Medicinal Plants in the Treatment of Colitis: Evidence from Preclinical Studies.

Ulcerative colitis is a chronic inflammatory condition whose treatment includes aminosalicylates, corticosteroids, and immunomodulators. Medicinal plants seem to be an important alternative treatment for this condition. They have been the subject of a great number of studies in recent years. This study was conducted to systematically review the medicinal plants tested in experimental models of ulcerative colitis. We conducted a systematic literature search through specialized databases (PUBMED, SCOPUS, EMBASE, MEDLINE, LILACS, SCIELO, and SCISEARCH) and selected articles published between January 2000 and June 21, 2016 by using "medicinal plants" and "ulcerative colitis" as key words. Sixty-eight studies were included, and the families Asteraceae and Lamiaceae presented the largest number of studies, but plants from several other families were cited; many of them have shown good results in experimental animals. However, only a few species (such as Andrographis paniculata and Punica granatum) have undergone clinical tests against ulcerative colitis, and the observation that many preclinical studies reviewed are purely descriptive has certainly contributed to this fact. Chemical constituents (mainly flavonoids and terpenes) seem to play a role in the effects of the plants. Thus, the data herein reviewed reinforce the potential of medicinal plants as a source of alternative approaches to the treatment of ulcerative colitis.

Orofacial antinociceptive effect and antioxidant properties of the hydroethanol extract of Hyptis fruticosa salmz ex Benth.

ETHNOPHARMACOLOGICAL RELEVANCE: Hyptis fruticosa is a plant native to Brazil with antinociceptive and antiinflamatory properties. This study evaluated the antinociceptive activity of the hydroethanol extract of the plant leaves (CHEE) against orofacial pain as well as its in vitro effect against lipid peroxidation. MATERIALS AND METHODS: The antinociceptive activity was investigated in mice orally treated with different doses of the CHEE (50, 100, and 200 mg/kg) and morphine (5 mg/kg) using formalin, glutamate, and capsaicin orofacial pain models using. Lipoperoxidation was induced in egg yolk by AAPH and FeSO4 in the absence and presence of the CHEE (5, 50, 100, and 150 µg/mL). RESULTS: CHEE (200 mg/kg) significantly reduced (ρ<0.001) the pain response in the first (69.6%) and second (81.8%) phases of the formalin test, while the nociception caused by capsaicin was significantly (ρ<0.001) reduced by up to 62% at 200 mg/kg of extract. When glutamate was used as algogen, a significant (ρ<0.001) nociception reduction of up to 85% at 200 mg/kg extract was observed. CHEE showed a higher protection against lipoperoxidation caused by FeSO4 (82.3% TBARS inhibition) than AAPH (35.7% TBARS inhibition) at 150 µg/mL. CONCLUSION: Hyptis fruticosa leaf CHEE is of pharmacological interest because it was able to inhibit the peripheral and central transmission of orofacial pain, while reducing the spreading of the inflammatory processes by neutralizing reactive oxygen species, which are by-products in the biosynthesis of pain mediators.

Citronellol reduces orofacial nociceptive behaviour in mice - evidence of involvement of retrosplenial cortex and periaqueductal grey areas.

Citronellol (CT) is a monoterpenoid alcohol present in the essential oil of many medicinal plants, such as Cymbopogon citratus. We evaluated the antinociceptive effects of CT on orofacial nociception in mice and investigated the central pathway involved in the effect. Male Swiss mice were pretreated with CT (25, 50 and 100 mg/kg, i.p.), morphine (5 mg/kg, i.p.) or vehicle (saline + tween 80 0.2%). Thirty minutes after the treatment, we injected formalin (20 µl, 2%), capsaicin (20 µl, 2.5 µg) or glutamate (40 µl, 25 µM) into the right limb. For the action in the CNS, ninety minutes after the treatment, the animals were perfused, the brains collected, crioprotected, cut in a criostate and submitted in an immunofluorescence protocol for Fos protein. CT produced significant (p < 0.01) antinociceptive effect, in all doses, in the formalin, capsaicin and glutamate tests. The immunofluorescence showed that the CT activated significantly (p < 0.05) the olfactory bulb, the piriform cortex, the retrosplenial cortex and the periaqueductal grey of the CNS. Together, our results provide first-time evidence that this monoterpene attenuates orofacial pain at least, in part, through an activation of CNS areas, mainly retrosplenial cortex and periaqueductal grey.

