Anti-obesity properties and mechanism of action of flavonoids: A review.

Obesity is a major public health problem, and there is increasing scientific interest in its mechanisms, as well as a search for new compounds with antioxidant and anti-inflammatory properties that can minimize the metabolic complications associated with its pathology. One potential source of these compounds is natural products; Among these, flavonoids are a promising group of natural substances. Flavonoids are active constituents with diverse biological activities and are widely found in plants kingdom. Numerous studies have shown that flavonoids can effectively inhibit obesity and related metabolic disorders. The review synthesizes recent evidence in respect of progress in the understanding of the anti-obesity effects of flavonoids. Such effects which occurs through the modulation of proteins, genes and transcriptional factors involved in decreasing lipogenesis, increasing lipolysis, expenditure energy, stimulating fatty acids B-oxidation, digestion and metabolism of carbohydrates. In addition to mitigating inflammatory responses and suppress oxidative stress. A better understanding of the modulating effects and mechanisms of flavonoids in relation to obesity will allow us to better use these compounds to treat or even prevent obesity and its associated comorbidities.

Resistance training increases insulin-induced vasodilation in the mesenteric artery of healthy rats.

This study evaluated the ability of resistance training (RT) of moderate intensity to promote vascular changes in insulin-induced vasodilation in healthy animals. Wistar rats were divided into two groups: control (CON) and trained (eight weeks of training, performing 3 sets with 10 repetitions at 60% of maximum intensity). Forty-eight hours after the last session of the RT, the animals were sacrificed and vascular reactivity to insulin in the absence and presence of LY294002 (phosphatidylinositol 3-kinase inhibitors (PI3K), L-NAME (nitric oxide synthase (NOS) inhibitors) and BQ123 (endothelin A antagonist (ET-A) receptor). In addition, phenylephrine (Phe)-induced vasoconstriction in the absence and presence of L-NAME was also evaluated. The RT group showed greater vasodilation in maximal response compared to the CON group. After PI3K inhibition, vasodilation was reduced in both groups. However, when the NOS participation was evaluated, the RT group showed contraction in relation to the CON group, which was abolished by BQ123. In addition, the RT group had an increase in nitrite levels compared to the CON group. When the Phe response was evaluated, there was a reduction in tension in the RT group compared to the CON group. The results suggest that RT improves vascular reactivity.

Wound healing properties of flavonoids: A systematic review highlighting the mechanisms of action.

BACKGROUND: Flavonoids are a class of compounds with a wide variety of biological functions, being an important source of new products with pharmaceutical potential, including treatment of skin wounds. PURPOSE: This review aimed to summarize and evaluate the evidence in the literature in respect of the healing properties of flavonoids on skin wounds in animal models. STUDY DESIGN: This is a systematic review following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. METHODS: This was carried out through a specialized search of four databases: PubMed, Scopus, Web of Science and Embase. The following keyword combinations were used: "flavonoidal" OR "flavonoid" OR "flavonoidic" OR "flavonoids" AND "wound healing" as well as MeSH terms, Emtree terms and free-text words. RESULTS: Fifty-five (55) articles met the established inclusion and exclusion criteria. Flavonoids presented effects in respect of the inflammatory process, angiogenesis, re-epithelialization and oxidative stress. They were shown to be able to act on macrophages, fibroblasts and endothelial cells by mediating the release and expression of TGF-ß1, VEGF, Ang, Tie, Smad 2 and 3, and IL-10. Moreover, they were able to reduce the release of inflammatory cytokines, NFκB, ROS and the M1 phenotype. Flavonoids acted by positively regulating MMPs 2, 8, 9 and 13, and the Ras/Raf/MEK/ERK, PI3K/Akt and NO pathways. CONCLUSION: Flavonoids are useful tools in the development of therapies to treat skin lesions, and our review provides a scientific basis for future basic and translational research.

Role of peripheral and central sensitization in the anti-hyperalgesic effect of hecogenin acetate, an acetylated sapogenin, complexed with ß-cyclodextrin: Involvement of NFκB and p38 MAPK pathways.

