Vanessa Angonesi Zborowski

Pomegranate seed oil nanoemulsions improve the photostability and in vivo antinociceptive effect of a non-steroidal anti-inflammatory drug

The combination of pomegranate seed oil and ketoprofen in nanoemulsions aiming to improve the antinociceptive effect was evaluated according to the writhing test and Complete Freuds Adjuvant induced paw inflammation in mice. The formulations showed adequate characteristics and improved ketoprofens photostability against UVC radiation exposure. The dialysis bag technique showed that 100% of the drug was released from the nanoemulsions after 3h and the oil amount had no influence on the releasing. Furthermore, time- and dose-response curves were obtained to determine the antinociceptive effect of the formulations. In the post-test, the nanoemulsion containing ketoprofen significantly reduced abdominal constrictions in time-response curve, showing effect up to 12h while the free ketoprofen showed effect up to 3h. In addition, the blank nanoemulsion presented a reduction of abdominal constriction up to 1h of pre-treatment. Regarding the dose-response curve, the free ketoprofen presents effect at 0.5mg/Kg dose and nanoemulsion at 1.0mg/Kg dose. Time- and dose-response curves were performed to determine the antinociceptive effect in inflammatory pain. After the evaluation of mechanical allodynia testing at the Von Frey Hair, the free ketoprofen showed effect up to 6h while nanoemulsions presented effect up to 10h. Moreover, acute toxicity was performed with ALT and AST activity evaluations and urea levels. After 7 days of treatment, no toxic effects for nanoemulsions were found. In conclusion, ketoprofen-loaded pomegranate seed oil nanoemulsions presented adequate characteristics and a high antinociceptive activity in the animal models tested.

Ketoprofen-loaded pomegranate seed oil nanoemulsion stabilized by pullulan: Selective antiglioma formulation for intravenous administration

This study aimed to prepare pomegranate seed oil nanoemulsions containing ketoprofen using pullulan as a polymeric stabilizer, and to evaluate antitumor activity against in vitro glioma cells. Formulations were prepared by the spontaneous emulsification method and different concentrations of pullulan were tested. Nanoemulsions presented adequate droplet size, polydispersity index, zeta potential, pH, ketoprofen content and encapsulation efficiency. Nanoemulsions were able to delay the photodegradation profile of ketoprofen under UVC radiation, regardless of the concentration of pullulan. In vitro release study indicates that nanoemulsions were able to release approximately 95.0% of ketoprofen in 5h. Free ketoprofen and formulations were considered hemocompatible at 1 μg/mL, in a hemolysis study, for intravenous administration. In addition, a formulation containing the highest concentration of pullulan was tested against C6 cell line and demonstrated significant activity, and did not reduce fibroblasts viability. Thus, pullulan can be considered an interesting excipient to prepare nanostructured systems and nanoemulsion formulations can be considered promising alternatives for the treatment of glioma.

Evidence for the contribution of multiple mechanisms in the feeding pattern of rats exposed to p-chloro-diphenyl diselenide-supplemented diets

Preliminary findings suggest that food intake reduction induced by p-chloro-diphenyl diselenide [(p-ClPhSe)2] in rats is mediated by a satiating action; however, additional experiments are necessary to clarify its actions. The purpose of this study was to investigate the effects of diets supplemented with (p-ClPhSe)2 on feeding behavior of rats as well as the (p-ClPhSe)2 effectiveness in producing aversive reactions or specific flavor. The results demonstrated that behavioral satiety sequence (BSS) was preserved in animals exposed to (p-ClPhSe)2-supplemented diets (0.01 and 0.1%) and associated with a shift of the onset of resting to the left indicating a satiating action at the first contact. In addition, the frequency, the mean duration and the mean size of meals were decreased in rats exposed to a 0.1% (p-ClPhSe)2 diet. Alternatively, a second contact with a 0.01% (p-ClPhSe)2 diet caused disruption of BSS and pronounced changes in the meal pattern, suggesting that it produces aversiveness. In fact, rats developed a significant taste aversion to the saccharin solution after receiving the administration of (p-ClPhSe)2 (1 and 10mg/kg; i.p.). Lastly, a diet containing 0.1% of (p-ClPhSe)2 seems to alter the palatability of food given that rats had a preference for the control diet. The findings of the present study suggest that (p-ClPhSe)2 reduced the food intake of rats by inducing a satiating action at the first contact, but it also produced aversive reactions when rats were re-exposed to it. A specific flavor seems also to contribute to (p-ClPhSe)2 suppressant effects on feeding.

p,p′-Methoxyl-diphenyl diselenide elicits an antidepressant-like effect in mice without discontinuation anxiety phenotype

