Neuropharmacological effects of carvacryl acetate on δ-aminolevulinic dehydratase, Na+, K+-ATPase activities and amino acids levels in mice hippocampus after seizures.

Epileptic syndromes are highly prevalent neurological conditions and can often be disabling. In order to find an alternative for treatment, this study evaluated anticonvulsant effects of carvacryl acetate (CA), a derivative of monoterpene carvacrol, after seizures induced by pilocarpine (P400), picrotoxin (PIC) or pentylenetetrazol (PTZ). We also analyzed the CA effects on Na+, K+-ATPase and δ-aminolevulinic acid dehydratase (δ-ALA-D) activities in hippocampus mice after seizures induced by P400, PIC or PTZ. In addition, glutamate, δ-aminobutyric acid (GABA), glutamine and aspartate levels in mice hippocampus treated with CA after seizures induced by P400, PIC or PTZ were also measured. CA produced anticonvulsant effects against seizures induced by P400, PIC or PTZ, and its effects were reversed by flumazenil, suggesting that action mechanism can be mediated by GABAergic system. CA increased GABA levels, but did not alter glutamate and aspartate concentrations in mice hippocampus after seizures induced by P400, PIC or PTZ when compared with seizures induced by P400, PIC or PTZ (p<0.05), respectively, as well as decreased glutamine content in mice hippocampus after seizures induced by PIC when compared with seizures induced by PIC (p<0.05). In addition, CA also increased Na+, K+-ATPase and δ-aminolevulinic acid dehydratase activities after seizures induced by P400, PIC or PTZ when compared with seizures induced by P400, PIC or PTZ (p<0.05), respectively. This study demonstrated that CA could be a future therapeutic option for treatment of epilepsy, with a multifactorial brain action mechanism.

Valproic acid: an anticonvulsant drug with potent antinociceptive and anti-inflammatory properties.

Valproic acid (VA) is a major antiepileptic drug, used for several therapeutic indications. It has a wide activity spectrum, reflecting on mechanisms of action that are not fully understood. The objectives of this work were to study the effects of VA on acute models of nociception and inflammation in rodents. VA (0.5, 1, 10, 25, and 50 mg/kg, p.o.) effects were evaluated on the carrageenan-induced paw edema, carrageenan-induced peritonitis, and plantar tests in rats, as well as by the formalin test in mice. The HE staining and immunohistochemistry assay for TNF-α in carrageenan-induced edema, from paws of untreated and VA-treated rats, were also carried out. VA decreased paw edema after carrageenan, and maximum effects were seen with doses equal to or higher than 10 mg/kg. VA also preserved the tissue architecture as assessed by the HE staining. Immunohistochemical studies revealed that VA significantly reduced TNF-α immunostaining in carrageenan-inflamed rat paws. In addition, the anti-inflammatory action of VA was potentiated by pentoxifylline (a phosphodiesterase inhibitor, known to inhibit TNF-α production), but not by sodium butyrate or by suberoylanilide hydroxamic acid (SAHA), nonspecific and specific inhibitors, respectively, of histone deacetylase. However, the decrease in the number of positive TNF-α cells in the rat paw was drastically potentiated in the VA + SAHA associated group. VA also reduced leukocytes and myeloperoxidase (MPO) releases to the peritoneal exudate, in the carrageenan-induced peritonitis. Although in the formalin test, VA inhibited both phases, the inhibition was mainly on the second phase. Furthermore, VA significantly increased the reaction time to thermal stimuli, as assessed by the plantar test. VA is a multi-target drug, presenting potent antinociceptive and anti-inflammatory properties at a lower dose range. These effects are partly dependent upon its inhibitory action on TNF-α-related pathways. However, the participation of the HDAC inhibition with the VA anti-inflammatory action cannot be ruled out. Inflammatory processes are associated with free radical damage and oxidative stress, and their blockade by VA could also explain the present results.

Effects of hecogenin and its possible mechanism of action on experimental models of gastric ulcer in mice.

This study investigates the gastroprotective effects of hecogenin, a steroid saponin isolated from Agave sisalana, on experimental models of gastric ulcer. Male Swiss mice were used in the models of ethanol- and indometacin-induced gastric ulcer. To clarify the hecogenin mechanism of action, the roles of nitric oxide (NO), sulfhydryls (GSH), K⁺(ATP) channels and prostaglandins were also investigated, and measurements of lipid peroxidation (TBARS assay) and nitrite levels in the stomach of hecogenin-treated and untreated animals were performed. Furthermore, the effects of hecogenin on myeloperoxidase (MPO) release from human neutrophils were assessed in vitro. Our results showed that hecogenin (3.1, 7.5, 15, 30, 60 and 90 mg/kg, p.o.) acutely administered, before ethanol or indomethacin, exhibited a potent gastroprotective effect. Although the pretreatments with L-NAME, an iNOS inhibitor, and capsazepine, a TRPV1 receptor agonist, were not able to reverse the hecogenin effect, this was reversed by glibenclamide, a K⁺(ATP) blocker, and indomethacin in the model of ethanol-induced gastric lesions. The hecogenin pretreatment normalized GSH levels and significantly reduced lipid peroxidation and nitrite levels in the stomach, as evaluated by the ethanol-induced gastric lesion model. The drug alone increased COX-2 expression and this effect was further enhanced in the presence of ethanol. It also decreased MPO release and significantly protected the gastric mucosa. In conclusion, we showed that hecogenin presents a significant gastroprotective effect that seems to be mediated by K⁺(ATP) channels opening and the COX-2/PG pathway. In addition, its antioxidant and anti-inflammatory properties may play a role in the gastroprotective drug effect.