Neuropathic pain develops due to injury to the somatosensory system, affecting the patient's quality of life. In view of the ineffectiveness of the current pharmacotherapy, substances obtained from natural products (NPs) are a promising alternative. One NP that has been discussed in the literature is hecogenin acetate (HA), a steroidal sapogenin with anti-inflammatory and antinociceptive activity. However, HA has low water solubility, which affects its bioavailability. Thus, the objective of this study was to evaluate the anti-hyperalgesic activity of pure and complexed hecogenin acetate (HA/ßCD) in an animal model of chronic neuropathic and inflammatory pain. The inclusion complex was prepared at a molar ratio of 1:2 (HA:ßCD) by the lyophilization method. For the induction of chronic inflammatory pain, the mice received an intraplantar injection of CFA (complete Freund's adjuvant), and were evaluated for mechanical hyperalgesia and for the levels of myeloperoxidase (MPO) in the skin of the paw after eight days of treatment. HA and HA/ßCD reduced mechanical hyperalgesia in relation to the vehicle group until the fourth and fifth hours, respectively, in the acute evaluation, with a superior effect of the complexed form over the pure form in the second and third hour after treatment (p < 0.001). In the chronic evaluation, HA and HA/ßCD reduced hyperalgesia in relation to the vehicle in the eight days of treatment (p < 0.001). Both pure (p < 0.01) and complexed (p < 0.001) forms reduced myeloperoxidase activity in the skin of the animals' paw. Groups of animals subjected to the same pharmacological protocol were submitted to the partial sciatic nerve ligation (PSNL) model and evaluated for mechanical and thermal hyperalgesia, and cold allodynia. HA and HA/ßCD reduced mechanical hyperalgesia until the fourth and sixth hours, respectively, and both reduced hyperalgesia in relation to the vehicle in the chronic evaluation (p < 0.001). HA and HA/ßCD also reduced thermal hyperalgesia and cold allodynia (p < 0.05 and p < 0.001, respectively). The analysis of the spinal cord of these animals showed a decrease in the levels of the pro-inflammatory cytokines TNF-α, IL-1ß and IL-6 and a reduction in the phosphorylation of NFκB and p38MAPK, as well as a decrease in microglioses compared to the vehicle group. In addition, HA/ßCD reduced the nociception induced by intraplantar injection of agonist TRPA1 (p < 0.01) and TRPM8 (p < 0.05). Treatment for eight days with HA and HA/ßCD showed no signs of gastric or liver damage. HA and HA/ßCD were, therefore, shown to have antinociceptive effects in chronic pain models. Based on our exploration of the mechanisms of the action of HA, these effects are likely to be related to inhibited leukocyte migration, interaction with the TRPA1 and TRPM8 receptors, reduced pro-inflammatory cytokines levels, microglial expression and suppression of NF-κB p65 and p38 MAPK pathway signaling. Therefore, HA/ßCD has great potential for use in the treatment of chronic pain.

Resistance training prevents the reduction of insulin-mediated vasodilation in the mesenteric artery of dexamethasone-treated rats.

This study evaluated whether resistance training (RT) could prevent glucocorticoid-induced vascular changes. Wistar rats were divided into groups: control (CO), dexamethasone (DEX), and Dexamethasone+RT (DEX+RT). On the eighth week, dexamethasone was administered in the DEX and DEX+RT groups. Thereafter, the animals were sacrificed and blood samples were used to assess the lipid profile, glucose and insulin. Vascular reactivity to insulin and phenylephrine (Phe) were evaluated. The DEX+RT group presented an improvement in the lipid profile, fasting glucose, and insulin levels compared to the DEX group. In addition, vasodilation was reduced in the DEX group compared to the CO group, and was increased in the DEX+RT group. After inhibition of phosphatidylinositol 3-kinase, DEX group showed contraction, in which it was in the DEX + RT group. When nitric oxide synthase (NOS) participation was evaluated, the DEX group presented a contraction compared to the CO group, with no contractile effect in the DEX+RT group. Moreover, vasoconstriction caused by NOS inhibition was abolished by BQ123 (endothelin receptor antagonist). In respect Phe response, there was an increase in tension in the DEX group compared to the CO group, being reduced in the DEX+RT group. The results suggest that RT prevented damage to vascular reactivity.

