Clarice de Carvalho Veloso

Antinociceptive and anti-inflammatory properties of 7-epiclusianone, a prenylated benzophenone from Garcinia brasiliensis

7-Epiclusianone, a natural prenylated benzophenone, was extracted from Garcinia brasiliensis Planch. & Triana (Clusiaceae), a native plant commonly known as bacupari and used in traditional Brazilian medicine for the treatment of inflammatory diseases. As a result of the wide spectrum of biological activities attributed to polyisoprenylated benzophenones, the aim of this study was to evaluate the analgesic and anti-inflammatory effects of 7-epiclusianone using two animal models. Carrageenan-induced paw oedema and peritonitis were used to investigate the anti-inflammatory activity of 7-epiclusianone in rats. The acetic acid-induced writhing, formalin and hot-plate tests were used to investigate its antinociceptive activity in mice. At test doses of 5, 10 and 15 mg/kg p.o., 7-epiclusianone had an anti-inflammatory effect as demonstrated by the reduction of paw oedema induced by carrageenan and the inhibition of leukocyte recruitment into the peritoneal cavity. At the same doses, 7-epiclusianone inhibited nociception induced by an intraperitoneal injection of acetic acid, observed by the decrease in the number of writhing episodes. Additionally, 7-epiclusianone decreased licking time caused by a subplantar injection of formalin. Moreover, the hot plate test produced a significant increase in latency reaction, demonstrating an antinociceptive effect. The experimental data demonstrated that the polyisoprenylated benzophenone 7-epiclusianone has remarkable anti-inflammatory and antinociceptive activities.

Tingenone, a Pentacyclic Triterpene, Induces Peripheral Antinociception Due to Opioidergic Activation

Plants belonging to the genus Maytenus are routinely used in folk medicine for the treatment of pain diseases. Our previous phytochemical study of the roots of Maytenus imbricata resulted in the isolation and characterization of tingenone, a pentacyclic triterpene. Natural triterpenoids are of growing interest because they have several biological activities, including analgesic properties. The present study assessed the involvement of the opiodergic pathway in the tingenone-induced antinociceptive effect against hyperalgesia induced by prostaglandin E2 (2 µg) in the peripheral pathway. We evaluated the effect of several antagonists to opioid receptors using the mouse paw pressure test. Tingenone administered into the right hind paw induced a local antinociceptive effect that was antagonized by naloxone, a nonselective antagonist to opioid receptors. Clocinnamox, naltrindole, and nor-binaltorphimine are selective antagonists to µ, δ, and κ receptors, respectively, which reverted the peripheral antinociception induced by tingenone. Bestatine acts as an inhibitor of aminopeptidase, an enzyme that degrades endogenous opioid peptides, and was shown to intensify the antinociceptive effect of tingenone. The results suggest that the opioidergic system participates in the peripheral antinociception induced by tingenone.

Antinociceptive and anti-inflammatory effects of myricetin 3-O-β-galactoside isolated from Davilla elliptica: involvement of the nitrergic system

We aimed to study the antinociceptive effects of myricetin 3-O-β-galactoside (Mi), a substance isolated from the hydroalcoholic extract of Davilla elliptica. This study examined male Swiss mice, inducible nitric oxide synthase C57B16/J knockout mice (iNOS−/−), and their corresponding wild type (WT). Formalin and tail-flick tests were used to evaluate the nociceptive threshold, and the carrageenan-induced paw edema test was used as a model for inflammation. The following drugs were administered to investigate the involvement of the nitrergic and opioidergic systems: l-NAME, a nonspecific nitric oxide synthase (NOS) inhibitor; l-arginine (l-Arg), a precursor for the synthesis of nitric oxide (NO); d-arginine (d-Arg), an inactive isomer for the synthesis of NO; aminoguanidine (Am), an inducible nitric oxide synthase (iNOS) inhibitor; and naloxone, a nonselective antagonist of opioid receptors. The results showed that oral pretreatment with Mi caused a dose-dependent inhibition of the inflammatory phase of the formalin test and did not alter motor performance. Intraperitoneal injection of l-NAME caused a reduction in the licking time during the second phase of the formalin test. The administration of l-Arg (but not d-Arg) reversed the antinociceptive effect of l-NAME. Furthermore, pre-administration of aminoguanidine potentiated the antinociceptive effect. Mi did not cause an antinociceptive effect in iNOS knockouts and led to a reduction in the nitrite concentration in the paws of mice. Carrageenan-induced paw edema was reduced in Swiss mice and WT mice when compared to iNOS−/− mice. Pre-administration of naloxone (NLX) did not reverse the antinociceptive effect of Mi, excluding the opioidergic system as a mediator of the antinociceptive effect. Thus, the results suggest that the antinociceptive and anti-inflammatory effects of myricetin 3-O-β-galactoside are related to peripheral inhibition of nitric oxide synthesis, mainly iNOS.

