RESUMEN
CONTEXT: Hypericum caprifoliatum Cham & Schlecht (Guttiferae) extracts have a potential antidepressant-like effect in rodents. However, the molecular mechanisms by which these extracts exert this effect remain unclear. OBJECTIVE: This study evaluated the effect of HC1, a fraction obtained from H. caprifoliatum enriched in phloroglucinol derivatives, on the Naâº, K⺠ATPase activity in mouse brain and verified the influence of veratrine on the effect of HC1 in the forced swimming test (FST). MATERIALS AND METHODS: Veratrine (0.06 mg/kg) and HC1 (360 mg/kg) were given alone or combined i.p. 60 and p.o. 30 min, respectively, before FST. The effect of single and repeated administration (once a day for 3 consecutive days) of HC1 (360 mg/kg) on Naâº, K⺠ATPase activity was evaluated ex vivo in the cerebral cortex and hippocampus of mice subjected or not to FST. RESULTS: HC1 reduced the immobility time (103.15 ± 18.67 s), when compared to the control group (183.6 ± 9.51 s). This effect was prevented by veratrine (151.75 ± 22.19 s). Mice repeatedly treated with HC1 presented a significant increase in Naâº, K⺠ATPase activity, both in cerebral cortex (46 ± 2.41 nmol Pi/min·mg protein) and hippocampus (49.83 ± 2.31 nmol Pi/min·mg protein), in relation to the respective controls (30 ± 2.66 and 29.83 ± 2.31 nmol Pi/min·mg protein respectively). DISCUSSION AND CONCLUSION: The HC1 antidepressant-like effect on FST might be related to its capacity to inhibit Na⺠influx. HC1 increases hippocampal and cortical Naâº, K⺠ATPase activities possibly through long-term regulatory mechanisms.
Asunto(s)
Antidepresivos/farmacología , Depresión/tratamiento farmacológico , Floroglucinol/farmacología , Extractos Vegetales/farmacología , Animales , Antidepresivos/administración & dosificación , Antidepresivos/aislamiento & purificación , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Modelos Animales de Enfermedad , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hypericum , Masculino , Ratones , Floroglucinol/administración & dosificación , Floroglucinol/aislamiento & purificación , Extractos Vegetales/administración & dosificación , Sodio/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Natación , Veratrina/administración & dosificación , Veratrina/farmacologíaRESUMEN
Valepotriates are iridoids found in variable amounts in Valerianaceae and might be among the bioactive compounds which confer anxiolytic properties to the Valeriana species. On the other hand, unspecific cytotoxicity has also been described. Presently, however, no particular molecular target has been defined for these compounds. Here we studied the effect of valtrate, acevaltrate, and 1- ß-acevaltrate isolated from Valeriana glechomifolia on the enzymatic activity of rat P-type ATPases. Valepotriates did not affect rat skeletal muscle sarco/endoplasmic reticulum Ca²âº-ATPase (SERCA) activity at the highest concentration used (100 µM). In contrast, the same concentration inhibited roughly half of the total Hâº/Kâº-ATPase activity from rat gastric epithelium (valtrate 54.6 ± 3.2â%, acevaltrate 60.7 ± 7.3â%, 1- ß-acevaltrate 50.2 ± 3.1â%; mean ± SEM, n = 3-5). Finally, these substances showed the highest inhibitory potency toward Naâº/Kâº-ATPase, and the inhibition curves obtained provided a similar IC50 (in µM) for rat kidney α1 isoform (valtrate 21.2, acevaltrate 22.8, 1- ß-acevaltrate 24.4) and brain hemispheres α2/ α3 isoforms (valtrate 19.4, acevaltrate 42.3, 1- ß-acevaltrate 38.3). Our results suggest that P-type ATPases are differentially inhibited by valepotriates and that Naâº/Kâº-ATPase might be one of their molecular targets in vivo.