Naringenin complexed with hydroxypropyl-ß-cyclodextrin improves the sciatic nerve regeneration through inhibition of p75NTR and JNK pathway.

Peripheral nerve injuries are common conditions that often lead to dysfunctions. Although much knowledge exists on the several factors that mediate the complex biological process involved in peripheral nerve regeneration, there is a lack of effective treatments that ensure full functional recovery. Naringenin (NA) is the most abundant flavanone found in citrus fruits and it has promising neuroprotective, anti-inflammatory and antioxidant effects. This study aimed to enhance peripheral nerve regeneration using an inclusion complex containing NA and hydroxypropyl-ß-cyclodextrin (HPßCD), named NA/HPßCD. A mouse sciatic nerve crush model was used to evaluate the effects of NA/HPßCD on nerve regeneration. Sensory and motor parameters, hyperalgesic behavior and the sciatic functional index (SFI), respectively, improved with NA treatment. Western blot analysis revealed that the levels of p75NTR ICD and p75NTR full length as well phospho-JNK/total JNK ratios were preserved by NA treatment. In addition, NA treatment was able to decrease levels of caspase 3. The concentrations of TNF-α and IL-1ß were decreased in the lumbar spine, on the other hand there was an increase in IL-10. NA/HPßCD presented a better overall morphological profile but it was not able to increase the number of myelinated fibers. Thus, NA was able to enhance nerve regeneration, and NA/HPßCD decreased effective drug doses while maintaining the effect of the pure drug, demonstrating the advantage of using the complex over the pure compound.

Involvement of the PKA pathway and inhibition of voltage gated Ca2+ channels in antihyperalgesic activity of Lippia grata/ß-cyclodextrin.

Neuropathic pain (NP) is a difficult condition to treat because of the modest efficacy of available drugs. New treatments are required. In the study we aimed to investigate the effects of the essential oil from Lippia grata alone or complexed in ß-cyclodextrin (LG or LG-ßCD) on persistent inflammatory and neuropathic pain in a mouse model. We also investigated Ca2+ currents in rat dorsal root ganglion (DRG) neurons. Male Swiss mice were treated with LG or LG/ß-CD (24 mg/kg, i.g.) and their effect was evaluated using an acute inflammatory pleurisy model and nociception triggered by intraplantar injection of an agonist of the TRPs channels. We also tested their effect in chronic pain models: injection of Freund's Complete Adjuvant and partial sciatic nerve ligation (PSNL). In the pleurisy model, LG reduced the number of leukocytes and the levels of TNF-α and IL-1ß. It also inhibited cinnamaldehyde and menthol-induced nociceptive behavior. The pain threshold in mechanical and thermal hyperalgesia was increased and paw edema was decreased in models of inflammatory and neuropathic pain. PSNL increased inflammatory protein contents and LG and LG-ßCD restored the protein contents of TNF-α, NF-κB, and PKA, but not IL-1ß and IL-10. LG inhibited voltage gated Ca2+ channels from DRG neurons. Our results suggested that LG or LG-ßCD produce anti-hyperalgesic effect in chronic pain models through reductions in TNF-α levels and PKA, and inhibited voltage-gated calcium channels and may be innovative therapeutic agents for the management of NP.

D-limonene exhibits superior antihyperalgesic effects in a ß-cyclodextrin-complexed form in chronic musculoskeletal pain reducing Fos protein expression on spinal cord in mice.

Chronic musculoskeletal pain is one of the main symptoms found in Fibromyalgia with unclear etiology and limited pharmacological treatment. The aim of this study was to complex LIM in ß-cyclodextrin (LIM-ßCD) and then evaluate its antihyperalgesic effect in an animal model of chronic musculoskeletal pain. Differential scanning calorimetry and scanning electron microscopy was used for the characterization of the inclusion complex. Male Swiss mice were used for experimental procedures where mechanical hyperalgesia, thermal hyperalgesia, muscular strength, Fos immunofluorescence was studied after induction of hyperalgesia. Mechanism of action was also investigated through tail flick test and capsaicin-induced nociception. Endothermic events and morphological changes showed that the slurry complex method was the best method for the complexation. After induction of hyperalgesia, the oral administration of LIM-ßCD (50mg/kg) significantly increased the paw withdrawal threshold compared to uncomplexed limonene. Fos immunofluorescence showed that both compounds significantly decreased the number of Fos-positive cells in the dorsal horn. In nociceptive tests, FLU was able to reverse the antinociceptive effect of LIM-ßCD. After intraplantar administration of capsaicin, LIM was able to significantly decrease time to lick. LIM-ßCD has antihyperalgesic action superior to its uncomplexed form, with possible action in the dorsal horn of the spinal cord. These results suggest the possible applicability of LIM, uncomplexed or complexed with ßCD, in conditions such as FM and neuropathic pain, for which there are currently only limited pharmacological options.