Phytochemical screening, antinociceptive and anti-inflammatory effects of the essential oil of Myrcia pubiflora in mice

This report aimed to investigate the chemical composition and possible antinociceptive and anti-inflammatory effects of the essential oil from fresh leaves of Myrcia pubiflora DC., Myrtaceae (EOMP), through different experimental tests. The essential oil of M. pubiflora (EOMP) was obtained by hydrodistillation, analyzed by GC-MS, and tested at doses of 25, 50, and 100 mg/kg (i.p.) in three different tests of nociception (acetic acid-induced writhing test, formalin test, and hot plate test) and one test of inflammation (leukocyte migration to the peritoneal cavity) in order to evaluate the motor activity in mice treated with EOMP. The major component of EOMP was caryophyllene oxide (22.16 percent). This oil significantly reduced the number of writhes in an acetic acid test and the time spent licking the paw at the second phase of the formalin test. Furthermore, EOMP inhibited the carrageenan-induced leukocyte migration to the peritoneal cavity. However, administration of EOMP did not alter reaction time in the hot plate test, and did not affect the motor coordination test. These results indicate antinociceptive and anti-inflammatory properties of EOMP probably mediated via inhibition of inflammatory mediator synthesis or other peripheral pathway.

Carvacrol attenuates mechanical hypernociception and inflammatory response.

Carvacrol is a phenolic monoterpene present in the essential oil of the family Lamiaceae, as in the genera Origanum and Thymus. We previously reported that carvacrol is effective as an analgesic compound in various nociceptive models, probably by inhibition of peripheral mediators that could be related with its strong antioxidant effect observed in vitro. In this study, the anti-hypernociceptive activity of carvacrol was tested in mice through models of mechanical hypernociception induced by carrageenan, and the involvement of important mediators of its signaling cascade, as tumor necrosis factor-alpha (TNF-α), prostaglandin E(2) (PGE(2)), and dopamine, were assessed. We also investigated the anti-inflammatory effect of carvacrol on the model of carrageenan-induced pleurisy and mouse paw edema, and the lipopolysaccharide (LPS)-induced nitrite production in murine macrophages was observed. Systemic pretreatment with carvacrol (50 or 100 mg/kg; i.p.) inhibited the development of mechanical hypernociception and edema induced by carrageenan and TNF-α; however, no effect was observed on hypernociception induced by PGE(2) and dopamine. Besides this, carvacrol significantly decreased TNF-α levels in pleural lavage and suppressed the recruitment of leukocytes without altering the morphological profile of these cells. Carvacrol (1, 10, and 100 µg/mL) also significantly reduced (p < 0.001) the LPS-induced nitrite production in vitro and did not produce citotoxicity in the murine peritoneal macrophages in vitro. The spontaneous locomotor activity of mice was not affected by carvacrol. This study adds information about the beneficial effects of carvacrol on mechanical hypernociception and inflammation. It also indicates that this monoterpene might be potentially interesting in the development of novel tools for management and/or treatment of painful conditions, including those related to inflammatory and prooxidant states.

Ocimum basilicum leaf essential oil and (-)-linalool reduce orofacial nociception in rodents: a behavioral and electrophysiological approach

The present study investigated the antinociceptive effects of Ocimum basilicum L. (Lamiaceae) leaf essential oil (LEO) and (-)-linalool (LIN) in formalin (2 percent)-, glutamate (25 µM)- and capsaicin (2.5 µg)- induced orofacial nociception models in mice. The involvement of these substances was further evaluated on the neuronal excitability of the hippocampal dentate gyrus. Male mice (n=8/group) were pretreated separately with LEO and by LIN (50, 100, and 200 mg/kg, i.p.), morphine (5 mg/kg, i.p.) and vehicle (saline + Tween 80 0.2 percent), before injection of nociceptive agent into the right upper lip (perinasal area). The LEO and LIN reduced the nociceptive face-rubbing behaviour in both phases on formalin test. LEO and LIN, at high doses, produced significantly antinociceptive effect in the capsaicin and glutamate tests. In hippocampal slices, LEO inhibited the population spike generated by stimulation of the hylus (antidromic stimulation), with an IC50 of 0.1±0.05 mg/mL. This response was reversibly blocked by lidocaine (0.5 mg/mL), a known voltage-dependent sodium channel antagonist and by LIN (0.5 mg/mL). Our results suggest that LEO and LIN modulate neurogenic and inflammatory pain in the tests of orofacial nociception induced by formalin, capsaicin and glutamate. Part of these effects may be associated with decreased peripheral and central neuronal excitability.