Tingenone, a pentacyclic triterpene, induces peripheral antinociception due to NO/cGMP and ATP-sensitive K+ channels pathway activation in mice

Substances derived from plants play an important role in the development of new analgesic drugs, among them, triterpenoids. The connection between the participation of L-arginine/NO/cGMP pathway and the activation of ATP-sensitive K(+) channels (KATP) has been established on the peripheral antinociception induced by various drugs. The study assessed the involvement of L-arginine/NO/cGMP/KATP pathway in the antinociceptive effect induced by tingenone, from Maytenus imbricata, against the hyperalgesia evoked by prostaglandin E2 (PGE2) in peripheral pathway. The paw pressure test was used, with hyperalgesia induced by intraplantar injection of PGE2 (2 μg). Tingenone (200 µg/paw) administered into the right hind paw induced a local antinociceptive effect, that was antagonized by l-NOArg, nonselective nitric oxide synthase (NOS) inhibitor and by L-NPA, selective neuronal NOS (nNOS) inhibitor. The L-NIO, selective inhibitor of endothelial (eNOS), and the L-NIL, selective inhibitor of inducible (iNOS), did not alter the peripheral antinociceptive effect of the tingenone. The ODQ, selective soluble guanylyl cyclase inhibitor, prevented the antinociceptive effect of tingenone, and zaprinast, inhibitor of the phosphodiesterase that is cyclic guanosine monophosphate (cGMP) specific, intensified the peripheral antinociceptive effect of the smaller dose of tingenone. Glibenclamide, ATP-sensitive K(+) channels (KATP) blocker, but not tetraethylammonium chloride, voltage-dependent K(+) channel blocker; dequalinium dichloride, blocker of the small conductance Ca(2+)-activated K(+) channel, and paxilline, a potent blocker of high-conductance Ca(2+)-activated K(+) channels, respectively, prevented the peripheral antinociceptive effect of tingenone. The results demonstrate that tingenone induced a peripheral antinociceptive effect by L-arginine/NO/cGMP/KATP pathway activation, with potential for a new analgesic drug.

Hydroethanolic extract of Pyrostegia venusta (Ker Gawl.) Miers flowers improves inflammatory and metabolic dysfunction induced by high-refined carbohydrate diet

ETHNOPHARMACOLOGICAL RELEVANCE Pyrostegia venusta is used in traditional Brazilian medicine as a general tonic to treat any inflammatory disease. Several studies have demonstrated that medicinal plants constitute a therapeutic approach for the treatment of obesity-related metabolic and inflammatory disarrangement. Accordingly, we investigated the effects of hydroethanolic extract of Pyrostegia venusta flowers (PvHE) supplementation for the treatment of inflammatory and metabolic dysfunction induced by high-refined-carbohydrate (HC) diet. MATERIAL AND METHODS The BALB/c mice were fed chow or HC diet for 8 weeks. Part of these animals was fed with HC diet supplemented with PvHE on the 9th week until the 12th week. At the end of the dietary intervention, animals were sacrificed. RESULTS We observed that PvHE decreased adiposity and adipocyte area; improved glucose intolerance; reduced serum triacylglycerol levels and systemic inflammatory cells; and also reduced some inflammatory mediators levels in adipose tissue and liver. CONCLUSION The results showed that PvHE has beneficial effects and may treat inflammatory and metabolic dysfunction induced by HC diet, that are associated to a negative modulation of the inflammatory process at systemic and local levels.

Peltatoside Isolated from Annona crassiflora Induces Peripheral Antinociception by Activation of the Cannabinoid System.

Peltatoside is a natural compound isolated from leaves of Annona crassiflora Mart., a plant widely used in folk medicine. This substance is an analogue of quercetin, a flavonoid extensively studied because of its diverse biological activities, including analgesic effects. Besides, a previous study suggested, by computer structure analyses, a possible quercetin-CB1 cannabinoid receptor interaction. Thus, the aim of this work was to assess the antinociceptive effect of peltatoside and analyze the cannabinoid system involvement in this action. The mouse paw pressure test was used and hyperalgesia was induced by intraplantar injection of carrageenan (200 µg/paw). All used drugs were administered by intraplantar administration in Swiss male mice (n = 6). Peltatoside (100 µg/paw) elicited a local inhibition of hyperalgesia. The peripheral antinociceptive action of peltatoside was antagonized by the CB1 cannabinoid antagonist AM251 (160 µg/paw), but not by CB2 cannabinoid antagonist AM630 (100 µg/paw). In order to assess the role of endocannabinoids in this peripheral antinociceptive effect, we used (i) [5Z,8Z,11Z,14Z]-5,8,11,14-eicosatetraenyl-methyl ester phosphonofluoridic acid, an inhibitor of anandamide amidase; (ii) JZL184, an inhibitor for monoacylglycerol lipase, the primary enzyme responsible for degrading the endocannabinoid 2-arachidonoylglycerol; and (iii) VDM11, an endocannabinoid reuptake inhibitor. MAFP, JZL184, and VDM11 did not induce antinociception, respectively, at the doses 0.5, 3.8, and 2.5 µg/paw, however, these three drugs were able to potentiate the peripheral antinociceptive effect of peltatoside at an intermediary dose (50 µg/paw). Our results suggest that this natural substance is capable of inducing analgesia through the activation of peripheral CB1 receptors, involving endocannabinoids in this process.

3-Hydroxy-piperidinyl-N-benzyl-acyl-arylhydrazone derivatives reduce neuropathic pain and increase thermal threshold mediated by opioid system

Here in, we report the preparation and evaluation of four 3-hydroxy-piperidine-N-benzyl-aryl-acylhydrazone derivatives (6a-d) for their potential antinociceptive activity. In the tail flick test, compounds 6a and 6d exhibited a significant increase in the latency time of the animals, in comparison to the control group. These two compounds also showed a significant increase in the nociceptive threshold from 1 to 6 h after treatment in the CCI neuropathic pain model. In both cases, the antinociceptive activity was blocked by naloxone, suggesting an opioid mechanism of action, but without sedative or motor coordination effects.