New perspectives for chronic pain treatment: a patent review (2010-2016).

INTRODUCTION: Chronic pain is a major problem of public health worldwide and is responsible for the increase in health costs. The therapeutic options available in the market for the treatment of chronic pain are often rather ineffective due to; the high number of adverse reactions, tolerance and dependence, reducing the quality of life, pharmacotherapy adherence and functional capacity. Hence, several studies have been conducted in the search for new treatment alternatives for chronic pain syndromes. Areas covered: This review brings together the therapeutic patents published over the past six years reporting the discovery of new drugs for the treatment of chronic pain, based on the perspective that these compounds are candidates for the management of chronic pain conditions. Expert opinion: Over the past 6 years, several pharmaceutical companies, as well as universities and researchers, have synthesized a series of compounds, which have been shown to be effective in controlling chronic pain in preclinical studies. These findings nurture the hope of discovering new therapeutic options for chronic pain. However, such studies are in early stages and there is a long and hard path to be followed until these compounds can become chemical entities available to the public.

Natural products assessed in animal models for orofacial pain – a systematic review

ABSTRACT Orofacial pain is related to tissues of the head, face, neck and all the intraoral structures; it is rather debilitating to the patient and also difficult to treat. There are relatively few studies dedicated to the use of natural products to alleviate orofacial pain in preclinical experiment models (performed in experimental animals which provide support for clinical trials). Main objectives of the present systematic review summarize the studies on natural products assessed in animal models for orofacial pain seeking to give evidence to future development of new pharmaceutical products to manage the orofacial pain. Our review includes a thorough search of literature using the terms of orofacial pain, facial pain, medicinal plants and natural products. This search was performed using to retrieve English language articles in Medline-PubMed, Scopus and Web of Science. A total of eighteen studies were included in our survey for the inclusion criteria. Firstly, this review identified 210 citations from electronic search, after removal of duplicates and screening for relevant titles and abstracts, a total of eighteen articles were selected to the inclusion criteria established. Our findings suggest that natural products can be a promising or a trump tool for the development of new drugs to treat orofacial pain conditions, but the researchers that deal with experimental preclinical trials of new drugs (including natural products or synthetic drugs) for orofacial pain conditions urgently need to show translational evidence (with clinical approach) of these compounds.

Pharmacologic Treatment of Vitiligo in Children and Adolescents: A Systematic Review.

BACKGROUND: The true pathogenic mechanism of vitiligo is still unknown. About half of the patients with this disease have onset before the age of 20 years, making it a serious dermatologic disorder in childhood. OBJECTIVES: The objective of this study was to review the literature in a systematic way and identify the main pharmacologic treatments and outcomes in children and adolescents with vitiligo. METHODS: Four databases-the National Library of Medicine (MEDLINE-PubMed), Web of Science, Scopus, and Latin American and Caribbean Health Sciences (LILACS)-were used for the search up to January 2015. All electronic search titles, selected abstracts and full-text articles were independently reviewed by a minimum of two reviewers. RESULTS: There were 15 articles from 13 different countries: 3 were retrospective and 12 were prospective; the number of participants in the studies varied between 9 and 400, ages ranged from 0 to 18 years, and the duration of disease ranged from 1 to 17 years. The most commonly used drugs were tacrolimus alone (or combined with clobetasol), pimecrolimus, corticosteroids, and calcipotriol. Treatment duration ranged from 10 days to 6 months with a topical route of administration. CONCLUSIONS: The main outcome measurements were morphometric analysis performed using a computer program, hematologic or biochemical change, and photography (predominant). It is unclear which was the most effective treatment for vitiligo, however, it was found that these therapies are all promising in the treatment of the disease. With proper care, disease control and repigmentation, even if partial, can be achieved.