Abstract Major depressive disorder is the most severe and debilitating disease among psychiatric illnesses. The abrupt interruption of antidepressant treatment may lead to a complex physiological and neuropsychiatric syndrome. The organoselenium compound (MeOPhSe)2 has been reported to have neuroprotective properties in animal models. The study aimed to investigate the effects of single or repeated administration of (MeOPhSe)2 on depressive‐like behavior and if the compound administration, and its discontinuation, may affect the anxiolytic‐like phenotype in Swiss mice. The results showed that repeated intragastric administration of (MeOPhSe)2 (dose range: 0.1–5 mg/kg), different from a single administration, reduced the immobility time in the mouse tail suspension test. A single administration of (MeOPhSe)2 at a dose of 5 mg/kg decreased the immobility time, increased the swimming time and did not alter the climbing behavior in the modified forced swimming test (mFST). Repeated administration of (MeOPhSe)2 decreased the immobility time, did not alter the swimming time and increased the climbing behavior in the mouse mFST. Repeated administration of (MeOPhSe)2 at a dose of 5 mg/kg elicited a mouse anxiolytic‐like phenotype in the elevated plus maze and light–dark tests. Markers of hepatic and renal function tests were not altered by repeated administration of (MeOPhSe)2 to mice. The findings indicate that a single or repeated administration of (MeOPhSe)2 elicited an antidepressant‐like action in mice. Moreover, repeated treatment with (MeOPhSe)2 produced an anxiolytic‐like action in mice and its profile remained stable after discontinuation. Highlights(MeOPhSe)2 single administration elicited an antidepressant‐like effect.(MeOPhSe)2 repeated administration elicited an antidepressant‐like effect.(MeOPhSe)2 repeated administration elicited an anxiolytic‐like action.(MeOPhSe)2 discontinuation did not cause anxiogenic‐like effect.(MeOPhSe)2 repeated administration caused neither renal nor hepatic toxicity.

p,p′-Methoxyl-diphenyl diselenide-loaded polymeric nanocapsules are chemically stable and do not induce toxicity in mice

Graphical abstract Figure. No caption available. Highlights(OMePhSe)2 polymeric nanocapsules were physicochemically characterized.The nanocapsules increased the (OMePhSe)2 stability.(OMePhSe)2 nanocapsules showed no hemolytical effect in vitro and in vivo toxicity.(OMePhSe)2 had wide tissue distribution that was improved by nanocapsules. ABSTRACT Organoselenium compounds have been targeted to new therapeutic tools development due to their pharmacological actions. However, some toxicity issues and physicochemical limitations delay the clinical application of these compounds. The incorporation of organoselenium molecules into nanostructured systems arises as a promising alternative to overcome such restrictions. The current study proposed the characterization of the polymeric nanocapsules of p,p′‐methoxyl‐diphenyl diselenide [(OMePhSe)2] as well as the evaluation of the in vivo toxicity and biodistribution profile. The nanocapsules, which were composed by medium‐chain triglycerides as the oil core and poly(&egr;‐caprolactone) as the polymeric wall, showed nanometric size (236 ± 4), low polydispersity (<0.2), negative zeta potential (−5.4 ± 0.06), neutral pH values (7.2 ± 0.08) and a high encapsulation efficiency (98%). Besides, the nanoencapsulation process increased the (OMePhSe)2 stability. The repeated intragastric administration of (OMePhSe)2 nanoencapsulated (25 mg/kg/day during 7 days) did not cause any alteration in the oxidative status, hematological parameters, and plasma biochemical markers of cellular damage. Moreover, the (OMePhSe)2 incorporation into nanocapsules increased the selenium concentrations in the tissues (kidneys, liver and plasma) suggesting an improvement in its oral bioavailability.

p,p′-Methoxyl-diphenyl diselenide-loaded polymeric nanocapsules as a novel approach to inflammatory pain treatment: Behavioral, biochemistry and molecular evidence

ABSTRACT The current study investigated the effect of organoselenium compound p,p′‐methoxyl‐diphenyl diselenide [(OMePhSe)2], free or incorporated into nanocapsules, on behavioral, biochemical and molecular alterations in an inflammatory pain model induced by complete Freunds adjuvant (CFA). Male Swiss mice received an intraplantar injection of CFA in the hindpaw and 24 h later they were treated via the intragastric route with a single (OMePhSe)2 administration, in its free form (dissolved in canola oil) or (OMePhSe)2 NC. The anti‐hypernociceptive time‐ and dose‐response curves were carried out using the von Frey hair test. Biochemical and histological parameters were determined in samples of injected paws and those of cerebral contralateral cortex were collected to determine immuno content of inflammatory proteins. Both (OMePhSe)2 forms reduced the hypernociception induced by CFA as well as attenuated the altered parameters of the inflammatory process in the paw (paw edema, myeloperoxidase and histological). However, the (OMePhSe)2 NC had a more prolonged anti‐hypernociceptive action (7 h) at a lower dose (10 mg/kg) and superior effects on the paw alterations than the free compound form (4 h and 25 mg/kg). Furthermore, independent of the (OMePhSe)2 form, its administration decreased the MAPKs pathway activation (JNK;ERK1,2; p38) as well as iNOS, COX‐2, Nf‐&kgr;B and IL‐1&bgr; protein contents in the cerebral contralateral cortex that were increased by paw CFA injection. Therefore, (OMePhSe)2 NC had superior anti‐inflammatory action, which possibly occurs by the inflammatory protein content modulation and also attenuates paw biochemical and histological inflammatory alterations induced by CFA injection. Graphical abstract Figure. No Caption available.