Bioassay-guided evaluation of central nervous system effects of citronellal in rodents

The central nervous system (CNS) depressant and anticonvulsant activities of citronellal (CT) were investigated in animal models. The CT in doses of 100, 200 and 400 mg/kg injected by i.p. route in mice caused a significant decrease in the motor activity of animals when compared with the control group. The highest dose of CT significantly reduced the remaining time of the animals on the Rota-rod apparatus up to 2 h. Additionally, CT at doses 100, 200 and 400 mg/ kg (i.p.) was also capable to promote an increase of latency for development of convulsions induced by pentylenetetrazole (PTZ). It was efficient in prevents the tonic convulsions induced by maximal electroshock (MES) in doses of 200 and 400 mg/kg, resulting in 30 and 40 percent of protection, respectively. This compound was also capable to promote an increase of latency for development of convulsions induced by picrotoxin (PIC) at 400 mg/kg. In the same way, the anticonvulsant effect of CT was affected by pretreatment with flumazenil, a selective antagonist of benzodiazepine site of GABA A receptor. These results suggest a possible CNS depressant and anticonvulsant activities.

Citral reduces nociceptive and inflammatory response in rodents

Citral (CIT), which contains the chiral enantiomers, neral (cis) and geranial (trans), is the majority monoterpene from Lippia alba and Cymbopogon citratus. The present study aimed to evaluate CIT for antinociceptive and anti-inflammatory activities in rodents. Antinociceptive and anti-inflammatory effects were studied by measuring nociception through acetic acid and formalin tests, while inflammation was verified by inducing peritonitis and paw edema with carrageenan. All tested doses of CIT had significant protection (p<0.001) against acetic acid (0.8 percent) induced nociceptive behavior and the effects were also similar to morphine while formalin induced nociception was significantly protected (p<0.05) only at higher dose (200 mg/kg) of CIT in the first phase of the test. CIT significantly reduce (p<0.001) nociceptive behavior emanating from inflammation in second phase at all the doses.The pretreatment with CIT (100 and 200 mg/kg) significantly reduced the paw edema induced by carrageenan. Moreover, systemic treatment with CIT (100 and 200 mg/kg) significantly reduced (p<0.001) the leukocyte migration in the carrageenan-induced migration to the peritoneal cavity. Our investigation shows that CIT possess significant central and peripheral antinociceptive effects. It was also verified an anti-inflammatory activity. All together these results suggest that CIT might represent important tool for treatment of painful conditions.

α-Terpineol reduces nociceptive behavior in mice.

CONTEXT: α-Terpineol (TPN) is a monoterpenoid alcohol present in the essential oils of several species of the Eucalyptus genus (Myrtaceae). OBJECTIVE: TPN was assessed for its antinociceptive activity in rodents. MATERIALS AND METHODS: The antinociceptive effect of TPN was examined using the acetic acid writhing reflex, formalin, glutamate, and capsaicin-induced nociception tests. RESULTS: TPN produced a significant (P < 0.01 or P < 0.001) analgesic effect by reduction at the early and late phases of paw licking and reduced the writhing reflex in mice (formalin and writhing tests, respectively). In the glutamate test, all doses of TPN produced significant (P < 0.01) nociceptive protection. When the capsaicin-induced nociception test was conducted, TPN produced dose-related inhibition of the nociceptive behavior. In addition, the results of a hot plate test showed central analgesic properties for TPN (P < 0.01 or P < 0.001). Such results were unlikely to be provoked by motor abnormality. CONCLUSION: Our results suggest that TPN might represent an important tool for management and/or treatment of painful conditions.

Antinociceptive and anti-inflammatory effects of Costus spicatus in experimental animals.

CONTEXT: Costus spicatus Swartz (Costaceae), commonly called "cana-do-brejo'" in Brazil's northeast, is a medicinal plant found in wet coastal forests. In folk medicine an infusion of the aerial parts is taken to treat inflammation and pain. OBJECTIVE: The methanol extract obtained from the leaves of Costus spicatus (MECs) was evaluated for antinociceptive and anti-inflammatory activities. METHODS: Analgesic and anti-inflammatory activities were studied by measuring nociception through acetic acid, formalin, and hot-plate tests, while inflammation was induced by carrageenan. All experiments were conducted with experimental animals. RESULTS AND DISCUSSION: Following oral administration, MECs (100, 200, and 400 mg/kg) significantly reduced the number of writhes (52.8, 43.1, and 55.3%, respectively) in the writhing test and the number of paw licks during phase 1 (61.9, 54.1, and 92.1%) and phase 2 (62.5, 82.9, and 98.1%, all doses) during the formalin test when compared to the control group animals. The reaction time during the hot-plate test was increased significantly and was dose-dependent, whereas pretreatment with naloxone rigorously reduced the analgesic potential of MECs, which suggested participation of the opioid system in the modulation of pain induced by MECs. Such results were unlikely to be provoked by motor abnormality, as MECs-treated mice did not exhibit any performance alteration during the Rota-rod test. The administration of 200 and 400 mg/ kg (i.p.) of MECs exhibited an anti-inflammatory effect during the carrageenan test, which was based on interference with inflammatory mediator synthesis. CONCLUSION: We conclude that MECs has antinociceptive and anti-inflammatory activities in rodents.