Phytochemical screening and analgesic profile of the lyophilized aqueous extract obtained from Chrysobalanus icaco leaves in experimental protocols.

CONTEXT: Chrysobalanus icaco L. (Chrysobalanaceae) has been used for the treatment of abdominal pain and cramps. OBJECTIVE: Assess the chemical and pharmacological profile of the lyophilized aqueous extract from C. icaco leaves (AEC). MATERIALS AND METHODS: Chromatographic methods were used to assess compounds from AEC. Mice were treated with vehicle (control group) or AEC (100, 200 or 400 mg/kg, p.o.) (group with 7-8 mice) and the analgesic profile was assessed employing the acetic acid-induced writhing, formalin, hot plate tests and hyperalgesia induced by carrageenan (CG) or tumour necrosis factor-alpha. The animal motor performance was assessed using rota-rod and grip strength tests. RESULTS: The chromatographic profile of AEC demonstrated the presence of terpenoid compounds. The acute pretreatment with AEC, at all doses, produced a significant (p < 0.01) inhibition of painful bahaviour (11.4 ± 3.6; 10.3 ± 2.8; 11.3 ± 2.2) when compared to the control group (24.7 ± 4.7) in acetic acid-induced writhing test. In the formalin test, AEC were effective in the second phase (p < 0.01) (57.2 ± 10.3; 56.3 ± 9.2; 54.7 ± 8.9) when compared to control group (121.9 ± 18.5). No response was observed in the hot plate test. The higher dose of AEC produced a significant (p < 0.01 or p < 0.05) inhibitory effect on the mechanical hyperalgesia test. AEC did not affect the motor performance of the mice. DISCUSSION: The terpenoids from AEC are known for its analgesic and anti-inflammatory properties. So, these results corroborate the experiments using the AEC in inflammatory pain protocols. CONCLUSION: Our results suggest that AEC act against inflammatory pain.

Evidence for the involvement of TNF-α and IL-1ß in the antinociceptive and anti-inflammatory activity of Stachys lavandulifolia Vahl. (Lamiaceae) essential oil and (-)-α-bisabolol, its main compound, in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Stachys lavandulifolia Vahl (Lamiaceae) is a medicinal plant widely used in Turkey and Iranian folk medicine due to its analgesic and anti-inflammatory properties, but little is known about its essential oil. AIM OF THIS STUDY: We studied the antinociceptive and anti-inflammatory effects of S. lavandulifolia essential oil (EOSl) and (-)-α-bisabolol (BIS), its main compound, in algogen-induced orofacial nociceptive behavior in mice, and assessed the possible involvement of pro-inflammatory cytokines in these profiles. MATERIALS AND METHODS: The GC-FID and GC-MS analysis of EOSl demonstrated the presence of (-)-α-bisabolol (56.4%), bicyclogermacrene (5.3%), δ-cadinene (4.2%) and spathulenol (2.9%) as the main compounds. Male Swiss mice were pretreated with EOSl (25 or 50mg/kg, p.o.), BIS (25 or 50mg/kg, p.o.), morphine (3mg/kg, i.p.) or vehicle (saline 0.9% with two drops of tween 80, 0.2%), before formalin- (20µl, 2%), capsaicin- (20µl, 2.5µg) or glutamate- (20µl, 25Mm) injection into the right upper lip (perinasal area) in mice. The anti-inflammatory profile of EOSl or BIS (50mg/kg) was assessed by the inflammatory response induced by carrageenan (2% in 0.2mL) in mice (pleurisy model). RESULTS: Our results showed that p.o. treatment with EOSl and BIS displayed significant inhibitory (p<0.05 or p<0.01 or p<0.001) effects in different orofacial pain tests on mice, but BIS proved to be more effective, significantly reducing nociceptive behavior in all tests including both phases of the formalin test. The analgesic effect is not related to any abnormality since EOSl- or BIS-treated mice exhibited no performance alteration in grip strength. Moreover, EOS1 and BIS exhibited a significant anti-inflammatory effect (p<0.001) in the pleurisy model of inflammation, which seems to be related to a significant reduction (p<0.05) of the pro-inflammatory cytokine TNF-α in BIS treatment, and of the pro-inflammatory cytokine IL-1ß (p<0.01) in EOS1 treatment. CONCLUSION: Our results corroborate the use of S. lavandulifolia in traditional medicine as an analgesic and anti-inflammatory, which seems to be related to (-)-α-Bisabolol, the main compound of EOSl.

