÃm do grau de lipoperoxidaÃÃo. A ripIII foi administrada agudamente, por via oral, na dose de 50 mg/kg, em todos os testes. Os resultados mostraram que a ripIII apresentou efeito antidepressivo nos modelos TNF e TSC sugerindo ser especÃfico, uma vez que os animais nÃo apresentaram alteraÃÃes na atividade locomotora no campo aberto. AlÃm disso, no TNF, os antagonistas sulpirida (D2), prazosina (a1), ioimbina (a2), NAN-190 (5-HT1A) e ondansentron (5-HT3) reverteram o tempo de imobilidade da ripIII sugerindo a participaÃÃo desses receptores para o efeito da substÃncia, enquanto nÃo houve alteraÃÃo deste efeito na presenÃa dos antagonistas SCH23390 (D1) e ritanserina (5- HT2A/2C) mostrando o nÃo envolvimento desses receptores no efeito da droga. A ripIII nÃo foi capaz de reverter a hipotermia induzida por apomorfina, que na dose utilizada, induz hipotermia por modular receptores b-adrenÃrgicos, sugerindo que o efeito da ripIII nÃo està relacionado com esses receptores. A ripIII apÃs o TNF, em corpo estriado e cÃrtex prÃfrontal, aumentou os nÃveis de DA, 5-HT e NA, diminuiu os metabÃlitos DOPAC, HVA, 5- HIAA e as taxas metabÃlicas e, no hipocampo, aumentou 5-HT e NA alÃm do metabÃlito 5- HIAA, mas manteve as taxas metabÃlicas. A administraÃÃode ripIII, antes do TNF, reverteu o aumento nos nÃveis de peroxidaÃÃo lipÃdica e nitrito-nitrato, reduziu a atividade da catalase mas aumentou os nÃveis de GSH em hipocampo, corpo estriado e cÃrtex prÃfrontal. Esses parÃmetros nÃo foram alterados nos animais nÃo submetidos ao estresse. Em conclusÃo, o estudo sugere uma aÃÃo moduladora, exercida por ripIII, sobre o funcionamento dos sistemas noradrenÃrgico, dopaminÃrgico e serotonÃrgico, em nÃvel central, como mecanismo para o efeito antidepressivo no TNF, bem como a participaÃÃo de propriedades antioxidantes diretas ou indiretas dessa droga, atravÃs da capacidade de modificar a resposta ao estresse oxidativo neuronal.Depression is a disabling and recurrent disease whose treatment is related to modulations in monoaminergic systems in several brain areas. Riparin III (ripIII), isolated from unripe fruit of Aniba riparia, has shown previously antidepressant-like effects. Thus, in order to investigate the antidepressant effect of ripIII, behavioral experiments were performed, as the forced swim (FST), tail suspension (TST), apomorphine-induced hypothermia and open field tests. To assess the involvement of monoaminergic system, animals were pretreated with specific antagonists to 5-HT1A-, 5-HT2A/2C-, and 5-HT3-serotonin (5-HT) receptors, to D1- and D2-dopamine (DA) receptors and to 1- and 2-noradrenaline (NA) receptors in FST. Further, animals pretreated with ripIII and submitted or not to the FST had their brain areas such as hippocampus, striatum and prefrontal cortex removed for detection of monoamine levels or to carry out the experiments of oxidative stress, in which, it was investigated enzymatic activities of catalase and superoxide dismutase, measured the levels of reduced glutathione (GSH) and nitrite/nitrate, and lipid peroxidation degree. RipIII was acutely administered orally at a dose of 50 mg/kg in all tests. The results showed that ripIII presented antidepressant effect on the FST and TST suggesting that this effect is specific, since the animals showed no changes in locomotor activity in open field test. In the evaluation of monoaminergic systems, the results showed that the antagonists sulpiride (D2), prazosin (1), yohimbine (2), NAN-190 (5-HT1A) and ondansentron (5-HT3) reversed the immobility time of ripIII on the FST suggesting the involvement of these receptors, while no change of this effect in the presence of the antagonists SCH23390 (D1) and ritanserin (5-HT2A/2C) was observed, suggesting non-participation of these receptors in the drug effect. RipIII was unable to reverse the hypothermia induced by apomorphine that at the dose used, modulates -adrenergic receptors inducing hypothermia, suggesting that the effect of ripIII is not related to these receptors. RipIII, after FST, in the striatum and prefrontal cortex, increased levels of DA, 5-HT and NA, decreased DOPAC, HVA, 5-HIAA metabolites and decreased metabolic rates, and in the hippocampus, increased 5-HT and NA and 5-HIAA metabolite, but maintained metabolic rates. The prior administration of ripIII before the forced swimming, reversed the increased levels of lipid peroxidation and nitrite-nitrate, reduced the activity of catalase but increased levels of GSH in hippocampus, striatum and prefrontal cortex. These parameters were not altered in animals not exposed to stress. In conclusion, the study suggests a modulating action exerted by ripIII on the functioning of the noradrenergic, dopaminergic and serotonergic levels in the brain, as a mechanism for the antidepressant effect in the FST, as well as the participation of direct or indirect antioxidant properties of this drug through the ability to modify the neuronal response to oxidative stres

Antidepressant-Like Effect of Lippia sidoides CHAM (Verbenaceae) Essential Oil and Its Major Compound Thymol in Mice

Depression is a common disease affecting more than 300 million people worldwide. Since Lippia sidoides has shown central nervous system effects in previous works, we aimed to investigate the effect of L. sidoides essential oil and its major compound, thymol on a corticosterone-induced depression model in mice. Male mice (20–25 g) received corticosterone (20 mg/kg, subcutaneously), once a day for 22 days. From the 16th day on, mice were grouped to receive either corticosterone or L. sidoides essential oil (100 and 200 mg/kg), or thymol (25 and 50 mg/kg) or fluoxetine (35 mg/kg) by gavage. The forced swimming test, tail suspension, open field, elevated plus maze and sucrose preference tests were performed from the 19th to 22nd day. Data were analyzed by ANOVA followed by the Student-Newman-Keuls as a post hoc test and the results were considered significant when p < 0.05. It was shown that L. sidoides essential oil, thymol and fluoxetine decreased the immobility time in the tail suspension and forced swimming tests and none of these altered locomotor activity in the open field test. However, the drugs increased the amount of grooming. In the elevated plus maze, all drugs increased the number of entries and the time of permanence in the open arms. In the sucrose preference test, the L. sidoides essential oil, thymol and fluoxetine reversed anhedonia. These results suggest that the thymol and L. sidoides essential oil have an antidepressant-like effect, similar to fluoxetine. However, future studies should be encouraged to enhance understanding of the effects of essential oil and thymol for the treatment of depression