Neuroprotective Effect of Natural Products on Peripheral Nerve Degeneration: A Systematic Review.

Peripheral nerve injury (PNI) is a serious public health problem that is linked with motor, sensory and autonomic deficits. Given the fact that this type of disorder leads to a decreased quality of life in most patients and adherence of available drugs is limited and have adverse effects, we investigated the efficacy of natural products in a PNI model. The search terms plants, medicinal, nerve regeneration, nerve crush, sciatic nerve as well as MeSH terms or free-text words were used to retrieve English language articles in PubMed, Scopus, Web of Science and LILACS published until July 2015. After sciatic nerve crush, natural products have improved significantly motor performance, sensory function and electrical conductance measured over weeks. Among the pharmacological targets suggested by the action of natural products, there were citations on the activation of the antiapoptotic signaling pathway, modulation in the expression of pro-inflammatory cytokines and neurotrophic factors. The systematic review provides scientific evidence that natural products are pharmacologically effective in the treatment of PNI such as sciatic nerve crush.

A review of recent patents on the ASICs as a key drug target.

Acid-sensing ion channels (ASICs) are scattered various cells of human body. Drugs like amiloride has demonstrated nonspecific antagonism ASICs. Toxins, such as Psalmotoxin-1, have been used in animal models. There are no drugs available in the market whose action mechanism acts through these channels. We revised all patents relating to pharmaceutical formulations of applicability in ASICs. Drugs acting as antagonist in ASIC1 or ASIC3 channels seem to be the most promising targets. Patent data have suggested a variety of approaches for selective ASICs drugs, such as neuroprotective and analgesic. Studies analysis suggested that ASICs are promising targets for new drugs.

Evaluation of the anti-inflammatory and antinociceptive effects of the essential oil from leaves of Xylopia laevigata in experimental models.

Xylopia laevigata (Annonaceae) is a medicinal plant used in folk medicine to treat pain and inflammation. Thus, we investigated the possible antioxidant, antinociceptive, and anti-inflammatory effects of X. laevigata leaf essential oil (EOX) in animal models. Our EOX sample showed the presence of γ-muurolene (17.78%), δ-cadinene (12.23%), bicyclogermacrene (7.77%), and α-copaene (7.17%) as main compounds. EOX presented a strong antioxidant potential according to the DPPH, TBARS, and nitrite production tests. Additionally, pretreatment with EOX, in mice, also significantly produced (P < 0.05 or P < 0.001) antinociceptive effect by reduction of nociceptive behavior (in formalin and writhing tests). The EOX showed c-Fos label in the olfactory bulb, piriform cortex, and periaqueductal gray. Acute administration of EOX exhibited a significant (P < 0.01 or P < 0.001) anti-inflammatory profile in the carrageenan-induced peritonitis and by the carrageenan-induced hindpaw edema tests in mice. Our results provide evidence for the use of X. laevigata by traditional medicine practitioners in the management of pain and inflammatory disorders.

Indole alkaloids from marine sources as potential leads against infectious diseases.

Indole alkaloids comprise a large and complex class of natural products found in a variety of marine sources. Infectious diseases remain a major threat to public health, and in the absence of long-term protective vaccines, the control of these infectious diseases is based on a small number of chemotherapeutic agents. Furthermore, the emerging resistance against these drugs makes it urgently necessary to discover and develop new, safe and, effective anti-infective agents. In this regard, the aim of this review is to highlight indole alkaloids from marine sources which have been shown to demonstrate activity against infectious diseases.

Evidence for the involvement of spinal cord-inhibitory and cytokines-modulatory mechanisms in the anti-hyperalgesic effect of hecogenin acetate, a steroidal sapogenin-acetylated, in mice.

Hecogenin is a steroidal sapogenin largely drawn from the plants of the genus Agave, commonly known as 'sisal', and is one of the important precursors used by the pharmaceutical industry for the synthesis of steroid hormones. Hecogenin acetate (HA) is a steroidal sapogenin-acetylated that produces antinociceptive activity. Thus, we evaluate the antihyperalgesic profile of HA in mice in inflammatory models, as well as its possible involvement with c-fos expression on spinal cord area and cytokines to produces analgesic profile. Acute pretreatment with HA (5, 10, or 20 mg/kg; i.p.) inhibited the development of mechanical hyperalgesia induced by carrageenan, TNF-α, dopamine and PGE2. Additionally, the immunofluorescence data demonstrated that acute pretreatment with HA, at all doses tested, significantly inhibited Fos-like expression in the spinal cord dorsal horn normally observed after carrageenan-inflammation. Moreover, HA did not affect the motor performance of the mice as tested in the Rota rod test. This antinociceptive profile seems to be related, at least in part, to a reduction of pro-inflammatory cytokines, as IL-1ß. The present results suggest that HA attenuates mechanical hyperalgesia by blocking the neural transmission of pain at the spinal cord levels and by cytokines-inhibitory mechanisms.

A systematic review of the wound-healing effects of monoterpenes and iridoid derivatives.

The search for more effective and lower cost therapeutic approaches for wound healing remains a challenge for modern medicine. In the search for new therapeutic options, plants and their metabolites are a great source of novel biomolecules. Among their constituents, the monoterpenes represent 90% of essential oils, and have a variety of structures with several activities such as antimicrobial, anti-inflammatory, antioxidant and wound healing. Based on that, and also due to the lack of reviews concerning the wound-healing activity of monoterpenes, we performed this systematic review-which provides an overview of their characteristics and mechanisms of action. In this search, the terms "terpenes", "monoterpenes", "wound healing" and "wound closure techniques" were used to retrieve articles published in LILACS, PUBMED and EMBASE until May 2013. Seven papers were found concerning the potential wound healing effect of five compouds (three monoterpenes and two iridoid derivatives) in preclinical studies. Among the products used for wound care, the films were the most studied pharmaceutical form. Monoterpenes are a class of compounds of great diversity of biological activities and therapeutic potential. The data reviewed here suggest that monoterpenes, although poorly studied in this context, are promising compounds for the treatment of chronic wound conditions.

ß-Cyclodextrin-complexed (-)-linalool produces antinociceptive effect superior to that of (-)-linalool in experimental pain protocols.

Many plants produce (-)-linalool, a plant-derived monoterpene alcohol, including members of the Lamiaceae (mints) and Lauraceae family (laurels, cinnamon, rosewood). The anti-inflammatory and analgesic effects of (-)-linalool have been widely suggested for various studies. Poor chemical stability and short half-life restrain the clinical applications of some essential oil and monoterpenes, including (-)-linalool. However, ß-cyclodextrin (ß-CD) has been used to increase solubility and stability of lipophilic compounds and also to improve the pharmacological effects. In this study, the antinociceptive effect of (-)-linalool and (-)-linalool/ß-CD was examined using the acetic acid writhing reflex, formalin and hotplate tests in rodents. (-)-Linalool and (-)-linalool/ß-CD demonstrated strong antinociceptive activity in all the chemical- and heat-induced mice models (p < 0.01 or p < 0.001). These findings imply the involvement of both peripheral and central antinociceptive mechanisms. In peritonitis induced by carrageenan, isolated monoterpene or ß-CD complex also reduced total leucocyte migration and TNF-α levels in peritoneal fluid. The inclusion complexes, (-)-linalool/ß-CD, revealed that the antinociceptive effect was significantly (p < 0.01) improved when compared with (-)-linalool alone. Such results were unlikely to be provoked by any motor abnormality. Together, our results suggest that ß-CD might represent an important tool for improvement of analgesic and anti-inflammatory profiles of (-)-linalool and other water-insoluble compounds, such as lipophilic monoterpenes or essential oils.